# Etiology of inflammatory bowel disease: A unified hypothesis



## Mark in Seattle

I came across this research report on pubmed, in which the author outlines a hypothesis that artificial sweeteners saccharin and sucralose are responsible for IBD.  I've posted the abstract below along with the link for the full text or pdf if you prefer.

I thought this was an interesting hypothesis and the author seems to have attempted to be thorough in his research.

David, I wonder if your sister would care to read this article and give any feedback as to whether the research seems rigorous and/or whether this sounds like a plausible and/or provable theory.


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3332284/?tool=pubmed

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3332284/pdf/WJG-18-1708.pdf


Abstract
Inflammatory bowel disease (IBD), including both ulcerative colitis (UC) and Crohn’s disease (CD), emerged and dramatically increased for about a century. Despite extensive research, its cause remains regarded as unknown. About a decade ago, a series of findings made me suspect that saccharin may be a key causative factor for IBD, through its inhibition on gut bacteria and the resultant impaired inactivation of digestive proteases and over digestion of the mucus layer and gut barrier (the Bacteria-Protease-Mucus-Barrier hypothesis). It explained many puzzles in IBD such as its emergence and temporal changes in last century. Recently I further found evidence suggesting sucralose may be also linked to IBD through a similar mechanism as saccharin and have contributed to the recent worldwide increase of IBD. This new hypothesis suggests that UC and CD are just two symptoms of the same morbidity, rather than two different diseases. They are both caused by a weakening in gut barrier and only differ in that UC is mainly due to increased infiltration of gut bacteria and the resultant recruitment of neutrophils and formation of crypt abscess, while CD is mainly due to increased infiltration of antigens and particles from gut lumen and the resultant recruitment of macrophages and formation of granulomas. It explained the delayed appearance but accelerated increase of CD over UC and many other phenomena. This paper aims to provide a detailed description of a unified hypothesis regarding the etiology of IBD, including the cause and mechanism of IBD, as well as the relationship between UC and CD.


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## handle

There are some interesting and well considered ideas in the article. However, there are two important issues that remain unexplained. 
The first is that only a very tiny percentage of people who consume saccharin or sucralose actually get I.B.D. And conversely, there are people who never consume those products who get I.B.D. (such as babies.)
The second issue is that removal of the colon cures U.C., even if people continue consumption of saccharin or sucralose.


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## David

Paging Judith.


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## Judith

Hi Mark in Seattle,

The paper seems interesting as a theory but I had a lot of problems with it as a major theory in causing IBD.

I agree with Handle's comments on the unexplained issues regarding IBD in persons who have never consumed sucralose or saccharin and that so many people can consume these artificial sweeteners and never get CD or UC.

Here are a few problems I had with the article:
1.  page 1714. The author states,


> "...The evidences demonstrated above provided a simple explanation for many puzzles of IBD such as the emergence and temporal changes of IBD in last century. It suggests saccharin might be the key causative factor for IBD, by primarily its inhibition on gut bacteria."


The citation for this statement is the author's previous work but no additional citations that support the statement. This is a bit odd. In addition, I noticed both of these works list the author as the _sole_ author. This is understandable for reviews but for any works requiring experiments it is out of the norm. It is a picky point but considering the author cites themselves alone to back up this statement, I thought I would bring it up. 

2.  page 1712, Figure 2, talks about Monroe County, NY and how it had a dramatic increase in the number of cases of IBD between the 1920's and 1980's. I may have missed this part but I did not find that the author stated the number of IBD cases were reported as "a proportion of the total population". Instead, it appears to me that these are straight numbers of IBD cases being reported. Again, I could have missed where the author clarifies this.

The author states a highly significant correlation between consumption of artificial sweetener and cases of IBD. The trends increase up through the 1970's but drop in the late 1970's early 1980's. I looked up the population of Monroe County, NY over this period and the population increases similarly as the curves shown in the charts in Figure 2 up until the mid-late 1970's. During this time, between 1970 and 1980, the population drops in Monroe County, NY. If the number of IBD cases are being reported as straight numbers and not as a proportion of the population this would reduce the significance of the reported effect.






Source of Monroe County, NY Census Data: http://en.wikipedia.org/wiki/Monroe_County,_New_York

3.  Furthermore, the author states that there are dramatic increases in the number of IBD cases and that this correlates with the artificial sweeteners in question. I have a few issues with this idea, in addition to the reasons already mentioned by Handle. First, there were cases of "IBD-like" illness reported in historical documents long before saccharin and sucralose were mass-marketed, even as early as 130AD. http://web.uct.ac.za/depts/git/ibd/history.htm

Secondly, it is quite probable that the number of IBD cases may not be increasing, but the number of reported patients affected  is increasing. Even today, many doctors mis- and under-diagnose CD and UC. With greater attention and understanding of Inflammatory Bowel Diseases in general, it increases the likelihood of diagnosis.

Lastly, artificial sweeteners are not the only chemicals our bodies are increasingly being exposed to as time goes on. The number of chemicals, pesticides, preservatives, etc. that we are exposed to every day is staggering. Little is known about their effects on our bodies over time, and even less is known about how these chemicals interact with each other to produce detrimental biological effects. I do not dismiss the possibility that artificial sweetener may have an effect on the gut microbiome but to pinpoint it as "the" effect- I have a serious issue with.

4. p. 1714  





> After the emergence of IBD about a century ago, numerous hypotheses had been suggested as the possible mechanism, which included infection, toxicants, psychogenic disturbances, nutritional deficiencies, allergy to pollens or foods, abdominal trauma, impaired vascular or lymphatic circulation, lysozymes and other enzymes or the excessive or deficient immune response due to reduced exposure to bacteria or helminthes. *Most of them were invalidated and forgotten*.


Uh, Really? I see the literature stating quite the opposite, that all of these mechanisms can have an effect on IBD. They may differ depending on the genetic and environmental background of the patient but I have seen all of these hypotheses validated in the literature to some extent.

5. I do agree with the author's point that (in certain cases) gut permeability has an effect on IBD. But, I take issue with the author's "lumping" of UC and CD in general, stating UC and CD " share virtually the same cause". I also have issue with the statement that "..more detailed descriptions regarding the mechanism [of IBD] can be found [in other references]". 

I believe UC and CD are very different diseases and that there are multiple types of CD. My reasoning behind this statement lies in the genetic factors that influence IBD and how it can have such a different disease course between patients. Research is slowly uncovering the mechanism behind IBD and how patients respond to the disease, environmental effects and treatment in such different ways. It is a slow process, largely because there are so many genes and systems involved. IBD may "appear" to have one cause because the symptoms appear somewhat similar. But, research as of late indicates multiple different causes are being "lumped" together and should not necessarily be, especially in the case of CD.

I have no doubt the gut microbiome plays a role in both UC and CD but I do not believe the author gave enough data to show the role of sucralose and saccharin as the causal factor in IBD. I would have also been interested to see more information regarding the genes involved in IBD and how they relate to the artificial sweetener theory.

Finally, there are some long term studies that track IBD patients for decades. The author did not appear to consult these studies and ask the question, "Do you, or have you ever consumed artifical sweetener?"

If artificial sweeteners were the cause of IBD. Should removal of saccharin and sucralose from an IBD patient's diet result in remission of symptoms? I wish it was that simple. Unfortunately, I do not believe this is the case.


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## DougUte

I despise diet sodas, so my exposure to artificial sweeteners has been minimal. But I still have Crohns.


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## Mark in Seattle

You're a gem Judith, thanks for sharing your thoughts!

The thing that I ponder the most regarding IBD is what the environmental variable(s) are.  I want to know what the environmental variables are so that future generations don't have to suffer this disease.  And I find it surprising that little headway has been made in identifying the environmental variables.  I think the researchers haven't been thoughtful or thorough enough.  For example, when there is an outbreak of a deadly disease, a pandemic, the researchers put boots on the ground until they trace the problem to the source.  But it seems to me that there are no boots on the ground at all regarding IBD, just researchers in offices sitting around conjecturing, but never really going into patients' homes and studying what is different about their lifestyle.  I think it's too late to put boots on the ground in the developed world but in developing countries where the disease first emerges, I can't help but think that a good approach might be to actually go into the patients' homes and/or live with them for a period of time and see what is different about their lifestyle compared to those around them, or to ask their parents how the lifestyle has altered during their generation.

I do believe it has something to do with the modern lifestyle - perhaps the additives or preservatives or pesticides, something like that.  Or perhaps even more complex - a combination of chemicals, as you mention.  It just seems like the researchers need to get serious about putting boots on the ground in the emerging areas before the whole world becomes developed, at which point we will no longer have an emerging landscape to study.

One of these days I'm going to see if I can ping an epidemiologist or two to get their feedback.

Thanks again!


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## Judith

Mark in Seattle,
I think the reason environmental factors are not more well documented in the literature is the result of a couple of factors. First, I believe the genetic components predispose one to IBD but the environmental effects that push one over the edge are probably not due to a single exposure but are probably additive over time and in number. From an epidemeological standpoint, it is very difficult to pinpoint factors under these conditions. If there is an outbreak of say, Salmonella, it is far easier to pinpoint the source and exposure since it is restricted in time and number of persons involved.

IBD, on the other hand, is found worldwide. There are so many factors that feed into a patient's disease (or not) that I believe we will find that it is extremely complex. I agree with you that IBD is likely exacerbated by industrialized living. I do feel that in the unindustrialized world IBD is probably underreported. The epidemeology of IBD is a very interesting topic.


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## yeldarb49

Disagree with This study,

AS a Crohn's patient for 24 years and diabetic for 9 years, I onsume lots of "diet" artificial sweetners.  I have been in remission for 20 years, I would think I would have definatly relapsed if this hypothesis is true.  Only one person though so obviously no science.

PS:  I never used diet products ever before I got sick with Crohn's, did take Accutane though...


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## wildbill_52280

alternate theory- antibiotics also came out in 1930's, so that could alternately explain the data. fast forward to today-with new ways of detecting bacterial species in the intestine via dna methods that have been recently applied finding reduced diversity in butyrate producing microbes in crohn's disease, i believe a combination of excessive hygiene, antibiotics, low fiber diet from highly processed foods, formula fed infants with poorly established gut integrity all these variables of industrialized society combine in unfortunate ways to lead to certain gi diseases. im sure the sacharrin theory has some contributions, but so do all other factors, antibiotics being the strongest. i also believe it could explain the geographic distribution of ibd, but related to vitamin d deficit where people are more likely to develop lung, sinus and middle ear infections and therefore turn to antibiotics for a treatment, thereby increasing exposure to gut bacteria altering treatments.

edit: actually antibiotics may not have been mainstream until 1940's, but white bread or "wonder bread" came out in 1921. inulin is a component of wheat which supports f. prausnitzzi bacteria found low in crohns patients, so theoretically, the consumption of refined wheat flour could have put people more at risk of developing gi disease's. supposedly white bread had a longer shelf life due to the removal of the oils.

edit: antibiotics came out in 1945, where coincidentally there is a spike in crohn's diagnosis.


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## yeldarb49

I can also believe that the correct gut flora of bacteria is critical in Crohns.  MY first GI Dr. Kept me on antibiotics, clavulin, for more then two years after my initial near death flare, I often wonder if the clavulin did something, kept the bacteria I needed there and killed others...and if my remission is related to that 2 plus years...


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## Judith

Agreed. Appropriate gut flora are an extremely important barrier to minimize mucosal invasion by pathogenic microbes.


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## DustyKat

My children likely had exposure to artificial sweeteners via foodstuffs but neither is a fan of soft drinks. In fact my daughter may have had a soft drink once or twice in 20 years, she hates them (it's the fizzy sensation that she can't abide) and my son's love of them isn't much more than hers. 

I see so many studies put forward on here and I think maybe this is it! only to find after reading the article that it does not fit my children. Antibiotics is a fine example. Maybe secondary exposure through meat products but certainly not through direct ingestion. Neither of my children had ever been prescribed antibiotics prior to their diagnosis with CD. Perhaps this is just further testament as to how complex this disease truly is. 

Dusty.


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## wildbill_52280

DustyKat said:


> My children likely had exposure to artificial sweeteners via foodstuffs but neither is a fan of soft drinks. In fact my daughter may have had a soft drink once or twice in 20 years, she hates them (it's the fizzy sensation that she can't abide) and my son's love of them isn't much more than hers.
> 
> I see so many studies put forward on here and I think maybe this is it! only to find after reading the article that it does not fit my children. Antibiotics is a fine example. Maybe secondary exposure through meat products but certainly not through direct ingestion. Neither of my children had ever been prescribed antibiotics prior to their diagnosis with CD. Perhaps this is just further testament as to how complex this disease truly is.
> 
> Dusty.



just curious, were your children breast fed or formula fed? 

also, did the mother have antibiotics before giving birth, if her flora was damaged before giving birth, that could have put your children at risk as the mothers flora is transferred to the children. also, being born c section may have put them at risk.


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## DustyKat

They were both breast fed.

I had not had antibiotics for 10+ years prior to giving birth to the eldest and had not any between pregnancies or whilst breast feeding. They were both normal vaginal deliveries. 

Dusty.


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## mf15

Hi everyone,new hear usually on the healingwell boards for UC but found your
discussion by accident using google. UC since 1980,been researching it for
many years. Anyhow I have also been researching this particular subject for a few days. Here are some thoughts I have,mostly copied from my post
on healingwell.




The basis of this theory is the reduction of gut bacateria activity due to saccharin, or other chemicals that we ingest. Basically it is saying that there is not enough bacterial B-glucorunidase to deconjugate bilirbuin,if the bilirbuin is not degonjuagated then the digestive proetases will not be deactived

Then the mucus barrier is destroyed,then the bacteria get to the mucosa, then the immune cascade starts.

Forget the saccharin at least for now.

I have started looking for  β-glucuronidase inhibitors besides saccharin.

Glucaric acid from foods.
There is also a glucose connection to UC.

Could it be that a high meat,white rice,and veggies if any with low glucaric acid content,

is the way to go. Just beginning to search out glucaric acid content of foods.

Seems this might be why a Paleo diet works in some people, and possibly if it

was more restrictive on certain veggies it would work better.

Also could be the reason vegetarians get UC, and for countries that are vegetarian
it might depend on which vegetables are eaten.

I also suspect that back in 1900 before a lot of UC, the average american did not
have access to all the veggies we have today,have to check into that. 

Have also found that aspartic acid is an inhibitor but not sure if it makes
it to the colon, also casein from milk which contains aspartic acid will
make it to the colon.


It is also interesting that aspartic acid is used to make aspartame, and of
course one of the digestive breakdown products is aspartic acid.


And here we have casein in infant formula with its mechanism of action.


So from the above there are quite a few other B-glucorunidase inhibitors
that can make it to the colon let alone the small intestine.
To my knoweldge I have never eaten artifical sweeteners unless by accident,
yet have UC since 1980.  But have eaten lots of dairy,and the veggies that contain glucaric acid.  I have not been able to locate a comprehensive
list of the glucaric acid content of foods.  
Still researching the above theory have not dug deeply yet into diet from
around 1920,except that canned orange juice started to hit the market around then, oranges are high in glucaric acid.
Any discussion on this subject is appreciated,it seems that the doc who wrote
the paper if fixated on saccharin,but as you can see there are many other
possible chemicals that can inhibit B-glucorunidase in the gut.

Well when I tried to post it seems I cannot include all my reference URLs until I
hit 10 posts. If you want to see my reference URLs go over to healing well
UC forum and read my post, If this doc is right about UC.

Prior to this I was not a Paleo diet advocate, but this now seems like it might
tie everything together,with the exception of too much red meat.
To get an idea of what went on with the american diet go to
foodtimeline.org. Popular foods and menues, it will start you at 1900.
Wish I could post URL's but can't.

Every thing else I read on pubmed indicates that high B-glucorunidase activity
is not good,especially for colon cancer.
Old Mike


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## DougUte

Thanks old mike.this makes more sense to me.


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## Xiaofa Qin

Hello, everyone,

This is Xiaofa Qin, the author of the article discussed here. 

Thanks for the interest in my hypothesis. Frankly, I am just a volunteer spare time IBD researcher. Actually, pursuit on this has caused me a lot of trouble and suffering, and this paper is just the result of tremendous efforts when I was out of work and the countless nights and weekends in the last decade. In fact, I paid more than $300 publish fee for the paper published in Medical Hypothesis in 2002 and more than $1800 publish fee for this paper by my own. I am very grateful for the understanding and support of my wife. 

As well clarified in the title, this remains a hypothesis awaiting further study to prove or disprove. Despite that, I still feel some of the arguments here are somewhat superficial. If this hypothesis were true, the relationship between saccharin and sucralose and IBD would be more like the one between smoking and lung cancer. According to the official website of Center for Disease Control and Prevention (CDC) (sorry I am not allowed to post the link yet because of the too few posts), cigarette smoking causes about 90% of lung cancers even in the United States, a country with strict smoking control. Despite that, most of the smokers do not have lung cancer and lung cancer also occurred in people who never smoke (by radon, air pollution, asbestos, etc, or just a natural cause). It would be also quite certain that lung cancer occurred in dinosaurs, long before human, or even mammals started to exist on earth. Can we thus conclude that smoking cannot be the main cause of lung cancer? 

Even Einstein made misjudge, like his strong rejection of the quantum theory. Therefore, the only way to tell the validity of a hypothesis would be a vigorous test against the facts, as advocated in the paper. In the last decade, I had contacted multiple national and international agents and IBD professionals suggesting to conduct some research in this area, but failed to raise any action so far. I have also tried multiple times to apply some grants to do some research, but remained unsuccessful. I cannot completely rule out that the vast amount of evidence presented in this paper were just pure coincidence, but you may agree with me that this area would be worthy of further study. Thanks again for the interest and discussion on this hypothesis.


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## kiny

Xiaofa Qin said:


> Actually, pursuit on this has caused me a lot of trouble and suffering, and this paper is just the result of tremendous efforts when I was out of work and the countless nights and weekends in the last decade. In fact, I paid more than $300 publish fee for the paper published in Medical Hypothesis in 2002 and more than $1800 publish fee for this paper by my own. I am very grateful for the understanding and support of my wife.


People are taking action against the fees. http://thecostofknowledge.com/

Thanks for posting on the forum.


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## Xiaofa Qin

Thanks, Kiny. I also feel the restriction by most of the journals has greatly limited the free access to the knowledge and sharing of information. I am glad that this paper was eventually published in an open access journal. Although I have to pay much higher publish fee, everybody in the world can access it for free that may help generating more new thoughts.  

I would also like to thank Judith for taking time to read through this paper, raising the questions, and found out the data of the Monroe county population. I agree that the population could be potentially a big confounding factor for this kind of analysis. It would be ideal to compare the incidence (rather the new cases) of IBD with the per capita (rather total) saccharin consumption, either both of them being from the Monroe county or from the Unites States. Unfortunately, we cannot get this kind of data. As the result, the analysis used in this paper could be overestimated but also could be more likely underestimated the real correlation. It seems that a correction by population would only have minor effects on the analysis. For instance, compared to that of 1960, the population in Monroe County increased 1.21-fold in 1970 and 1.20 fold in 1980. However, during the same period, both the new cases of IBD in Monroe County and the saccharin consumption in US increased about 5 to 6 folds. Nevertheless, we should also notice the remarkable decrease in IBD in the middle 1980s, which would likely contain more valuable information. It cannot be explained by the change of population and opposites the increased awareness and improved diagnosis, but it paralleled the reduced saccharin consumption after the finding of its carcinogenicity in animals and the attempt ban in 1977 and the launching and marketing of aspartame afterwards.  Certainly, more study would be needed for a more solid conclusion. Thanks Judith again for the critiques. Sparkling of conflicting thoughts may help clearing our vision. Hope we may have more chance to exchange our views.


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## kiny

For what it's worth, I checked the toothpasteswhile I was shopping, many of them have _sodium saccharin_ in them. The most commonly used is _Fluocaril _, that toothpaste and all of it's derivatives with flavors use saccharin. Then I went looking at the boxes of sweets and the soda brands, many many of them have saccharin in them like coca-cola etc, so at least here it's everywhere in foods and toothpaste. If you want saccharin free toothpaste, the only big brand I could find making it is OralB (and you need to buy the one called "saccharin free", their normal toothpaste has saccharin). Colgate uses saccharin.


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## Xiaofa Qin

Thanks kiny for the posts and information.

The same thing would also be true for sucralose, which was first approved by Canada in 1991, then by US in 1998 and by EU in 2004. It has long become the number one artificial sweetener in US and used in thousands of foods and drinks. I had mentioned the potential side effects of sucralose to a friend. He told me they had never used it. Actually he even did not know what sucralose was. Later, he found another job in another city and we came over for helping packaging staff and cleaning up the house. I found that the Diet Nestea Iced Tea and the flavor water his familiar drank everyday are actually sweetened by sucralose. So many people may even not know what they have taken through the processed foods and drinks.  

My interest in saccharin and IBD were virtually the result of a series of accidental events. Back to 2001, I found digestive proteases could be inhibited by unconjugated bilirubin. This led me to look into the literature regarding the mechanism of digestive protease inactivation in the gut. I thought this would have been well solved back to the time of Ivan Povlov, who got the Nobel Prize in physiology in 1904 for his many elegant studies on digestion. To my surprise, the mechanism of protease inactivation remains unresolved mystery even today. What people know is that under normal (conventional) condition there is hardly any digestive proteases detectable in the lower intestine, but large amounts of digestive proteases can be found in animals raised in germfree condition or fed with antibiotics. In the mean time, I came up with publications that patients with IBD also have high protease activity in the lower intestine. Frankly, that was the time I started to learn about IBD. Although I was graduated from medical university in China in 1980s, IBD was still very rare in China at that time and it was hardly taught in the class. Later I learnt that IBD includes two forms of diseases – ulcerative colitis and Crohn’s disease, and both of them have much high incidences in developed countries, especially those in the west, than developing countries. Later, I further found an article showing that there is also a large amount of digestive proteases in the lower intestine of rats fed with saccharin. I mentioned this to my wife and she told me the pink packets (Sweet'N Low) that we sometimes used to sweeten the coffee contained saccharin. Some people are very sensitive to the aftertaste of saccharin. My wife told me she could tell the presence of saccharin by the first sip. This surprised me, as people in China generally thought saccharin is toxic and used it very prudently, but here in the United States we can found it at almost every coffee machine or restaurant. Shortly after that, I lost my job. The good side for this was it gave me more time reading more literature. Then I found that many studies in 1970s and 1980s revealed that IBD patients consumed more refined sugar, but further study failed to show a correlation between these two over a longer history. I started to wonder if it was not the refined sugar but rather saccharin, the widely used artificial sweetener, caused the increased risk of IBD in people with a sweet-tooth. Further looking into the references I found more evidence, such as the finding of the carcinogenicity of saccharin in animals and attempt ban in 1977, and the peak of new IBD cases in 1978 in Monroe County, etc. I felt obliged to raise a warning on this, which led to the paper that was eventually published in Medical Hypothesis in 2002.


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## Gra

Mark in Seattle said:


> I came across this research report on pubmed, in which the author outlines a hypothesis that artificial sweeteners saccharin and sucralose are responsible for IBD.


One thing I DO know is that consuming soribitol (or even just having it in my mouth - ie: most modern toothpastes, sugar free gum - immediately makes my gut start to feel bad.  I have switched to a "natural" Olive Leaf based  toothpaste which seem to be OK in this regard.

oo:


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## Mark in Seattle

Xiaofa, 

I was just noticing on my elemental diet drink that it says it is sweetened with acesulfame-potassium, and when I read about this on the internet, it mentions that it is about as sweet as saccharin or sucralose.  I don't know how many artificial sweeteners are in use today, but would you tend to lump them all in together in terms of their effect on conjugation/deconjucation etc. of the digestive proteases?


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## nikimazur

Though there has been a steady rise of cases of IBD, not only must we question the cause of the disease, but also whether or not the surge of numbers is due to better medicine per say. Just like with other diseases, such as cancer, Autisim, there have been surges of disease, and higher prevalence as time goes in. The first documented case of cancer was seen in 1500 bc, in Egypt. Playing devil's advocate, Crohns/UC are both diseases that are extremely hard to diagnosis without expensive, modern tests. Whether it be blood tests or colonoscopys/biopsies to verify the disease, even going back 20-30 years it would be very hard to diagnosis this disease, not to mention two hundred years ago. 

From an epidemiological back round(masters in public health, Epi, and working on my phd) I just try to keep all sides in mind.


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## Xiaofa Qin

Thanks a lot for Mark in Seattle for the interest in my article and started this thread. The hypothesis proposed here lumped up those that can make a significant inhibition on gut bacteria rather than just artificial sweeteners. For instance, aspartame dominated the artificial sweetener market for many years after saccharin but before sucralose having played this role. However, aspartame is a compound composed of two natural amino acids that can easily be breakdown in the upper intestine and get absorbed into the body. Although some people have worried about the possible toxic effect of its metabolic products such as formaldehyde and formic acid, the rapid clearance of aspartame from the upper intestine made it unlikely to cause a big effect on gut bacteria that are enriched in the lower small intestine and colon. As for acesulfame potassium (Ace K), I indeed suspected that it could have a similar impact as saccharin and sucralose. Here is a study showing that acesulfame K, cyclamate and saccharin all can inhibit gut bacteria (Pfeffer M, et al. Acesulfame K, cyclamate and saccharin inhibit the anaerobic fermentation of glucose by intestinal bacteria. Z Ernahrungswiss. 1985 Dec;24(4):231-5). Acesulfame K, cyclamate, saccharin and sucralose shared many similar properties, such as being very stable to heat and other conditions, hardly metabolized by the body, and inhibition on gut bacteria. I did not bring up the potential risk of Ace K and cyclamate as the paper is already pretty long, with overwhelmingly large amounts of new concepts, and I tried not to make it super complex. Ace K had been one of the major artificial sweeteners in some European countries. Although its use in US increased in recent years, Ace K remained a small fraction in the artificial sweetener market. In fact, there was more interesting stories on cyclamate. It has been banned in US since 1970s but allowed to be used in Canada even after the ban on saccharin since 1977, which may make cyclamate a possible important factor after the saccharin ban but before the approval and wide use of sucralose in Canada since 1991. 

Thanks nikimazur for reminding the possible role of better medicine and diagnose in the increased cases of IBD, and thanks kiny for the valuable information and insightful discussion. Even with the most advanced diagnose and best medication as today, IBD remains regarded as a life-long disease without a cure. As we know, the peak age of IBD occurred in young adults, which has been the case for today and also for early times. This nature of incurability and continuous progress of IBD made it more likely prone to a delayed but rather than missed diagnose under poor technology. Even today, IBD was mainly diagnosed after ruling out the other diseases. The poor technology may also caused misdiagnose of other digestive diseases as IBD. As quoted in the paper, Dr. Phillips had specifically point out the emergence of ulcerative colitis after 1888. We should notice that this statement was made more than a century ago in 1909. This would suggest the current world map of CD provided above by kiny were more likely real rather than just the difference in awareness and diagnose. We should also notice the recent worldwide increases of IBD, such as the rapid rise in incidence of Irish paediatric IBD being mentioned by kiny above and discussed in another thread in this forum. These dramatic increase of IBD in the developed countries at different but not the same periods may provide a rare chance for us to pin down some of the important causative factors for IBD. I think we should cherish this opportunity.


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## Xiaofa Qin

Here is how I got to sucralose and this unified hypothesis on the etiology of IBD. 

After I found the possible link between saccharin and IBD as described above and in the paper eventually published in Medical Hypothesis in 2002, I had contact multiple national and international agencies in US, Canada, UK, European Union, the Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO), advocating to do some research to check out this possibility. Although it failed to raise any action, I indeed got some response from some of these agents. In general, people were very skeptical for this hypothesis. For instance, Bureau of Chemical Safety, Health Canada specifically pointed out that Canada had adopted strict measures for saccharin use since 1977, which made it difficult to explain the high incidence of IBD in recent years. Although I felt the evidences I described in the 2002 paper were unlikely pure coincidence, this discrepancy also puzzled me. 

Until sometime in April last year, I found the paper by Abou-Donia MB, et al. (Splenda alters gut microflora and increases intestinal p-glycoprotein and cytochrome p-450 in male rats. J Toxicol Environ Health A 2008;71:1415-29), showing that Splenda (sucralose) can inhibit gut bacteria. I immediately realized that sucralose might also be a risk factor for IBD, through a similar mechanism as saccharin. A further pursuit on this led me to found more facts including: 1) Canada had been the first country to approve the sucralose use in 1991; 2) The incidence of IBD in Canada was much lower than many other western countries at least up to 1970s and the observed high incidence of IBD only starting to show up in recent studies; and, most importantly, 3) the study by Wrobel et al (Epidemiology of pediatric IBD in a population-based cohort in southern Alberta, Canada (1983-2005). J Pediatr Gastroenterol  Nutr 2006;43:S54-S5) clearly showing a dramatic increase of IBD only occurred since early 1990s. This made me to suspect that sucralose (Splenda) may be the answer for the high incidence of IBD in Canada observed in recent years. I wrote a paper that was eventually accepted for publication in Canadian Journal of Gastroenterology (Qin X. What made Canada become a country with the highest incidence of inflammatory bowel disease: could sucralose be the culprit? Can J Gastroenterol. 2011 Sep;25(9):511). Later, I actually found more evidence, such as the study by Lowe AM et al (Epidemiology of Crohn's disease in Quebec, Canada. Inflamm Bowel Dis 15:429-435, 2009) showing also the dramatic increase of Crohn’s disease in Montreal, Canada since early 1990s. As some other countries also approved sucralose use after Canada, I further looked into this issue and found more evidence for the possible link between sucralose consumption and IBD in countries like Australia, New Zealand, and Norway. I wrote another paper that was published by the journal of Inflammatory Bowel Disease (Qin X. What caused the recent worldwide increase of inflammatory bowel disease: should sucralose be added as a suspect? Inflamm Bowel Dis. 2011 Oct;17(10):E139). 

This provided a tentative explanation for the main cause (dietary chemicals like saccharin and sucralose) and mechanism (inhibition on gut bacteria and the resultant impaired inactivation of digestive proteases and over digestive damage of the mucus layer and the underling gut tissue), along with many other puzzles of IBD such as its emergence around the beginning of last century, its dramatic increase since 1950s, and the recent worldwide increase again of IBD. It is also in accordance with the high incidence of IBD in the developed countries along with the improved hygiene, as well as the increased risk of IBD along with the use of antibiotics, as shown in the study by Hviid A et al (Antibiotic use and inflammatory bowel diseases in childhood. Gut. 2011 Jan;60(1):49-54). 

I found the study by Hviid A et al being with very high quality, as it is a nationwide cohort study that included all Danish singleton children born from 1995 to 2003 (N=577,627). However, I was greatly puzzled by the fact that use of antibiotics was more related to Crohn’s disease rather than ulcerative colitis. As large amount of bacteria are in the colon rather than the small intestine, we would expect that use of antibiotics should have more impact on ulcerative colitis rather than Crohn’s disease. I pondered over this discrepancy for a long time and could not get an answer. This led me to eventually shift some of my attentions from epidemiological studies of IBD to the classification of ulcerative colitis and Crohn’s disease. To my surprise, I found multiple studies showing a shift of Crohn’s disease from the small intestine to the colon over time. Some recent studies have found the Crohn’s disease with only the involvement of colon (Crohn’s colitis) has been the main form. This made me to realize that the relative increase in Crohn’s disease versus ulcerative colitis along with the continuous improvement in hygiene condition or the use of antibiotics would largely due to a shift from ulcerative colitis to Crohn’s colitis. This would be again in accordance with my hypothesis that both ulcerative colitis and Crohn’s disease are due to a weakening in gut barrier, they only differ in that ulcerative colitis are mainly due to the increased infiltration of gut bacteria, but Crohn’s disease are mainly as the result of increased infiltration of particles or antigens from gut lumen. This notion also provided explanations for many more puzzles in IBD, such as the high incidence of Crohn’s colitis in young children, etc, as described in the paper. The shift from ulcerative to Crohn’s colitis along with the reduction of gut bacteria would suggest ulcerative colitis and Crohn’s disease are virtually two symptoms of the same disease rather than two diseases. I felt IBD no more a mystery. That led me to write this paper discussed here, with a unified hypothesis on etiology of IBD, including the cause and mechanism of IBD as well as the relationship between Crohn’s disease and ulcerative colitis. I included in it more evidence I collected such as the increase in IBD in California. However, the study regarding the increase in pediatric IBD in Ireland was released after this paper was published. This finding in Ireland is not surprising to me, as it is just what was predicted in this paper. 

I also believe that there would be multiple factors that may cause or affect the development of IBD one way or another. However, this would also be true for lung cancer. Despite that, according to CDC, we know now that about 90% of lung cancer are caused by smoking, 10% by radon, 1% by air pollution, and even less by many other factors. We would also need quantitative assessment like this on IBD. Antibiotics would have more strong effect on gut bacteria than saccharin and sucralose. But saccharin and sucralose may have a much big impact on the general population because of their wide and sustained use. The century-long great efforts have produced enormous amounts of information on IBD, but many of them may be superficial, confusing, or even erroneous and misleading. I agree with Mark in Seattle that, to identify and make a rational (ideally quantitative) assessment of environmental variables, we would need to be more thoughtful and thorough enough. A big breaking through in the effective treatment and prevention of IBD would largely depend on finding out the main cause and thus the root mechanism. Hope that day would not be too far.


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## mf15

Xiaofa Qin:Hi,This is Mike we corresponded by email about a month back.
Anyhow have you also looked into Johne's disease and its correlation with IBD,the countries with high IBD rates also have high Johne's cattle disease rates.  Also what is most
interesting is Crohn's/UC clustering.  I cannot post links yet but search google for
the broad street pump revisited.
The paper discusses a most recent cluster in Forest Virginia.
I moved into my current house in 1979,which is about two blocks from a working dairy farm, I got UC 1980. I also quit smoking in 1977.
Also search Johne's disease history read the first hit.
Johne's first described in the USA 1908.
MAP may cause both Crohn's and UC.  
Mike/Old Mike


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## wildbill_52280

Xiaofa Qin said:


> Here is how I got to sucralose and this unified hypothesis on the etiology of IBD.
> 
> 
> I found the study by Hviid A et al being with very high quality, as it is a nationwide cohort study that included all Danish singleton children born from 1995 to 2003 (N=577,627). However, I was greatly puzzled by the fact that use of antibiotics was more related to Crohn’s disease rather than ulcerative colitis. As large amount of bacteria are in the colon rather than the small intestine, we would expect that use of antibiotics should have more impact on ulcerative colitis rather than Crohn’s disease. I pondered over this discrepancy for a long time and could not get an answer. This led me to eventually shift some of my attentions from epidemiological studies of IBD to the classification of ulcerative colitis and Crohn’s disease. To my surprise, I found multiple studies showing a shift of Crohn’s disease from the small intestine to the colon over time. Some recent studies have found the Crohn’s disease with only the involvement of colon (Crohn’s colitis) has been the main form. This made me to realize that the relative increase in Crohn’s disease versus ulcerative colitis along with the continuous improvement in hygiene condition or the use of antibiotics would largely due to a shift from ulcerative colitis to Crohn’s colitis. This would be again in accordance with my hypothesis that both ulcerative colitis and Crohn’s disease are due to a weakening in gut barrier, they only differ in that ulcerative colitis are mainly due to the increased infiltration of gut bacteria, but Crohn’s disease are mainly as the result of increased infiltration of particles or antigens from gut lumen. This notion also provided explanations for many more puzzles in IBD, such as the high incidence of Crohn’s colitis in young children, etc, as described in the paper. The shift from ulcerative to Crohn’s colitis along with the reduction of gut bacteria would suggest ulcerative colitis and Crohn’s disease are virtually two symptoms of the same disease rather than two diseases.


i currently agree that there is likely some unifying explanation to crohns and U.C., and that the extinction of certain bacterial species important for gut barrier function in combination with various pathogens may explain the differences. What is also interesting is that both diagnosis can be either mixed falling into both categories or indetermined and uncharacterizable falling into neither category. reading some personal testimonys on c. difficile infection a man described his disease and it sound precisely like crohns, yet he was officially diagnosed with C. difficile, but this is a very casual observation.

some support for missing bacteria linking cases of "colitis"
Low counts of Faecalibacterium prausnitzii in colitis microbiota
http://onlinelibrary.wiley.com/doi/10.1002/ibd.20903/full

f. prausnitzii sensitive to Amoxicillin-Clavulanic Acid
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC375311/


on another note, there is the data we have on the tendancy for ibd to occur more frequently in the northern areas of the globe, i have tried to explain this with the fact that vitamin d deficits increase susceptibility to upper respiratory infections although i have not worked on this yet to see how probable this is. If this is a probable scenario we may see the utilization of more antibiotics exposing these populations to a higher risk of IBD through antibiotic disruption of gut flora.

also, it has been reported that rates among women had increased after the antibiotic usage in 1945, i wonder if that could be explained by differences in antibiotic usage for urinary tract infections.


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## Xiaofa Qin

Hi, Old Mike, sorry for the delay. I am in a vacation with my family with busy schedules and limited access to Internet. It had been a pleasure to have exchanged thoughts, ideas and information over the email, and thanks for your interest in my opinion on the possible link between Mycobacterium avium subsp. paratuberculosis (MAP) and IBD, especially Crohn’s disease (CD).

Not like saccharin and sucralose, MAP as the possible cause of Crohn’s disease had been suspected for about a century, with extensive studies by some researchers, especially in the last several decades. Despite that, the results remains highly controversial, largely because the conflicting “facts” in almost every aspects. To my knowledge, there is also a big discrepancy between the incidence of IBD and contamination of MAP in some countries. For instance, Sweden had been one of the countries with the highest incidence of IBD, including both CD and ulcerative colitis (UC), but MAP contamination had been extremely low (see Sternberg Lewerin S et al. Control of paratuberculosis in Sweden. Proceedings of the 9th International Colloquium on Paratuberculosis 2007, p. 319-323. http://www.paratuberculosis.info/web/images/stories/pdfs/274). Back to 1952, MAP had been included in the Swedish Epizootic Act (SFS 1999:657). According to this legislation any suspicion of MAP is notifiable for animal owners, veterinarians or other professionals with animal contact, regardless of the species of the animal. Moreover, it required the Swedish Board of Agriculture must investigate all suspect cases and take all necessary means to eradicate and prevent the spread of the infection, if confirmed. As the result, although there were a few sporadic cases of MAP infection in cattle since 1993, all the cases were directly or indirectly linked to the imported animals, with all cases being beef herds, but none in dairy herds. The negative finding of domestically originated MAP in the more than 1.5 million of cattle and about half a million of sheep all over the country suggested the extremely low, if not zero, MAP contamination in Sweden, despite the very high incidence of CD and UC seen in many cities in Sweden like Stockholm, Uppsala, Orebro, Malmo, and Gothenburg. 

In addition, there were also many conflict results regarding other aspects on the suspected link between MAP and IBD. Although some studies (like the one in Forest Virginia) suspected that contamination of MAP in the pasteurized milk or the water supply may cause CD in human, other studies failed to show any increased risk for dairy farmers with a more direct and certain contact with MAP through the infected animals (Jones PH, et al. Crohn's disease in people exposed to clinical cases of bovine paratuberculosis. Epidemiol Infect 2006;134:49-56). Although study indeed found MAP in the lymph nodes of feral cats on the contaminated farm, they did not had the signs of IBD (Palmer MV  et al. Isolation of Mycobacterium avium subsp paratuberculosis (Map) from feral cats on a dairy farm with Map-infected cattle. J Wildl 2005;41:629-35). 

At beginning people were suspected a similar origin for both Johne’s disease in cattle and CD in humans as they both showed the obstructive damage near the end of the ileum. However, as shown in some of the recent studies, there was a shift of CD from the small intestine to large intestine over time and the involvement of only large intestine has become the main form for CD (the Crohn’s colitis). I suspected that IBD now would be more mimic the commonly seen IBD in pet dogs and cats rather than the Johne’s disease in cattle (Qin X. What is human inflammatory bowel disease (IBD) more like: Johne's disease in cattle or IBD in dogs and cats? Inflamm Bowel Dis. 2008 Jan;14(1):138). There were also many other fundamental differences between Johne’s disease and CD. For instance, large amounts of MAP can be found in the mucosa or feces of cattle with Johne’s disease, which can be transmitted to healthy herds; in contrast, the bacteria are hardly seen in the tissues and feces of patients with CD, and IBD in general is regarded as noncontiguous. Although studies showed higher rates of existence of MAP in gut tissue of CD patients by the high sensitive methods such as the PCR detection of the IS900 DNA segments, there are also increase in other bacteria such as Helicobacter spp., Listeria monocytogenes and Escherichia coli, suggesting this could be just reflected the weakening of gut barrier and increased gut permeability (Tiveljung A, et al. Presence of eubacteria in biopsies from Crohn's disease inflammatory lesions as determined by 16S rRNA gene-based PCR. J Med Microbiol 1999;48:263-8). Finding of viable MAP in patients with CD would be important evidence for the possible link. However, the more rigorous test organized by NIH failed to repeat and confirm these findings (Van Kruiningen HJ. Where are the weapons of mass destruction - the Mycobacterium paratuberculosis in Crohn's disease? J Crohns Colitis 2011;5:638-44). Therefore, it would be no surprising that there are many deep believers on both sides. Both sides think they hold enough scientific evidences. However, one thing would be true: one side must be wrong, along with the many “solid scientific facts”.


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## mf15

Xiaofa: Thank you for your insight.
I guess my main point for my post is the clustering of IBD,in Forrest Vir,it would seem highly
unusual.
Old Mike


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## kiny

here's a map of Europe 2007 with crohn indices

I have lived in Belgium, France, Spain and Switzerland. Habit wise, outside of people in spain and southern france sleeping during the day because it's so hot in the summer, there is no difference. Food is very similar, brands are very similar. 

The North-South crohn gradient theory about climate does not make a lot of sense on this map, Eastern Europe has a very low crohn indice and it's damn cold there. This map is a reply that questioned the North-South grade study because it didn't include Easter Europe, once Eastern Europe is included the North-South theory stops making sense.

The study and many people say "Westernisation", which makes sense on that map until you look at croatia,  is one of the least westernised country on that map and it's bright green.

I notice that all the countries with high crohn are clustered together. There isn't one country that pops out or is wrong, there is a real gradient running over that map.

I don't think it has much to do with underdiagnosis either, Eastern Europe might have that issue but Greece is yellow on that map too and it's almost 100 times as low than Western Europe. I've lived in Greece and Krete a while, their hospitals are not that bad that they would miss a 100 cases for every 1 case rightly diagnosed in Western Europe.

I think Europe is a much more interesting case than looking at the US, because Europe up until a few years ago, did not have the same free trade and movement of populous as the US has had for decades, whatever differences and clues there are, it will be much more pronounced in Europe.

All I know is if you showed a map to someone like this, and you did not tell them what disease it was, the first thing they would say is infectious disease / epidemic. Why are all those countries clustered together? *What else is there that explains clustering like that outside of infection?*

Genes don't explain crohn at all anymore. Many many people with CD don't have a genetic predisposition, man y in Asia with crohn have none of the genetic markers. Ireland rising by 90% in 10 years can't be explained by genes either. Genetic predisposition is all I believe in.


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## wildbill_52280

kiny said:


> here's a map of Europe 2007 with crohn indices
> 
> I have lived in Belgium, France, Spain and Switzerland. Habit wise, outside of people in spain and southern france sleeping during the day because it's so hot in the summer, there is no difference. Food is very similar, brands are very similar.
> 
> The North-South crohn gradient theory about climate does not make a lot of sense on this map, Eastern Europe has a very low crohn indice and it's damn cold there. This map is a reply that questioned the North-South grade study because it didn't include Easter Europe, once Eastern Europe is included the North-South theory stops making sense.
> 
> The study and many people say "Westernisation", which makes sense on that map until you look at croatia,  is one of the least westernised country on that map and it's bright green.
> 
> I notice that all the countries with high crohn are clustered together. There isn't one country that pops out or is wrong, there is a real gradient running over that map.
> 
> I don't think it has much to do with underdiagnosis either, Eastern Europe might have that issue but Greece is yellow on that map too and it's almost 100 times as low than Western Europe. I've lived in Greece and Krete a while, their hospitals are not that bad that they would miss a 100 cases for every 1 case rightly diagnosed in Western Europe.
> 
> I think Europe is a much more interesting case than looking at the US, because Europe up until a few years ago, did not have the same free trade and movement of populous as the US has had for decades, whatever differences and clues there are, it will be much more pronounced in Europe.
> 
> All I know is if you showed a map to someone like this, and you did not tell them what disease it was, the first thing they would say is infectious disease / epidemic. Why are all those countries clustered together? *What else is there that explains clustering like that outside of infection?*
> 
> Genes don't explain crohn at all anymore. Many many people with CD don't have a genetic predisposition, man y in Asia with crohn have none of the genetic markers. Ireland rising by 90% in 10 years can't be explained by genes either. Genetic predisposition is all I believe in.



the north south gradient is more evident on a North american map, as the european equivalent to "south" is not land.


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## Xiaofa Qin

Thanks kiny for posting this informative map on CD. This map clearly showed that Sweden were among countries with the highest incidence of CD, which was higher than countries like Germany, despite that Sweden are almost free of MAP while some parts of Germany may have as high as 84.7% of MAP positive in dairy herds (Khol JL, et al. Examples and suggestions for the control of paratuberculosis in European cattle. Jpn J Vet Res. 2012 Feb;60 Suppl:S1-7. http://eprints.lib.hokudai.ac.jp/dspace/bitstream/2115/48527/1/60, Suppl.-1.pdf). This would a strong indication that the development of CD is indeed unnecessarily related to MAP. 

It seems inaccurate to say Dr. Van Kruiningen never finds MAP. In fact, he had been a key author of the first report of finding MAP in gut tissues from CD patients (Chiodini RJ, Van Kruiningen HJ, Thayer WR, Merkal RS, Coutu JA. Possible role of mycobacteria in inflammatory bowel disease. I. An unclassified Mycobacterium species isolated from patients with Crohn's disease. Dig Dis Sci 1984;29:1073–9), which had been just the study that refreshed the interest and kindled the extensive study on the possible link between MAP and CD in the last several decades.  He had also been the key author for the report of the possible existence of spheroplastic phase of mycobacteria in CD patients (Chiodini RJ, Van Kruiningen HJ, Thayer WR, Coutu JA. Spheroplastic phase of mycobacteria isolated from patients with Crohn's disease. J Clin Microbiol. 1986 Sep;24(3):357-63). He seemed to be an expert in this area with thorough and detailed information for both sides of the MAP controversy. It would need great courage to acknowledge that these glorious studies that he authored and have been “verified” by many followers as a possible contamination, and the change in his believe over time and along with the accumulation of knowledge would not be arbitrary. It was not Dr. Van Kruiningen but rather multiple other researchers such as Drs Hugh Freeman and Michael Noble from University of British Columbia, Canada (Freeman H, Noble M. Lack of evidence for Mycobacterium avium subspecies paratuberculosis in Crohn's disease. Inflamm Bowel Dis. 2005 Aug;11(8):782-3) and Nicole M.Parrish et al from John Hopkins (Parrish NM, et al. Absence of mycobacterium avium subsp. paratuberculosis in Crohn's patients. Inflamm Bowel Dis. 2009 Apr;15(4):558-65) that failed to repeat the crucial finding of the existence of MAP in the blood of CD patients. 

Hope the Crohn's Disease Initiative, led by Dr. Chiodini who had first isolated M. paratuberculosis from a CD patient and initiated the MAP controversy, will also bring an end to this controversy. I found their site has a fairly detailed description for the history of the MAP controversy and the formation of the two camps (http://www.thecrohnsdiseaseinitiative.com/index.php). As stated there, there are some critical questions we will have to answer. For instance, large amounts of MAP can been found in gut tissue and feces of cattle with Johne’s disease, while most positive findings of MAP in CD patients was detected by methods like PCR, after more than 30 cycles of doubling (billions of times of amplification), along with the increased possibility of false-positive. How come such a trance amount of MAP, hidden deeply inside the cell, may have caused the much severe and extensive damage of the gut and other tissues as seen in the CD patients than Johne’s disease. As even a combination of the well tested anti-mycobacterial drugs such as clarithromycin, rifabutin and clofazimine failed to show a sustained effect on CD patients, the anti-TNF (like infliximab) and immune suppression agents would more likely exert their effect on CD through a direct inhibition of inflammation rather than MAP. As described in the paper discussed here, I personally suspect that factors like the digestive proteases produced by us to digest the food rather than pathogens like MAP, Helicobacter pylori, invasive E. coli, etc might be the primary cause for gut damage. However, this remains a hypothesis awaiting further tests.


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## kiny

nm, I get way too worked up about this because it affects me

thanks for your info Xiofa


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## Moe.

But if it is MAP. Then we can kill it. Otherwise they will look around for
Another hundred years to what causes. Hence no cure.


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## tots

nikimazur-

Your right better technology means a rise in the diagnosis of CD and UC. Just as better fetal monitoring has given a higher c-section rate. 

I think UC and CD are just that- disease we are "lucky" enough to have. Some groups are predispossed to it and others aren't. Just as some groups are predispossed to diseases we don't get.

I dont think the artificial sweetners are the cause- my mom never used them and neither have I. ( I have had this my whole life )  I don't think antibioitcs "cause" IBD. There are certinly antibiotics can bring on a "flare" up. I didnt use them as a child and my mom didnt take them during her pregnency. Likewise my three kids had chronic cases of ear infections and strep throat. And none of them have Crohns.


Lauren


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## Mark in Seattle

Having read many research reports over the years, I've read little that speaks to the question of why CD tends to occur so frequently at the terminal ileum.  Having spent the last few years sleeping on my left side due to severe GERD (look at the shape of the curvature of the stomach/ GE valve to see why sleeping on left side prevents food/acid from escaping from the stomach while lying down), and having recently developed severe CD on my left side of my intestines somewhere for the first time in my 30 years of suffering with CD, I have come to suspect that CD occurs when food/chyme comes in contact with the intestines for a prolonged period.  I guess that for most people, terminal ileum is where the food contacts the intestine for the longest time period, as it awaits opening of the ileocecal valve.  And for me, the food undoubtedly comes to rest at night somewhere on my left side since I lie on my left.  I'm not exactly sold on the notion of sweeteners, but the notion of bile burning the mucosa if it comes to rest at the terminal ileum is an idea I would not dismiss, unless someone could argue why it doesn't make sense.  I've also noticed that when I eat a fibrous meal, such as a burrito with some beans, it slows the transit of the food, and at the same time causes more burning pain as a result of the increased time in my guts.  So there is clearly something there that my gut does not like to be in contact with.  Or perhaps the tissue is inflamed for some other reason and simply does not like to be in contact with anything, even something inert perhaps.

Another thing I've noticed is that if I take a proton pump inhibitor medication 2 days in a row (omeprazole) then my CD flares/burns badly.  Same thing if I try to take an antibiotic - can't do it, it hurts me too bad.  These two things suggest in my mind that there is some problem with bacteria doing battle in my guts.  The ppi meds I suppose let some bacteria come in, more than usual, while the antibiotic perhaps wipes out the minority of good bacteria, leaving only the majority dwellers which are probably pro-inflammatory bacteria.  So at least in my mind, I'm picturing a messed up configuration/distribution of bacteria as causing alot of the problem somehow.  

Anyhow, Xiaofa, how would you propose to test the hypothesis that unconjugated bile acids & such are causing the damage, not to mention the hypothesis about the sweeteners?


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## Xiaofa Qin

Thanks tots for sharing the story. There would be definitely other causes of IBD other than saccharin and sucralose. I personally believe anything that caused a prolonged and sustained damage and inflammation of gut may increase the risk for IBD.

Thanks Mark in Seattle for the interest in my opinion. More accurately, I suspected that the impaired deconjugation of conjugated biliary bilirubin (rather than bile acids) had caused a poor inactivation of the digestive proteases and further damage of the gut. As this deconjugation depends on an enzyme called beta-glucuronidase enriched in gut bacteria, I had suggested in my grant application to give animals some inhibitors of the enzyme such as 1,4-saccharolactone to see how the deconjugation of bilirubin, the inactivation of digestive proteases and gut damage correlate with each other, but it never got funded. Months ago, Old Mike (mf15, see some posts by him in the same thread) had discussed with me via email his suspecting that glucaric acid  existed in some vegetables, fruits and other foods may have contributed to IBD by its inhibition on beta-glucuronidase. I was very impressed by his great efforts and knowledge. In fact, 1,4-saccharolactone is just another name for glucaric acid.

It has been well documented that damage of the gut in IBD indeed related to luminal contents, which is demonstrated by facts that diversion of luminal contents resulted in remission and relapse occurred after re-introduction, and the damage of gut mostly occurred in areas with prolonged retention of the luminal contents.


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## Mark in Seattle

Thanks Xiaofa.  Sorry I messed up a bit on the terminology (digestive proteases, etc.) -not my specialty.  

So I'm still curious about your animal proposal.  Any particular kind of animal?  Would you have a means of measuring/correlating the deconjugation, the inactivation of proteases, and damage done to the intestines?  I can envision being able to measure the damage that is done or not done relative to control animals, but I wonder how you would measure the deconjugation of bilirubin and the inactivation of proteases.  I'm guessing you'd have to kill the animal and lavage the intestines sometime before the meal is excreted, is that about right?  And do the same for control animals?

Do you know how much such an animal study would cost?

Regarding glucaric acid, as I check this web site,  

http://www.livestrong.com/article/330279-foods-high-in-glucaric-acid/

it appears that there are a great many fruits & veggies high in glucaric acid.  I don't know what to make of that.  I would guess that the glucaric acid in those many food items must not have the ability to significantly disrupt the bilirubin/proteases/etc.  Otherwise I would think everyone would get a gut ache when eating those things.


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## Mark in Seattle

kiny said:


> croatia,  is one of the least westernised country on that map and it's bright green.
> 
> 
> 
> 
> http://www.ncbi.nlm.nih.gov/pubmed/10377694
> 
> Apparently Croatia saw a 10-fold increase in CD incidence from 1973 to 1994.  Something must have happened during that time period.
> 
> Interesting when I check wikipedia about their foods, it sounds like they stick to real food, not so much to processed food.  I'm guessing though that this all has something to do with the processed food industry.  I basically think there is some problem with the processed food industry.  Processed foods are so filled with chemicals.
Click to expand...


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## Xiaofa Qin

Thanks Mark in Seattle for interest in the proposed research. For this kind of study, the commonly used laboratory animals like mice and rats may be used. Deconjugation of bilirubin and inactivation of digestive proteases can be assessed by measuring the amount of conjugated bilirubin and protease activity in the luminal contents collected from the animals. These assays are actually easier than scoring gut damage. The reagents and materials are pretty cheap. The main cost would be the labor and animals, and the scale of the study may be adjusted according to the resources.

Large amounts of digestive proteases can be found in animals or people treated with antibiotics but not under normal condition, suggesting the components in diet just had minimal effect compared to a change in gut bacteria. Glucaric acid is readily absorbed through the intestine, thus a fairly large amount would be needed to reach the lower intestine and exert a significant effect on beta-glucuronidase enriched in gut bacteria. An accurate evaluation would need more study in this area.


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## Xiaofa Qin

This paper suggested that ulcerative colitis (UC) and Crohn’s disease (CD) are just two phenomena of the same disease rather than two different diseases. This notion came to my mind when I saw the consecutive shift of CD from the small to large intestine over time, and thus likely a shift from UC to Crohn’s colitis. The many case of Crohn’s colitis today would be just diagnosed by Dr. Crohn and colleagues as UC but not CD, the so called regional ileitis at that time (Crohn BB, Ginzburg L, Oppenheimer GD. Regional ileitis: a pathologic and clinical entity. 1932. Mt Sinai J Med. 2000 May;67(3):263-8). I knew this notion would be very difficult to be accepted by many people. However, I took it as a crucial part in this unified hypothesis. I realized that it is against the current main stream of thoughts and efforts, trying to divide UC and CD into multiple subtypes with each corresponding to a specific cause. This would be no surprising, as it is just what people usually do in facing the many perplex phenomena without a reasonable explanation.  

In deed, strictly to say, each IBD patient is different from the others: each one has a unique set of genes, and even identical twins may have different diet, different sanitary habit, and thus different spectrums of bacteria (microbiome) in the gut.  However, time and again, the overwhelmingly perplexed phenomena were usually fallen into some simple explanation. A couple of decades ago, when I was a postgraduate student, I wrote a paper entitled “the phenomenal diversity and complexity and the essential simplicity and unity upon life” that was published in Philosophy and Medicine. I hold this philosophy and belief then and also now. We definitely should realize and explore the diversity and complexity of things. However, we should also put more efforts to find out the principles and laws behind them, which are usually characterized by simplicity and unity. There are numerous different forms and species of life on earth, with a constant disappearance of some old ones and the emergence of some new ones, but we now know all the differences are just governed by the different sequences of base-pairs in DNA. 

CD and UC have many similarities in clinical, pathological and epidemiological features. People may easily attribute this to the gene. However, this notion would be immediately embarrassed by the fact that the NOD2/Card15, also called IBD1 gene, is shared by Crohn’s disease with diseases other than IBD such as the Blau’s syndrome and early onset sarcoidosis, but not with UC, its twin brother of IBD. As we know, there are always some IBD patients that cannot be classified to either UC or CD, the misclassification between UC and CD frequently occurred. Pet dogs and cats are also just diagnosed as IBD without further classification. This misclassification or the lump up of UC and CD seems without big consequences for the treatment. These suggested the great similarity in nature between UC and CD. All hypotheses would have to address this close relationship between them and the dynamically changed faces of UC and CD. Otherwise, the theory would likely bear some fatal defects or at least some potentially severe flaws. The great efforts of a century long extensive research on IBD had generated a vast amount of information. Some of them may somehow reflect the true nature of the disease, but many of them may be superficial, erroneous and misleading, as demonstrated by the many totally opposite or conflicting evidences (such as those regarding MAP). To get to the nature of IBD, we may need more in-depth, insightful, thorough and critical thoughts.


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## Xiaofa Qin

This is the era of genome. We all expect research on genes may solve the big problems, and this is indeed where we have put the greatest enthusiasm, attention, hope, trust and belief as well as the energy, efforts and resource. However, it seems not that easy to get the miracle. 

I found the possible link between saccharin and IBD in 2001, about the same time people hailed the finding of the first IBD gene, NOD2/Card15, also called IBD1, associated with the Crohn’s disease. In the May 31 issue of Nature, three papers were published: two research articles and one commentary. At that same moment, I thought I probably had found an important causative factor in the environment and thus would also draw some attention, as the emergence and dramatic increase of IBD clearly suggested IBD being caused by changes in the environment rather than the genes. However, the manuscript I wrote with the evidence suggesting the possible link between saccharin and IBD was rejected by journals even specialized in gastroenterology. Finally, I found the previously unknown journal named Medical Hypotheses, and the paper was eventually published there. 

A decade later, we can see the paper published in Nature was cited thousands of times and NOD2 was studied again and again by many researchers. In contrast, my paper was hardly mentioned or cited by any of the dozes of thousands of paper even in IBD area. 

Failed to raise any action and get any grant, I had to continue the pursuit by myself and the paper discussed here is just the result of the decade-long effort during my spare time. Although it is still hypothetical in nature, at least it constituted a tangible unified theory that provided cohesive and comprehensive explanations for many puzzles in IBD. For me, I felt IBD no more a mystery. 

On the other hand, multiple millions, if not billions, had been spent on mostly gene related research on IBD (NIH alone funded 113 million on IBD research in 2011). However, despite of the more than a decade extensive research, we still do not know exactly how NOD2 related to IBD. It is speculated that mutation in NOD2 (and also autophage genes like ATG16L) may caused IBD as the result of the impaired clearance of gut bacteria, but why IBD is lower before modernization with poor hygiene condition, and is more closely related to CD in the small intestine rather than CD in large intestine or UC, where there would be more bacteria in the gut. 

With the many puzzles regarding NOD2 awaiting to be solved, the great effort in last decade have lead to the hailed achievements of finding further about a hundred more genes related to IBD, with more to be discovered along with the ongoing endeavor on both the host and gut bacteria. As the relationship of these genes with IBD would be more remote, ambiguous, and perplex, it would be likely more difficult and take more time to decode. We still do not know how and when a united hypothesis on the etiology of IBD would be constructed based on these genetic findings that, according to the main stream of thought, would take into consideration not only the interaction among these genes but also their interaction with the environment, the gut microbiota and the immune system. Nevertheless, one thing would be sure: it will generate many fantastic theories, remarkable achievements, momentous new advances, and magnificent scientific articles published in the renowned journals along this process.  

One day the history would make a judgment as whether the establishment of this unified hypothesis discussed here or the finding of the more than 100 IBD genes would make us more closer to a final solution of IBD. I personally felt we should put more efforts to find out the causative factor(s) of IBD in the environment and thus the root mechanism (Qin X. How can we really reduce the morbidity of inflammatory bowel disease - Research on genes and cytokines, or find out the causative factors in the environment? J Crohns Colitis. 2009 Dec;3(4):315). We now know that 90% of lung cancer is caused by smoking and only about 1% is caused by air pollution, thus a big reduction in lung cancer should largely rely on stopping smoking rather than stopping driving the car. This kind of knowledge can only be got by epidemiological studies rather than research on genes, thus I think we should realize the importance of both studies and treat them with balanced enthusiasm, attention, appreciation and efforts.


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## Judith

Thank you for your interest in IBD research and the great long post! 
I believe the causes and effects of IBD are so complex that investigation must occur from multiple different avenues. The interaction of causal factors and the individualized nature of symptoms under the broad umbrella of Crohn's / IBD indicates that this disease does not have just one answer.

I fully support and appreciate any and all research into Crohn's Disease and hope one day we can piece it together for more effective treatments - and a cure!

Thank you for all of your hard work in adding to piecing together the puzzle of Crohn's Disease.


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## Xiaofa Qin

Thanks Judith for the comments. IBD indeed seems very complex, as suggested by the many articles published in some of the most renowned journals. However, time and again, this kind of overwhelmingly bewildering complexity may largely due to the failure of knowing its cause. For instance, infection of the gut by Mycobacterium Tuberculosis can exhibit many symptoms virtually indistinguishable from Crohn’s disease. In addition, this bacteria can also infect many other organs like the lung, brain, liver, kidney, spleen, and bone, with much more complex spectrums of symptoms different greatly among individuals. Despite that, all these can be cured by eradicating the bacteria using some antibiotics. 

As stated in the paper, I totally agree with the notion that the development of IBD must involve multiple factors, just like there are many risk factors for tuberculosis such as overcrowding, malnutrition, alcoholism, smoking, HIV, diabetes, silicosis, corticosteroids, anti-αTNF antibodies like infliximab, and genes like HLA-DR, INF-γ, SLC11A1, VDR, MAL/TIRAP, and CCL2 (http://en.wikipedia.org/wiki/Tuberculosis#Risk_factors).  However, we should realize that many of these factors are affecting factors but not the key causative factor, and we should not be confused and intimidate by them. The prompt ups and downs of IBD even in the developed countries in the west would strongly suggest there might also be some key causative environmental factors for IBD. As stated in the previous posts and illustrated in the paper, I suspect saccharin and sucralose could be just this kind of causative factors that should be checked out, but this does not exclude the possible existence of other important causative factors that need to be found. 

As for the cure, I believe the cure, as well as effective prevention, of IBD would largely depend on finding out the main cause and thus the root mechanism. I found a thread in this forum started by David with wonderful detailed descriptions regarding the strong relationship between the mucosal healing and the long-term prognosis of IBD (http://www.crohnsforum.com/showthread.php?t=36253). A more recent paper on this topic can be found in Gut (Neurath MF and Travis SP. Mucosal healing in inflammatory bowel diseases: a systematic review. Gut. 2012 Nov;61(11):1619-35; http://www.ncbi.nlm.nih.gov/pubmed/22842618). It becomes more and more clear that the long term remission and prognosis of IBD are most strongly related to mucosal healing as judged by the appearance and integrate of the gut surface observed with the naked eye through an endoscope, but rather than the set of genes the patients being baring, the amount and type of inflammatory cells aggregated in the mucosa, the amounts and type of bacteria hide in the macrophages, the type and strength of antibodies in the blood, the feelings and symptoms of the patients, and even those gold standards of clinical remission. Doctors and IBD professionals seem still greatly puzzled by this phenomenon and wondering this mucosal healing is indeed essential or just cosmetics. However, this close relationship is not surprising to me. If you read through my paper, you may find that this hypothesis simply suggested that the weakening of the gut barrier as the result of over digestion of the mucus layer and underlying gut tissue by the poorly inactivated digestive proteases have been the primary cause of IBD. The many changes of the immune system, which may be greatly affected by genes and many other factors, might be just a natural response to the increased infiltration of bacteria or dietary components. It suggested the close relationship between mucosal healing and prognosis had actually reflected the root mechanism of IBD and a cure may largely depend on a full restoration of the function of gut barrier. This may just like a group of bandit sneaked into a well-built castle through a small leftover opening of the gate. They were found by the well-trained guards and the fighting between the guards and the intruders caused some turmoil. To solve the problem, some people tried hard to find out the defects of the castle and would like to rebuild it. Other authorities put a great effort to disarm and disable the guards loyal to their duty, and the temporary peace thus achieved made many people believe this would be the wonderful approach. However, there might be a more easy and complete solution, i.e., to close the door tightly.


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## mf15

Xiaofa Qin:I agree the immune system is attacking someting that is leaking through 
the barrier,bacteria/endotoxin. The immune system is not stupid.
The question is why the leak.
We have to start around 1920 perhaps to figure this out.
One thing that might be implicated is all the synthetic surfactants and detergents we ingest,if some of them get to the colon then they will reduce the integrity of the hydrophobic mucus barrier,also the wrong type of bile acids,which can act as surfactants,or their non activation.
I also believe that over fortification of food with iron and B6 are involved.
I am starting a new thread that might be of interest,
which is some older and some new material.
Please see Radical Induction Theory.
Old Mike


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## Moe.

Interesting. 
Could you answer this question please? 
Qu biologics made a ssi vaccine for crohns (YouTube ssi vaccine crohns)
It put the individual in remission. The vaccine was to stop a certain strain of e.coli. Why would something like this work? Is it stopping the gut being infected by this bacteria? Very confusing because it seems that there is a different cause to everyone's ibd. Hence different response to treatment.? 
I'm probably guessing but ill link tonight a Saudi woman had tuberculosis which caused ibd, in Saudi it's .94 out of 100,000 people have ibd which is very small.
Anyhow ill link it up later tonight and have a read and tell me what u think.


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## Xiaofa Qin

Thanks Old Mike and Moe for sharing the thoughts and info. 

Yes, there are so many possibilities for IBD. It would be better we can sort them out and make some kind of quantitative assessment. Free radicals have been the weapon of white blood cells to fight bacteria. They definitely can cause damage to the tissue, and antioxidants may help reducing the inflammation. As for the anti E. coli vaccine, I do not know the detail. If it indeed work, one simple explanation I can think of would be also its fighting against the infiltrated bacteria, as E. coli is one of the most abundant bacteria in the gut. But the producer may have more sophisticated and profound explanation.


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## Moe.

BMJ Case Reports 2012; doi:10.1136/bcr.01.2012.5620

    Reminder of important clinical lesson

Crohn’s disease or TB – the perennial question and diagnostic pitfalls

    Rudra Krishna Maitra1,
    Tim Bowling2,
    Pradhib Venkatesan3,
    Charles Maxwell-Armstrong1

+ Author Affiliations

    1Surgery Department, Queens Medical Centre, Nottingham University Hospitals, Nottingham, UK
    2Gastroenterology Department, Queens Medical Centre, Nottingham University Hospitals, Nottingham, UK
    3Infectious Diseases Department, City Hospital, Nottingham University Hospitals, Nottingham, UK

    Correspondence to Mr Rudra Krishna Maitra, rudra.k.maitra@gmail.com

Summary

A previously healthy 28-year old lady from Saudi Arabia presented with recurrent peri-anal abscesses progressing to fistula-in-ano. These were treated with incision and drainages and with setonisation of the fistula. Multiple biopsy and culture specimens were taken to rule out tuberculosis (TB) or Crohn’s disease – all showed granulomatous disease suggestive of either Crohn’s or TB, no mycobacteria were grown. MRI scanning also suggested either TB or Crohn’s disease. Tuberculin skin test was inconclusive and Quantiferon Gold test was negative. Treatment for Crohn’s was started with oral prednisolone – the patient deteriorated and adalimumab (tumour necrosis factor α antagonist) was commenced. With continued deterioration in the absence of intra-abdominal abscesses, a clinical diagnosis of TB was made, Crohn’s treatment suspended and quadruple therapy for TB was initiated. The patient rapidly improved and a delayed re-look histological specimen identified an isolated mycobacterium. Subsequent cultures confirmed drug-sensitive TB. The lady is currently well on TB eradication regimen.
Background

In the UK, Crohn’s disease (CD) has an incidence of 8.3 per 100 000 of population and is a common cause of recurrent peri-anal abscesses and fistulation. Tuberculosis (TB) is uncommon in the UK with a prevalence of 15 per 100 000 of the population (2009) of which only a small fraction present as intestinal TB; prevalence is significantly higher in developing countries.1 2 Diagnosing TB is difficult with no test providing 100% sensitivity and specificity. Delayed diagnoses can result in serious morbidity. Extra-pulmonary manifestations of TB accounted for 47% of cases in the UK (2009), more commonly in foreign-born individuals who account for the majority of cases.2 Intestinal TB presents with clinical features resembling CD and must be distinguished from it.

In the following case, TB was suspected as a differential for CD from the outset but all tests proved negative for TB. TB was correctly diagnosed after clinical deterioration following initiation of treatment for CD. This case highlights the difficulty of distinguishing intestinal TB and CD and the need for constant re-evaluation of the diagnosis in the face of deterioration.
Case presentation

A previously well 28-year-old lady from Saudi Arabia presented with a left-sided peri-anal abscess. She had BCG immunisation as a child and gave no personal, family or contact history of TB. In Saudi Arabia she did not drink any unpasteurised milk. She had a history of a previous peri-anal abscess. She was systemically well. An incision and drainage of the abscess was performed. Microbiology samples grew Escherichia coli and Enterococcus, both sensitive to co-amoxiclav, with which she was treated.

She returned 5 months later with a slow healing wound and discharge from the opposite side.
Investigations

MRI showed a fistula tract, thickened small bowel loops with a small quantity of fluid in the pelvis (figure 1). The MRI report suggested CD. A barium follow-through showed a dilated distal ileum and narrowing in multiple parts of the colon. Colonoscopy showed significant inflammation in the ascending colon. Biopsies were sent for histology but not for culture. Histology showed non-caseating granulomata, with no acid fast bacilli (AFB), consistent with CD but a differential of TB could not be ruled out. A CT scan showed some subcentimetre intra-abdominal lymph nodes, not amenable to percutaneous biopsy. A chest x-ray was clear.
Figure 1
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Figure 1

Initial MRI showing fistula tract and thickened small bowel loops with fluid in pelvis.
Differential diagnosis

TB and CD were the principle differential diagnoses. In the absence of any mycobacterial growth or evidence of TB on histology, a provisional diagnosis of CD was made.
Treatment

Treatment for CD was started with prednisolone while a seton suture was inserted in the persistent peri-anal fistula. The patient did not improve and re-presented with an ischio-rectal abscess on the opposite side. This was incised, tissue was sent for histology and swabs were sent for culture. The histology showed florid granulomatous inflammation. A second colonoscopy was performed to assess the need for an antitumour necrosis factor (TNF) α agent, namely adalimumab. Colonoscopy showed continuing active inflammation. No further samples were taken for histology or culture. Before commencing adalimumab a tuberculin skin test (TST) showed a 16 mm response and a Quantiferon Gold IT interferon γ release assay (IGRA) was negative. Within 1 month of starting adalimumab she presented with fever, rigors, diarrhoea and lethargy. A CT scan showed no abscesses, but found intra-abdominal fluid and multiple enlarged mesenteric lymph nodes. Adalimumab was immediately stopped. Her fever continued despite intravenous tazocin. Ascitic fluid was sent for culture (including for AFB) and all her previous samples were re-evaluated. At this point, an isolated acid fast bacillus was discovered on re-sectioning her first colonoscopic biopsy taken 8 months previously. She was commenced on quadruple therapy for TB (rifampicin, isoniazid, pyrazinamide and ethambutol).
Outcome and follow-up

On commencement of anti-TB therapy, she improved dramatically. Fully sensitive Mycobacterium tuberculosis subsequently grew from ascitic fluid. An HIV test was negative. She was discharged from hospital 1 week later and is currently well on treatment.
Discussion

The phenomenon of mycobacterial infection revealed by the use of anti-TNF α agents is well recognised.3 Guidance exists on assessment for latent or active TB infection before the use of such agents.4 5 When screening for latent TB, a chest x-ray and TST or IGRA are performed. Our patient had a normal chest x-ray and a positive TST. The latter could have been due to either mycobacterial exposure or prior BCG. If this had been interpreted as a marker of latent TB infection one possible option might have been to prescribe isoniazid chemoprophylaxis and continue with anti-TNF α therapy. A risk from this course of action arises when active TB, rather than latent TB, is present, isoniazid monotherapy is insufficient to treat the higher mycobacterial burdens of active TB and will eventually select for isoniazid resistance, although a false sense of clinical response may occur initially as isoniazid kills sensitive organisms. Our patient had an IGRA Quantiferon Gold IT, in addition to a TST. BCG would not have affected an IGRA, given the specificity of this test for M tuberculosis infection. Her positive TST with a negative IGRA could have been interpreted as a false positive TST due to her prior BCG, but this was in fact a false negative IGRA.

Our patient gave no clear exposure history to TB, had a clear CXR and had had BCG as a child. Although taking a BCG vaccination history is routine, its value in reducing the probability of a TB diagnosis is uncertain. The efficacy of BCG varies between populations, may wane with time and some argue may apply more to reactivation of latent infection than new exposure to TB.6 7 In some patients for example, with established rheumatoid arthritis, there may be no additional clinical considerations before starting anti-TNF. However in our patient there was the added complexity that active TB was a possibility.

The UK NICE guidelines do not advocate the use of IGRAs or tuberculin skin tests for the diagnosis of active TB.8 These tests do not have sufficient sensitivity to exclude disease when results are negative and lack the specificity to distinguish latent from active disease when results are positive.9 The diagnosis of active TB depends on clinical suspicion and sampling for culture. The clinical pictures of intestinal TB and CD can be very similar, although some differences have been reported.10 At colonoscopy and on histology TB can cause superficial, transverse ulcers which do not penetrate beyond the muscularis mucosa. In CD, ulcers can be longitudinal and serpiginous. Granulomas in the intestine or local lymph nodes can be non-caseating with either diagnosis, but only caseating with TB and some other infections. Mycobacterial culture of suitable samples (lymph node, intestinal tissue, fluid or pus) not placed in formalin is key to the diagnosis of TB. Swabs are not suitable for mycobacterial culture. Staining for AFB may occasionally be misleading as atypical mycobacteria may be found in the intestine. In coming years new PCR methodologies will augment diagnostic rates.11

The diagnosis of active TB depends on clinical suspicion and sampling for culture. The clinical pictures of intestinal TB and CD can be very similar, although some differences have been reported.10

Clinical suspicion is influenced by epidemiological knowledge. CD is uncommon in Saudi Arabia with a reported incidence of 0.94 per 100 000, compared with 8.3 per 100 000 in the UK.12 13 The prevalence of TB in Saudi Arabia is 22 per 100 000 and not that much higher than the overall prevalence in the UK.1 However, in the UK in 2009 the prevalence of all forms of TB ranged from 7 per 100 000 (only a fraction of which would be intestinal TB) in Caucasians to 273 per 100 000 in Black Africans.2


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## Moe.

Direct website with refrences

http://casereports.bmj.com/content/2012/bcr.01.2012.5620.full


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## Xiaofa Qin

Thanks Moe for sharing the info. This is really a very interesting case that demonstrated the difficulty to distinguish between intestinal tuberculosis and Crohn’s disease on symptoms. 

It would be also very interesting for the very low Crohn’s disease in Saudi Arabia. We can see a thread in this forum with fervent discussion regarding the relationship between less sunshine and low vitamin D level and Crohn’s disease (http://www.crohnsforum.com/showthread.php?t=23826). Studies have shown that vitamin D deficiency and insufficiency occurred in as high as 80 – 90% of Saudi Arabian men (Ardawi MS, et al. High prevalence of vitamin D deficiency among healthy Saudi Arabian men: relationship to bone mineral density, parathyroid hormone, bone turnover markers, and lifestyle factors. Osteoporos Int. 2012 Feb;23(2):675-86. http://www.ncbi.nlm.nih.gov/pubmed/21625888) and women (Ardawi MS, et al. Vitamin D status in relation to obesity, bone mineral density, bone turnover markers and vitamin D receptor genotypes in healthy Saudi pre- and postmenopausal women. Osteoporos Int. 2011 Feb;22(2):463-75. http://www.ncbi.nlm.nih.gov/pubmed/20431993). If vitamin D is really so important, we would expect to see extremely high incidence of Crohn’s disease in this country. Why not?


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## Moe.

Well then in this case we can rule out  Vitaman D??? possibly vitamin D?
Could crohns be a mutated form of intestinal tuberculosis?
Only way we will find out is if a doctor has the balls to infect himself with MAP and go from there


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## Moe.

Also would just like to add. For MAP wasnt the Koschs postulates accepted. Im not 100% what it means. But what I understood is this ;
Take MAP from the Cow infect a Goat,Sheep,Any animal and its gets Johnes Disease. Has this been done by purposely infecting a Human? If so why not? Wouldn't an answer lay there.


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## MiciCom

Hello

Thanks for your great job Xiaofa Qin !

I don't see C. albicans in your document, I think that its proliferation in the digestive tract and buccal microbiota has a role determining with the apparation of saccharin and aetiology IBD, Crohn's disease, I know better than the UC, and that is linked (I summarizes...) to an overconsumption and bad decomposition of sugars (MAP linked to mannose, etc The foods additives such as starches, the cereal lectins, etc and of course saccharin, aspartam etc., medications such as saccharose ingredients, lactose, maltodextrin, toothpastes with what is known, etc. etc. These links is actually etablished between Crohn's and C. albicans. I would like to put links about the publications on this subject but the system of protection of the forum does me not, do I actually post 10 posts to get there?

Have you done research on these links between c. albicans and your work on saccharin Xiaofa Qin?

Greetings from France
Sorry for my English vocabulary, thanks to google trad


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## wildbill_52280

Xiaofa Qin said:


> If vitamin D is really so important, we would expect to see extremely high incidence of Crohn’s disease in this country. Why not?


i suggest, that there is no major direct causative connection between vitamin d and crohns disease, it is merely an association the simply occurs together, it  doesnt guarauntee anyone will develop crohns disease or ibd its not an absolute predictor.

 I theorize that the proposed vitamin d connection is only in relation to vitamin d's larger role in respiratory infections, which are treated with antibiotics. it is the antibiotics that have  a more direct connection to crohn's and ibd. this theory will become stronger when you compare rates of crohns disease with industrialized and non industrialized countries rates of ibd. with the concept of industrialization almost synonomous with westernization, such as western medicine opposed to older traditional medicinal systems. between the lowest recorded rates(non-industrialized) and the highest rates which are always more developed countries, the difference is up to 70x higher in developed countries. that is a huge difference. the #1 one environmental risk for ibd i believe, is antibiotics. many other substances in our environment may contribute, but taking lots of antibiotics is the fastest route to ibd.


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## Xiaofa Qin

Thanks Moe, MiciCom and wildbill_52280 for sharing the thoughts and info. Here I attached a link to a review article regarding the controversy on the possible link between MAP and Crohn’s disease, as well as some information on Koch’s postulation (Rosenfeld G, Bressler B. Mycobacterium avium paratuberculosis and the etiology of Crohn's disease: a review of the controversy from the clinician's perspective. Can J Gastroenterol. 2010 Oct;24(10):619-24; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2975476/pdf/cjg24619.pdf ). According to Koch’s postulation, MAP should be isolated from the patients and be capable of transmitting the disease to others. However, the MAP controversy largely attributed to the extremely low MAP in CD patients and the fact that there is no evidence suggesting IBD is contagious. The MAP controversy will likely continue, as the extreme complexity of our body made it difficult to completely turn down an argument, no matter how unlikely it would be. In facing such a big controversy we would have to think deep and thorough to make a judgment. I feel a really breaking through in the etiology of CD would rather rely on finding out the answer as what caused the high incidence of IBD in countries like Sweden where MAP is extremely low, or identify agents other than MAP as the main cause of IBD.  

I have not realized any causative role of C. albicans in IBD and would appreciate MiciCom to share more info on this.

As for antibiotics, multiple large-scale studies such as the nationwide study in Denmark (Hviid A, et al. Antibiotic use and inflammatory bowel diseases in childhood. Gut. 2011 Jan;60(1):49-54; http://www.ncbi.nlm.nih.gov/pubmed/20966024 ) have clearly demonstrated the increased risk of IBD. However, the recent increase in IBD in the developed countries seems difficult to be explained by the increased use of antibiotics. In fact, antibiotics are more widely used in countries like China than the western countries, despite that both CD and UC are still very low in China. Here is a link to an article regarding the antibiotics abuse in China (http://www.wanchuanlin.org/papers/Antibiotic Abuse in China.pdf). According to the paper, 90% of inpatients and 80% of outpatients in China are prescribed antibiotics, compared to only 30% of inpatients and 20% of outpatients in the West. As discussed in my paper, I suspected that dietary chemicals may have imposed much more strong impact on the gut bacteria and IBD in the general population than antibiotics simply because of their wide use. 

The great efforts in the last century have suspected numerous agents as the cause of IBD. However, many of them were largely based on some pieces of evidence with the ignorance of some other key facts. Currently the cause of IBD remains regarded as unknown, as none can fit into the many features of IBD. When I found the possible link between saccharin and IBD a decade ago, I also wondered how valid and how important such a link might be. This drove me digging hard piece by piece into the origin and history of both saccharin and IBD, with many references being published a century ago. The more information I got, the more evidence seemed to support the primary hypothesis rather than denied it. The paper discussed here is virtually the result of this decade-long efforts. Although it remained a hypothesis, I still strongly recommend checking out dietary chemicals like saccharin and sucralose as the possible main cause of IBD.


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## wildbill_52280

Xiaofa Qin said:


> As for antibiotics, multiple large-scale studies such as the nationwide study in Denmark (Hviid A, et al. Antibiotic use and inflammatory bowel diseases in childhood. Gut. 2011 Jan;60(1):49-54; http://www.ncbi.nlm.nih.gov/pubmed/20966024 ) have clearly demonstrated the increased risk of IBD. However, the recent increase in IBD in the developed countries seems difficult to be explained by the increased use of antibiotics. In fact, antibiotics are more widely used in countries like China than the western countries, despite that both CD and UC are still very low in China. Here is a link to an article regarding the antibiotics abuse in China (http://www.wanchuanlin.org/papers/Antibiotic Abuse in China.pdf). According to the paper, 90% of inpatients and 80% of outpatients in China are prescribed antibiotics, compared to only 30% of inpatients and 20% of outpatients in the West. As discussed in my paper, I suspected that dietary chemicals may have imposed much more strong impact on the gut bacteria and IBD in the general population than antibiotics simply because of their wide use.



thanks for the article on antibiotic use in china, yet this article does not say how may people in china utilize western medicine as whole, and this distinction must be made to explain the still low but rising rates of ibd in china. certainly within the community that does utilize western medicine, they may be exposed to antibiotics more then a similar amount of people in america, but there is way more people in china then america. 

here is where i got the data on ibd rates and when comparing the lowest rate occuring in china with the highest rate recorded in nova scotia, ibd is around 70X higher in nova scotia. 
http://biologie.univ-mrs.fr/upload/p87/Economou.pdf 

i wish i had more time to get back with more references, but i did find some studys on chinas utilization of western medicine compared to traditional system, and their transition from traditional medicine has been very slow. This fact may explain the current low rates of ibd, despite high rates of antibiotic prescriptions.

i hope i am reading all this correctly, but at least for now, that is my take on it. I certainly want to avoid defending my position at all costs to avoid my own bias, if you disagree for any good reason, let me know, but it still seems like there is a possibility antibiotics can explain some of these patterns in ibd rates. it certainly cannot explain all cases, im aware of this.


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## Xiaofa Qin

Antibiotics are indeed heavily abused in China. Here is a link to an article published in Jan. 5, 2012 with some information ( http://www.time.com/time/world/article/0,8599,2103733,00.html ). It stated that “Last month, the country (China)'s Ministry of Health revealed that on average each Chinese person consumes 138 g of antibiotics per year — 10 times the amount consumed per capita in the U.S.” This suggests that even if antibiotics played some role in IBD as shown in some big-scale studies, something else have played a much, much big role. We need to find out what’s that.


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## wildbill_52280

Xiaofa Qin said:


> Antibiotics are indeed heavily abused in China. Here is a link to an article published in Jan. 5, 2012 with some information ( http://www.time.com/time/world/article/0,8599,2103733,00.html ). It stated that “Last month, the country (China)'s Ministry of Health revealed that on average each Chinese person consumes 138 g of antibiotics per year — 10 times the amount consumed per capita in the U.S.” This suggests that even if antibiotics played some role in IBD as shown in some big-scale studies, something else have played a much, much big role. We need to find out what’s that.


this is interesting information indeed, but i think the information we need on china is how many people are utilizing western medicine compared to traditional medicines over the course of say the last thirty years. i recall reading some good studies on this saying that the chinese were very reluctant to embrace western medicine, and only recently have the trends been on an upswing, recently meaning the last 10-15 years. 


to say that on average chinese consume 10x more antibiotics then the U.S., we must see how they chose a representative sample. by unintentionally cherry picking only people that use western medicine, it may appear that the rate of antibiotic use is 10 times higher then the U.S. To draw more certain conclusions, we would have to see how they came up with this data.

thats all the brain power i have for now.


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## wildbill_52280

Here is what we need, not sure if the full article is available though.
http://www.deepdyve.com/lp/elsevier...-in-the-use-of-chinese-medicine-in-JUK9sYSual


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## Xiaofa Qin

To my knowledge, the per capita data would be usually calculated as the amount (tons) of chemical used in a country divided by the population, rather than sampling. It seems the average amounts of antibiotics use in China was just calculated this way. Here is another link: http://en.uuuwell.com/article-246742-1.html. It states that China produces 210,000 tons of antibiotics annually, with 30,000 tons for export, and the remaining 180,000 tons left for domestic use. 180,000 tons antibiotics divided by 1.3 billion people equals to 138.46 gram per person.  This heavy antibiotics use in China has a long history rather than just started in recent years. In fact, much more people in China have deeper belief in modern medicine rather than the traditional medicine like the herbs. In China, more than 60% of patients with mild flu symptoms are prescribed with antibiotics by the doctor, with the intention to prevent the development of bacteria infection. However, here in the US, antibiotics will be given to flu patients only after they indeed showed symptoms of bacteria infection.


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## wildbill_52280

Xiaofa Qin said:


> To my knowledge, the per capita data would be usually calculated as the amount (tons) of chemical used in a country divided by the population, rather than sampling. It seems the average amounts of antibiotics use in China was just calculated this way. Here is another link: http://en.uuuwell.com/article-246742-1.html. It states that China produces 210,000 tons of antibiotics annually, with 30,000 tons for export, and the remaining 180,000 tons left for domestic use. 180,000 tons antibiotics divided by 1.3 billion people equals to 138.46 gram per person.  This heavy antibiotics use in China has a long history rather than just started in recent years. In fact, much more people in China have deeper belief in modern medicine rather than the traditional medicine like the herbs. In China, more than 60% of patients with mild flu symptoms are prescribed with antibiotics by the doctor, with the intention to prevent the development of bacteria infection. However, here in the US, antibiotics will be given to flu patients only after they indeed showed symptoms of bacteria infection.


i see what you are saying, by calculating it that way it tells us how much antibiotics are being consumed by the entire population of china. but it does not tell us what types of people are consuming it. a sampling bias would not exist in this method.

If these facts are true it may shed some doubt on the role of antibiotics, but doesnt seem like enough detailed information to come to any final conclusions.
the low rates of ibd were calculated over a time span of 50 years worth of data collection, without any hard data on chronological trends of antibiotic consumption, who is to say this trend in antibiotic consumption didnt just begin 5 years ago or even 2 years ago, which then wouldnt be reflected in the previous calculations for low rates, again leaving the possibility of low rates being explained by low antibiotic consumption. just not enough hard data yet.


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## Xiaofa Qin

The positive link between antibiotics and IBD would likely be true, as it not only demonstrated in the nationwide study of Denmark (Hviid A, et al. Antibiotic use and inflammatory bowel diseases in childhood. Gut. 2011 Jan;60(1):49-54. http://www.ncbi.nlm.nih.gov/pubmed/20966024) but also in multiple other recent large-scale studies such as those in Finland (Virta L et al. Association of repeated exposure to antibiotics with the development of pediatric Crohn's disease—a nationwide, register-based finnish case-control study. Am J Epidemiol. 2012 Apr 15;175(8):775-84; http://www.ncbi.nlm.nih.gov/pubmed/22366379 ), UK (Kronman MP, et al. Antibiotic Exposure and IBD Development Among Children: A Population-Based Cohort Study. Pediatrics. 2012 Oct;130(4):e794-803. http://www.ncbi.nlm.nih.gov/pubmed/23008454), and Canada (Shaw SY, et al. Association between the use of antibiotics and new diagnoses of Crohn's disease and ulcerative colitis. Am J Gastroenterol. 2011 Dec; 106(12):2133-42. http://www.ncbi.nlm.nih.gov/pubmed/21912437). It just seems the existence of some other factors that make the effect of even such heavily used agents like antibiotics becomes trivial.


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## wildbill_52280

Xiaofa Qin said:


> The positive link between antibiotics and IBD would likely be true,  It just seems the existence of some other factors that make the effect of even such heavily used agents like antibiotics becomes trivial.


i am in awe of its complexity, its a mind bender for sure. there is some order in this chaos, i like to focus on the most basic "hard" facts we have, the north south gradient and vitamin d theory, most apparent in north america. as well as what seems to be a spike after 1945 in rates, this is when antibiotics were on the market, but like you suggest some other factors seem to make antibiotics trivial, a small but good piece of the puzzle, if in fact there is a connection and there seems to be. but there was a spike in rates from about 1910 to 1930 so how could we explain that, that was before antibiotics. the best i could do here, is dietary influences processed manufactured food high in sugar low in fiber, but i believe its even more complex yet, then there comes the different types of bacteria that may be living down there, all these factors come into play for someone to develop crohns disease, it really may take the right combo of events, it could include ANY chemical that could reduce our defenses against bacterial invasion in a permanent way, such as damage to the microbiome, this would allow chronic infections/inflammation, even the relapsing remitting nature of the more mild and moderate cases suggest this a bit, some infective agent.

here is one of my new favorite studys on crohns that uses a new model of crohns disease, i come to realize the models we had before needed updating with all the new info we have in the disease, im glad someone(many) has done it, it could really advance our understanding, even though just its just a theoretical model.

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0041594


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## Xiaofa Qin

I totally agree that any assumption and hypothesis must be kept checked against the hard facts and only the facts have the power for the ultimate judgments.  

As even the effects of antibiotics and smoking become trivial, there must be some more dominant factors for IBD. I suspected that saccharin might be just such a factor. Among the many other evidences, the unified hypothesis discussed here had also included a piece of information regarding the “pike” of IBD during 1910s and 1930s before the invention of antibiotics – it is suspected that the wide spread use of saccharin since World War I may have made a contribution. Again, this remains a hypothesis that needs stringent tests.  I kept advocating checking out the possible link between saccharin and IBD just because saccharin consumption met many features of IBD and thus provided a simple explanation for many puzzles of IBD that most of the other suspected agents failed to explain.

The north south gradient seems one of the many features of IBD, as shown in many, despite not all, of studies. Again, the latitude would be just an affecting factor rather than a sufficient important causative factor, as IBD in countries like Russia remained very low. This north-south gradient had used to be explained by the likely more hygiene condition (low bacteria in the environment), but recently the notion of sunshine/vitamin D become more popular. I feel the hygiene theory fits better with more other facts such as the emergence of IBD in modern society along with the improved sanitary condition, the positive link between IBD and antibiotics, etc. 

Thanks wildbill_52280 for sharing the article (Craven M, et al. Inflammation drives dysbiosis and bacterial invasion in murine models of ileal Crohn's disease. PLoS One. 2012;7(7):e41594. http://www.plosone.org/article/info:doi/10.1371/journal.pone.0041594). I read trough this paper and feel it a very interesting study. It is just a little bit of regret that the feces was flushed out (with 10 ml PBS) and missed the important information as how the inflammation changed the microbiota inside the luminal content, which would be the place where the dysbiosis seen in IBD patients originated. Thus this paper actually reflected the change of the bacteria in the collected gut tissue after flush, which may make the dysbiosis seemingly more dramatic. The main bacteria in the gut of mice are Firmicutes (see Figure 2 of this linked paper: http://www.sciencedirect.com/science/article/pii/S0092867406001929). Thus the predominately Firmicutes found in the normal animals would be just reflected this fact. However, according to the study by Johansson ME et al (The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):15064-9. http://www.ncbi.nlm.nih.gov/pubmed/18806221), under normal condition, these gut bacteria are actually separated from the gut tissue through the adhesive mucus layer. Thus the measured bacteria in the normal animals would be just those within the feces or loose mucus that left behind after the flush. In contrast, with the depletion of goblet cells (thus the mucus) after the inflammation, the bacteria in animals treated with Toxoplasma gondii or high dose indomethacin would be mainly those capable of infiltrating into the gut tissue and then readily growing in this totally different new environment. The invasive E. coli would just be such a kind of bacteria. Thus a key question of this dysbiosis would be how the invasive E. coli get into the tissue. I believe the breaking down of the gut barrier would be the critical factor. Here I would like to give a simple example. I think the dysbiosis seen in this study would be somehow like an infection of the skin after a cut. There are many kinds of bacteria on our skin (http://en.wikipedia.org/wiki/Skin_flora). If we take a piece of this normal skin to analyze, the bacteria would reflect this diverse skin flora. But these bacteria are actually on the surface of the skin mixed with the dead skin cells, rather than inside the tissue. After a wound, the skin became easily got infected. The bigger the wound, the more likely and the more severe would be the infection, no matter how the wound was caused, either by cut, scrape, scratch, bite by a dog or cat, or burn. Although there are many kinds of bacteria on the skin, the most common skin infection has been Staphylococcus and Streptococcus that only make up a tiny portion of skin flora. Most of the many kinds of bacteria on skin can never grow and thus make an infection inside the wounds. In fact, many of the skin bacteria have never been able to be cultured by us. The infection would also be affected by the genetic background. Those with immune defects would likely result in more severe infection, more Staphylococcus or Streptococcus being detected in the tissue, thus a more severe inflammation and “dysbiosis”.

Actually, here lies the fundamental difference between my vision of the cause of IBD versus the main stream of thoughts. I suspected that the inflammation in IBD would be by nature just as simple as the infection of the skin after a cut. The skin is protected by a layer of dead skin cells, while the gut is protected mainly by the mucus layer secreted by the goblet cells. The skin could be cut by a knife, while the mucus layer may be broken down by the digestive proteases that became poorly inactivated due to a reduction in gut bacteria. I believe that the infection and inflammation are more determined by the tightness of the barrier rather than the absolute amount of bacteria in the surrounding environment and suspect the inflammation in IBD would be just a natural secondary reaction to the infiltrated bacterial and other harmful luminal components through the damaged gut barrier, while the main stream of thoughts in IBD kept wondering what caused the accumulation of inflammatory cells in the gut, why there is an enhanced immune response in the gut despite of the reduction in gut bacteria along with the improved hygiene, how the immune tolerance was lost, why some bacteria like the invasive E. coli become present in gut tissue, etc, and constructed a lot of sophisticated fascinating hypotheses and theories about that.


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## mf15

Xiaofa Qin: I also have been trying to figure out the spikes in UC starting in the 1910/20/30 era.  It could be anything such as Wession oil/corn oil first sold 1899,Crisco 1911,use of excess nitrate fertilizer,to chlorination of water,cold chain,lack of fermented food in the diet, or many others.  Part of the spike in the USA may even have been due to immigration from Eastern Europe. As far as saccharin goes I never ate any to my knowledge and my UC started in 1980.
We of course know that bacteria play an important role,since some can be put into UC remission from Fecal Transplant.  Lack of vitamin K2 in the diet may play a role since it is necessary for certain bacteria to grow including MAP,but others also need it.
UC might also be a disease of oxidation,where hydrogen peroxide is not quenched fast enough. Another possible is lack of Bromine in the diet,low taurine,the taurine bromine complex is a potent killer of bacteria,as is the TAUCl.
Please keep up the good work.
Old Mike


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## Xiaofa Qin

Thanks Old Mike for the comments. Yes, there are numerous possibilities. Hope one day people can still figure out the fundamental cause(s) and mechanism(s) of IBD.


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## wildbill_52280

Xiaofa Qin said:


> As even the effects of antibiotics and smoking become trivial, there must be some more dominant factors for IBD. I suspected that saccharin might be just such a factor. Among the many other evidences, the unified hypothesis discussed here had also included a piece of information regarding the “spike” of IBD during 1910s and 1930s before the invention of antibiotics – it is suspected that the wide spread use of saccharin since World War I may have made a contribution. Again, this remains a hypothesis that needs stringent tests.  I kept advocating checking out the possible link between saccharin and IBD just because saccharin consumption met many features of IBD and thus provided a simple explanation for many puzzles of IBD that most of the other suspected agents failed to explain.


i am now interested in looking more into the possible role of saccharin as contributing factor in ibd. just from a few minutes of casual research i learned that during world war 1 there was reportedly a shortage in sugar, which may have motivated the popularization of saccharin, the increase of rates during this time period is associated with the reported popularization of saccharin, so i see the possibility may exist.



> The north south gradient seems one of the many features of IBD, as shown in many, despite not all, of studies. Again, the latitude would be just an affecting factor rather than a sufficient important causative factor, as IBD in countries like Russia remained very low. This north-south gradient had used to be explained by the likely more hygiene condition (low bacteria in the environment), but recently the notion of sunshine/vitamin D become more popular. I feel the hygiene theory fits better with more other facts such as the emergence of IBD in modern society along with the improved sanitary condition, the positive link between IBD and antibiotics, etc.


the details on russia are interesting.
im not to sharp on what the hygiene theory exactly is,although i have heard the term, but from recent reading it is proposed that from lack of exposure to pathogens at an early age this may lead to abnormal immune responses later in life. i remember a study done on mice where they exposed them to different antibiotics and examined the intestinal flora changes, in an attempt to simulate similar conditions of dosing for humans, and there were certain population of bacteria that became extinct in the intestine, but the researchers then observed when the mice were reintroduced to the non antibiotic exposed mice, that mice would eat the feces of other mice, and then the flora would renormalize itself to pre-antibiotic conditions. If this actually translates to real life, our fear of human feces seems to be a detriment to our health rather then a benefit, but i suppose our attitudes towards feces cannot be simplified this easily, in an all good or all bad dichotomy.





> Thus a key question of this dysbiosis would be how the invasive E. coli get into the tissue. I believe the breaking down of the gut barrier would be the critical factor. Here I would like to give a simple example. I think the dysbiosis seen in this study would be somehow like an infection of the skin after a cut. There are many kinds of bacteria on our skin (http://en.wikipedia.org/wiki/Skin_flora). If we take a piece of this normal skin to analyze, the bacteria would reflect this diverse skin flora. But these bacteria are actually on the surface of the skin mixed with the dead skin cells, rather than inside the tissue. After a wound, the skin became easily got infected. The bigger the wound, the more likely and the more severe would be the infection, no matter how the wound was caused, either by cut, scrape, scratch, bite by a dog or cat, or burn. Although there are many kinds of bacteria on the skin, the most common skin infection has been Staphylococcus and Streptococcus that only make up a tiny portion of skin flora. Most of the many kinds of bacteria on skin can never grow and thus make an infection inside the wounds. In fact, many of the skin bacteria have never been able to be cultured by us. The infection would also be affected by the genetic background. Those with immune defects would likely result in more severe infection, more Staphylococcus or Streptococcus being detected in the tissue, thus a more severe inflammation and “dysbiosis”.
> 
> Actually, here lies the fundamental difference between my vision of the cause of IBD versus the main stream of thoughts. I suspected that the inflammation in IBD would be by nature just as simple as the infection of the skin after a cut. The skin is protected by a layer of dead skin cells, while the gut is protected mainly by the mucus layer secreted by the goblet cells. The skin could be cut by a knife, while the mucus layer may be broken down by the digestive proteases that became poorly inactivated due to a reduction in gut bacteria. I believe that the infection and inflammation are more determined by the tightness of the barrier rather than the absolute amount of bacteria in the surrounding environment and suspect the inflammation in IBD would be just a natural secondary reaction to the infiltrated bacterial and other harmful luminal components through the damaged gut barrier, while the main stream of thoughts in IBD kept wondering what caused the accumulation of inflammatory cells in the gut, why there is an enhanced immune response in the gut despite of the reduction in gut bacteria along with the improved hygiene, how the immune tolerance was lost, why some bacteria like the invasive E. coli become present in gut tissue, etc, and constructed a lot of sophisticated fascinating hypotheses and theories about that.


interesting idea with the wound analogy, i have not read much about wounds on the skin and how bacteria behave in that environment, so its hard to comment. but if ibd is a wound similar to the skin, how would we explain it not resolving itself ,permanantly all on its own, also like a wound?
we likely could be wounded by material from hard/sharp food components as well, but something so simple doesnt seem to be responsible for ibd, those small wounds likely heal very fast and occur frequently without our awareness.

but the question, how does the bacteria get in the wound is an interesting one, it reminds of the concept of intracellular bacteria, and i wondered, if the gut is covered in a protective layer of bacteria, of what importance is an intracellular pathogen at all? it seems it would have get past all the mucus and good flora, how would a pathogen be able to do that? if genetic defects of intracellular bacterial clearance play a large role, its seems that these genetic defects are another trivial detail in the events that are responsible for crohns, seemingly leading back to the gi flora.
im not suggesting that a pathogen alone is responsible for all the inflammation, as there are experiments the seem to show just food particles may lead to inflammation when coming in contact with a compromised intestinal wall.


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## PlutoCronie

The most obvious possible indicator of environmental stressors having been the instigator of my CD is that prior to having moved to the Upper Midwest, USA, I have  never had any serious digestive issues. Between going from one of the best drinking water sources in the nation, to water which has been problematic, to the lack of sunshine exposure, to possible dangerous insecticides even in organic foods, here, I can take my pick of what caused my CD. Also, emotional stress itself. I agree that artificial sweeteners can not be declared the primary culprit, for the reasons cited by other posters. :rosette2:


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## kiny

Xiaofa Qin said:


> The invasive E. coli would just be such a kind of bacteria. Thus a key question of this dysbiosis would be how the invasive E. coli get into the tissue. I believe the breaking down of the gut barrier would be the critical factor.


Invasive E. Coli is not an innocent bystander or secondary effect for me.

OmpC immunoglobulin tests are positive years before there is any damage to the intestine, the OmpC reaction is a reaction against the E Coli cell wall.

http://www.ncbi.nlm.nih.gov/pubmed/22842615

Serological markers predict inflammatory bowel disease years before the diagnosis.

*"anti-OmpC were most accurate in predicting incident CD"*

Before dysbiosis, before lesions, before they are diagnosed with crohn's disease they have OmpC immunoglobulin markers.


Increased OmpC reactions are associated with LF82 AIEC.

"High osmolarity induced a significant increase in the ability of LF82 bacteria to interact with Intestine-407 cells, which correlates with increased OmpC expression"

http://www.ncbi.nlm.nih.gov/pubmed/17367388


Not only that, LF82 is found in the place of inflammation and not in the place of the skip lesion and they directly stimulate the immune response. They are not innocent secondary bystanders, they are causative.


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## Xiaofa Qin

Thanks wildbill_52280, PlutoCronie and kiny for the comments. Following is my personal thoughts and opinion. 

As for why the inflammation in IBD became persistent rather than resolved quickly as a wound on a skin, there are several reasons I can think of: 1) the inflammation of the gut would also result in the reduction (depletion) of the goblet cells and thus the mucus production, which tends to generate a vicious circle that make it difficult to restore the full function; 2) the persistent existence of high level of digestive proteases (thus the cut). The disturbance of gut bacteria and impaired inactivation of digestive proteases can not only be caused by dietary chemicals and antibiotics but also drugs like sulphasalazine, one of the most important medication used for the treatment of IBD (http://www.ncbi.nlm.nih.gov/pubmed/7801055 ); 3) the consistent existence of large amounts of bacteria in the gut may also facilitate the persistent infection and inflammation. 

I am not saying invasive E. coli is an innocent bystander. As stated in my paper, I believe once getting into the tissue any bacteria would become the enemy of our body, no matter they are the foe or friends before the entry. Actually, I have expected that antibiotics should be more effective than they currently appeared to be, and suspect that the impaired inactivation of digestive proteases may be a factor confounded its real efficacy (Qin X. Impaired inactivation of digestive proteases: a factor that may have confounded the efficacy of antibiotics aimed at reducing the exposure to luminal bacteria and their components. Am J Gastroenterol. 2008 Nov;103(11):2955-6. http://www.ncbi.nlm.nih.gov/pubmed/19032485 ).

However, I indeed believe the appearance of invasive E. coli and other bacteria inside the tissue are largely secondary to the damage of the gut barrier. An increase in intestinal permeability had been observed not only in patients long before their diagnosis, but also in the healthy relatives and more importantly their spouse that may never develop into IBD (Söderholm JD, et al. Different intestinal permeability patterns in relatives and spouses of patients with Crohn's disease: an inherited defect in mucosal defence? Gut. 1999 Jan;44(1):96-100. http://www.ncbi.nlm.nih.gov/pubmed/9862833) and (Breslin NP, et al. Intestinal permeability is increased in a proportion of spouses of patients with Crohn's disease. Am J Gastroenterol. 2001 Oct;96(10):2934-8.  http://www.ncbi.nlm.nih.gov/pubmed/11693329). Their gut may appear very normal without any lesion, but they already have the problem in gut barrier function, which could probably be caused by the thinner in the mucus layer due to increased degradation by the poorly inactivated digestive proteases. As we know, ASCAs (the anti-Saccharomyces cerevisiae mannan antibodies) are actually much common than antibodies against Escherichia coli outer membrane porin C (OmpC) and flagellin CBir1, despite Saccharomyces cerevisiae are not invasive, adhesive, and not that “invincible”. Probably, before the defect in gut barrier is big enough to let large amount of whole bacteria sneak in, some debris of these bacteria, either those habited in gut lumen like E. coli or from the brewed foods like Saccharomyces cerevisiae, had already permeate into the tissue and generated some immune response. Interestingly, although ASCAs are the most commonly seen in Crohn’s patients, people hardly regard Saccharomyces cerevisiae as harmful. In my opinion, Saccharomyces cerevisiae might not be that innocent. The infiltration of the components of Saccharomyces cerevisiae would also result in some immune reaction. I wonder some of the beneficial effect of the so-called special carbohydrate diet may attribute to the exclusion of foods enriched with Saccharomyces cerevisiae such as bread, beers, etc.


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## wildbill_52280

Xiaofa Qin said:


> Interestingly, although ASCAs are the most commonly seen in Crohn’s patients, people hardly regard Saccharomyces cerevisiae as harmful. In my opinion, Saccharomyces cerevisiae might not be that innocent. The infiltration of the components of Saccharomyces cerevisiae would also result in some immune reaction. I wonder some of the beneficial effect of the so-called special carbohydrate diet may attribute to the exclusion of foods enriched with Saccharomyces cerevisiae such as bread, beers, etc.


in my experiance, this IS one way that the SCD diet is helpful, i utilize many of the concepts of the SCD to manage/improve my symptoms, so i never come into contact with this yeast, unless its on purpose, and this is how i determined the specific knowledge of how my body reacts to saccharomyces cerevisiae, when i changed from a source of wheat made without the yeast, to when i was making my own bread, which to rise i needed to add the yeast. going strictly from one wheat source with no yeast, to the bread i made with the yeast i saw more issues, mucus maldigestion etc. that was when i learned how my body reacted to yeast.

currently i consume 700 calories of wheat daily with no major issues.


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## kiny

thanks for the reply Xiaofa Qin, you're one of the few researches who came here to openly discuss their paper, it's appreciated


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## PlutoCronie

Regarding wheat, I do much better without any wheat products, but when I want pasta, I try to stay with the veggie macoroni, made from powered beet and spinach. I would like to get off of wheat enitrely.:soledance:


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## Xiaofa Qin

Thanks wildbill_52280 and PlutoCronie for sharing the experience and info, and thanks kiny for the kind praise. I also appreciate the many people having interest in this hypothesis and shared their opinion. As I described in earlier post, I found the possible link between saccharin and IBD just by chance. My feeling regarding the importance of this link also up and down many times. The dramatic decrease in IBD in Monroe County in later 1970s made me feel saccharin might be an important causative factor, because not much factors may explain such a decrease. Later, reports of the high incidence of IBD in Canada where the use of saccharin had been under strict control since later 1970s made me feel saccharin could not be that important. Then, the recent finding that sucralose, the new sweetener first approved in Canada in 1991, may be linked to IBD thorough a similar mechanism as saccharin made me regain some confidence in the original saccharin and protease hypothesis. Definitely, there would be some other dietary chemicals or other factors also linked to IBD one way or another. Hope one day we can get a clear picture of these risk factors and get rid of IBD from modern society.


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## wildbill_52280

Xiaofa Qin, 

ill have to say i have lost some of my mental sharpness for the past week or so, despite that, i tried to keep up with some of our conversations. having said that, if you recall the study i posted in this thread a few posts back about a new model of crohns disease utilizing t gondii to induce ileal inflammation, the study below is one reason why i like this model, due to the real possibility that t gondii may somehow be involved in IBD, I was just curious if you were aware of this study and of this possibility. I dont imply this study below proves very much about anything except for the facts that are reported/supposedly found. although the researchers propose some of their own interpretations of these facts, i suppose to me, i wonder what finding MAP or t gondii in ibd/crohns could imply about the disease. i read that not only map is an intracellular replicatiing organism but supposedly so is T gondii, and some intracellularlly replicate successfully by manipulating the inflammatory response and enhancing it on purpose, they seem to be able to proliferate in susceptible hosts that may already have some degree of inflammation, but  enhance this inflammation to successfully replicate, via tnf-alpha, and supposedly this is how tnf-alpha inhibitors can induce a remission. to lower tnf-alpha production, this lowers inflammation perhaps, by limiting the growth of some organism. and the relapsing remitting nature of ibd/crohns, may simply be the reintroduction of a new opportunistic organism to start the whole process over again. but this is one of the main processess of ibd, i do not imply that i believe this is some sort of complete model for the disease, just one of the main processes that may occur.

Ann N Y Acad Sci. 2009 Sep;1173:640-8.
Infectious serologies and autoantibodies in inflammatory bowel disease: insinuations at a true pathogenic role.
Lidar M, Langevitz P, Barzilai O, Ram M, Porat-Katz BS, Bizzaro N, Tonutti E, Maieron R, Chowers Y, Bar-Meir S, Shoenfeld Y.
Source
Center for Autoimmune Disease, Rheumatology Unit, Sheba Medical Center, Tel Hashomer, Israel.
Abstract
The aim of this study was to reevaluate the role of infection in inflammatory bowel disease (IBD). Sera from 119 patients with IBD [80 with Crohn's disease (CD); 39 with ulcerative colitis] and 98 healthy controls were assessed using the Bio-Rad BioPlex 2200 for the presence of Toxoplasma gondii, cytomegalovirus, Epstein-Barr virus, Treponema pallidum, and Saccharomyces cerevisiae. Hepatitis B virus, hepatitis C virus (HCV), and anti-Helicobacter pylori antibodies were assessed by ELISA. In addition, sera were tested for a panel of antibodies associated with thrombophilia as well as various autoantibodies. Titers of antibodies toward HCV and T. gondii, and S. cerevisiae were higher in IBD patients than in controls, while the H. pylori autoantibodies were less prevalent among the patient population. Several thrombophilia-associated antibodies were more common in CD patients, and a single patient had a thromboembolic event. Our results show an excess of anti-HCV and anti-T. gondii antibodies among patients with IBD compared to healthy controls. Whereas the former may be the result of immunosuppression from the inflammatory disease itself or from the medications used to treat it, the latter association suggests that T. gondii is involved in the etiopathogenesis of IBD, and especially CD, in humans, as has been shown in the murine model. However, our findings also reiterate the positive association between CD and anti-S. cerevisiae antibodies as well as the negative association with H. pylori infections. These, in turn, lend indirect support to the "hygiene hypothesis" in IBD as well as the newly proposed role of commensal bacteria in the initiation of the disease process.


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## Xiaofa Qin

Thanks wildbill_52280 for the interest in my opinion. Frankly, I have not read much on the possible link between Toxoplasma gondii and IBD. According to Wikipedia (http://en.wikipedia.org/wiki/Toxoplasma_gondii), “the rates of positive sero-prevalence in women at child-bearing age between 1990 and 2000 were 58% in Central European countries, 51–72% in several Latin-American countries and 54–77% in West African countries”, with only 11–28% in cold climate areas such as Scandinavian countries where IBD is very high. I do not know how Toxoplasma gondii infection would fit into the temporal and geographical features of IBD. As we know, it has been well documented that TNF-alpha is a pivotal factor for inflammation. The anti-TNF-alpha antibody had also been effectively used for other inflammatory diseases like rheumatoid arthritis, ankylosing spondylitis and psoriasis. The notion that efficacy of this kind of drugs primarily attributed to their inhibition on Toxoplasma gondii or other bacteria inside the macrophages seems a very odd interpretation. It also seems not true that macrophage can be easily disabled by bacteria like Toxoplasma gondii and let the bacteria hide deep inside them to launch a vehement attack to the host. In contrast, monocytes/macrophages are the valiant fighters that played a vital role in defending the body against Toxoplasma gondii. Some defects in these cells will result in extensive intestinal necrosis and rapid death of the animal. Here are several research articles by Dunay IR et al on this: 

1. Gr1(+) inflammatory monocytes are required for mucosal resistance to the pathogen Toxoplasma gondii. Immunity. 2008 Aug 15;29(2):306-17. http://www.ncbi.nlm.nih.gov/pubmed/18691912

2. Inflammatory monocytes but not neutrophils are necessary to control infection with Toxoplasma gondii in mice. Infect Immun. 2010 Apr;78(4):1564-70.  http://www.ncbi.nlm.nih.gov/pubmed/20145099

3. Monocytes mediate mucosal immunity to Toxoplasma gondii. Curr Opin Immunol. 2010 Aug;22(4):461-6.     http://www.ncbi.nlm.nih.gov/pubmed/20537517


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## wildbill_52280

Xiaofa Qin said:


> Thanks wildbill_52280 for the interest in my opinion. Frankly, I have not read much on the possible link between Toxoplasma gondii and IBD. According to Wikipedia (http://en.wikipedia.org/wiki/Toxoplasma_gondii), “the rates of positive sero-prevalence in women at child-bearing age between 1990 and 2000 were 58% in Central European countries, 51–72% in several Latin-American countries and 54–77% in West African countries”, with only 11–28% in cold climate areas such as Scandinavian countries where IBD is very high. I do not know how Toxoplasma gondii infection would fit into the temporal and geographical features of IBD. As we know, it has been well documented that TNF-alpha is a pivotal factor for inflammation. The anti-TNF-alpha antibody had also been effectively used for other inflammatory diseases like rheumatoid arthritis, ankylosing spondylitis and psoriasis. The notion that efficacy of this kind of drugs primarily attributed to their inhibition on Toxoplasma gondii or other bacteria inside the macrophages seems a very odd interpretation. It also seems not true that macrophage can be easily disabled by bacteria like Toxoplasma gondii and let the bacteria hide deep inside them to launch a vehement attack to the host. In contrast, monocytes/macrophages are the valiant fighters that played a vital role in defending the body against Toxoplasma gondii. Some defects in these cells will result in extensive intestinal necrosis and rapid death of the animal. Here are several research articles by Dunay IR et al on this:
> 
> 1. Gr1(+) inflammatory monocytes are required for mucosal resistance to the pathogen Toxoplasma gondii. Immunity. 2008 Aug 15;29(2):306-17. http://www.ncbi.nlm.nih.gov/pubmed/18691912
> 
> 2. Inflammatory monocytes but not neutrophils are necessary to control infection with Toxoplasma gondii in mice. Infect Immun. 2010 Apr;78(4):1564-70.  http://www.ncbi.nlm.nih.gov/pubmed/20145099
> 
> 3. Monocytes mediate mucosal immunity to Toxoplasma gondii. Curr Opin Immunol. 2010 Aug;22(4):461-6.     http://www.ncbi.nlm.nih.gov/pubmed/20537517


Xiaofa Qin,

Here is a study(abstract) that talks about these concepts, but it is regarding Adherent Invasive E. Coli, and not t. gondii or MAP. I now realize it sounds strange for a bacteria/organism to be living within a cell that is supposed to be destroying it, but this is what is being reported, i certainly do not make up the rules of the universe.

http://www.nature.com/labinvest/journal/v92/n3/full/labinvest2011156a.html


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## mf15

Can't forget Zonulin and what interferes with it.
Controls tight junctions in the small intestine,too much and you get celiac disease,wheat and others
cause the problem. Seems to act only in small intestine,but knockout mice get inflammed colons

from upregulated zonulin in the small intestine.

Here is some info read down. 

One thing to remember is if your small intestine is leaking then all kinds of stuff can pass through.

Old Mike

http://physrev.physiology.org/content/91/1/151.long



http://gut.bmj.com/content/58/1/41.full.pdf+html



Seems I might want to make my sourdough with vsl3.

Regular old sourdough may also do it,makes me wonder before bakers yeast breads were naturally fermented,the sourdough starter contains both bacteria and yeast.
Seems to tie in with your observations Wild Bill.
There seems a possibility that the use of bakers yeast in breads,as
opposed to sour fermentation might be part of the problem.Early 20th centruy.

"Commercially produced yeast first appeared in the United States in the 1860s. Charles and Maximillian Fleischmann, immigrants from Austria-Hungary, with the financial backing of James Gaff, patented and sold standardized cakes of compressed yeast...produced in their factory in Cincinati. By the early twentieth century, factory-produced yeast was widely available. Cookbook recipes began specifying that commercial yeast be added directly to bread dough in sufficient quantities to leaven it in less than two hours. Bread changed in texture, becoming lighter and softer, and its flavor turned blander..."
---Oxford Encylopedia of Food and Drink in America, Andrew F. Smith [Oxford University Press:New York], Volume 2, 2004 (p. 652

http://thefooddoc.blogspot.com/2007/02/probiotic-vsl3-breaks-down-toxic.html


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## PlutoCronie

Looking back to when my CD symptoms first began, I realize it was relatively soon after I had finished a course of antibiotics for upper respiratory illness. In fact, for about 5 years preceding the CD symptoms I had been on all kinds of antibiotics, as well as anti-inflammation Rx. I am not concluding that this alone is what caused my CD because there had been other substantial stressors present at the time, but I would not rule out that my digestive system had been seriously compromised by these Rx antibiotics/anti-inflammatory Rx.


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## Xiaofa Qin

Thanks wildbill_52280, Old Mike and PlutoCronie for sharing the info.

I read through the article provided by wildbill_52280 (http://www.nature.com/labinvest/journal/v92/n3/full/labinvest2011156a.html). I found it a very interesting study with fascinating conclusions. However, I was confused with the statement that “the amount of TNF-α released by infected macrophages is correlated with the load of intramacrophagic AIEC bacteria and their intracellular replication. TNF-α secretion was not related to the number of bacteria entering host cells because when the number of bacteria internalized in macrophage was decreased by blocking lipid raft-dependent and clathrin-coated pits-dependent endocytosis, the amount of TNF-α secreted by infected macrophages was not modified”. As per my understanding, the load of AIEC bacteria inside the cell and thus the amount of bacteria available for intracellular replication would be ultimately determined by how much bacteria got entered the cell. The similar TNF-α production with or without the blockage of bacteria entering would suggest the TNF-α production seemed more likely depending on interaction of the bacteria and macrophages at the surface rather than inside the macrophages. This notion would also be more in accordance with the current knowledge that TNF-α production can be greatly stimulated by lipopolysaccharides (LPS) (http://en.wikipedia.org/wiki/Tumor_necrosis_factor-alpha), the major component of the outer membrane of Gram-negative bacteria like E. coli (http://en.wikipedia.org/wiki/Lipopolysaccharide), through its binding with Toll-like receptor 4  (TLR 4) (http://en.wikipedia.org/wiki/TLR_4) on the surface of cells like macrophages and the activation of the related pathways. It does not need the bacteria to be alive and replicating. The LPS could be the purified agents or those from the debris of the dead bacteria. In fact, the feces contains large amounts of LPS with more than 1 mg/g. LPS is also called as endotoxin, and a dose of 1 µg/kg injected into the blood would be enough to induce shock in humans. The amount of endotoxin possessed by gut bacteria can cause the death of the host thousands times over. Thus, it is the effectiveness of gut barrier rather than the amount of these harmful components in the lumen determined the safety of the body. 

Thanks Old Mike for sharing the info on Zonulin. It is indeed a very interesting molecule and it further demonstrated the importance of gut barrier in some diseases.

Thanks PlutoCronie for sharing the antibiotics story. According to the multiple large-scale studies as listed in the previous post (#66 in this thread), the series use of antibiotics could be definitely one of the most important causative factors. You see, the cause of IBD might not be so complex that is beyond our ability to trace.


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## wildbill_52280

Xiaofa Qin said:


> , I was confused with the statement that “the amount of TNF-α released by infected macrophages is correlated with the load of intramacrophagic AIEC bacteria and their intracellular replication. TNF-α secretion was not related to the number of bacteria entering host cells because when the number of bacteria internalized in macrophage was decreased by blocking lipid raft-dependent and clathrin-coated pits-dependent endocytosis, the amount of TNF-α secreted by infected macrophages was not modified”. As per my understanding, the load of AIEC bacteria inside the cell and thus the amount of bacteria available for intracellular replication would be ultimately determined by how much bacteria got entered the cell. The similar TNF-α production with or without the blockage of bacteria entering would suggest the TNF-α production seemed more likely depending on interaction of the bacteria and macrophages at the surface rather than inside the macrophages. This notion would also be more in accordance with the current knowledge that TNF-α production can be greatly stimulated by lipopolysaccharides (LPS) (http://en.wikipedia.org/wiki/Tumor_necrosis_factor-alpha), the major component of the outer membrane of Gram-negative bacteria like E. coli (http://en.wikipedia.org/wiki/Lipopolysaccharide), through its binding with Toll-like receptor 4  (TLR 4) (http://en.wikipedia.org/wiki/TLR_4) on the surface of cells like macrophages and the activation of the related pathways. It does not need the bacteria to be alive and replicating. The LPS could be the purified agents or those from the debris of the dead bacteria.


You have a good point, it might not be entirely clear whether intracellular AIEC are manipulating the macrophage from the inside to produce more tnf-alpha, since tnf-alpha did not seem to reduce when the bacteria were blocked from entering the cell. I believe that is what i said before and was a mistake, the authors dont seem to be claiming that aeic is manipulating the production of tnf from the inside of the cell. but the important part is that they #1 AEIC can live inside the macrophage #2 somehow use tnf-alpha production to replicate intracellularly #3 replication can be influenced by reducing production or enhancing supply of tnf-a. 

"Interestingly, dose-dependent increases in the number of intracellular AIEC LF82 bacteria were observed when infected macrophages were stimulated with exogenous TNF-α, and neutralization of TNF-α secreted by AIEC-infected macrophages using anti-TNF-α antibodies induced a significant decrease in the number of intramacrophagic bacteria. These results indicate that AIEC bacteria use TNF-α as a Trojan horse to ensure their intracellular replication because replication of AIEC bacteria within macrophages induces the release of TNF-α, which in turn increases the intramacrophagic replication of AIEC. Neutralizing TNF-α secreted by infected macrophages may represent an effective strategy to control AIEC intracellular replication."

so i think at least in the abstract they are saying, despite the observation that suggests the amount of tnf-alpha secretion is not dependant upon the bacteria entering the cell, when they supply more tnf-a, the bacteria replication enhances, and when they inhibit tnf-a, they decrease, therefore their intracellular replication is somehow dependant upon tnf-a secretion, but not upon entering the cell.


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## Xiaofa Qin

Thanks wildbill_52280 for sharing the analysis and thoughts regarding this paper ((http://www.nature.com/labinvest/journal/v92/n3/full/labinvest2011156a.html). Actually, this paper you provided has made me read more on adherent and invasive Escherichia coli (AIEC) and related research in recent couple of days. These are really good studies. However, frankly, it also raised me a big concern regarding the crucial methodology used in these studies that I have hesitated to discuss in the previous post. As described in the paper (here is a link to a freely assessable article with detailed description on the methods:  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC546957/pdf/0770-04.pdf), the replication of AIEC was determined by the Gentamicin protection assay (http://en.wikipedia.org/wiki/Gentamicin_protection_assay). Basically, the bacteria and the macrophages were first incubated together for a period of time, and then the bacteria outside the macrophages were washed away. After that the cells were incubated for long periods with a media containing 20 µg/ml gentamicin to prevent the growth of bacteria outside the cell. At the wikepedia site regarding this assay, it clearly stated that “As for bacteria, only species susceptible to gentamicin can be assayed.” However, I am afraid of that 20 µg/ml of gentamicin used in these studies might be not enough ot have really completely prevented the growth of some resistant strains of AIEC. According to a study by  Mawer SL and Greenwood D. (Specific and non-specific resistance to aminoglycosides in Escherichia coli. J Clin Pathol. 1978 Jan;31(1):12-5. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC476711/pdf/jclinpath00171-0020.pdf), the minimum antibacterial concentration (MAC) of gentamicin for a regular Escherichia coli K12 (the type of E. coli used in many AIEC studies as the non-adherent and non-invasive control) strain J53 was 4 µg/ml. However, the MAC increased to 32 µg/ml once the bacteria got the R factor RS28. Interestingly, presence of the antibiotics just caused a delay in the rapid growth phase. Once the lag phase was overcome, the bacteria replicated just as fast as in the absence of antibiotics. Study had shown that multidrug (including gentamicin) resistance is common in Escherichia coli from patients with Crohn's disease (Dogan B, et al. Multidrug resistance is common in Escherichia coli associated with ileal Crohn's disease. Inflamm Bowel Dis. 2012 Apr 16. [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/22508665). Some researchers on AIEC study indeed found some strains of E. coli were resistant to gentamicin and they changed the antibiotics to 100 µg/ml kanamycin instead (Martinez-Medina M, et al. Adherent-invasive Escherichia coli phenotype displayed by intestinal pathogenic E. coli strains from cats, dogs, and swine. Appl Environ Microbiol. 2011 Aug 15;77(16):5813-7. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165260/pdf/zam5813.pdf). If the guess that 20 µg/ml gentamicin would be not enough to completely inhibit the growth of bacteria would be true, all the puzzles regarding the results could be easily explained: the TNF-α production is not related to the number of bacteria got entered into the cell, as this production would actually just determined by the amount of bacteria survived and became flourished in the culture media; the exogenous TNF-α will increase while the anti TNF-α antibody would decrease the amount of bacteria inside the cells as the phagocytosis of the macrophage could be greatly enhanced by TNF-α (Hess DJ, et al. Escherichia coli and TNF-alpha modulate macrophage phagocytosis of Candida glabrata. J Surg Res. 2009 Aug;155(2):217-24. http://www.ncbi.nlm.nih.gov/pubmed/19482303). TNF-α has not served as an accomplice that helped the replication of bacteria inside the cell; rather TNF-α served as a signal that mobilized the macrophages to fight. I believe this scenario would make more sense. Thus the more bacteria grown in the media, the more production of the TNF-α, the more active of the macrophages, and the more bacteria could be found inside the cell. If this would be true, at least some of the bacteria we saw inside the cells would be virtually actively captured by the macrophages to destroy. This guess does not mean to dispute the conclusion that AIEC can get inside and replicate within the macrophages and other cells just like some pathogenic strains of Shigella, Salmonella, Mycobacterium, and Listeria did, but it does suggest we may have overestimated the capability of AIEC living inside the cell and underestimate the capacity of macrophages against the bacteria. With the limited info available, this is just a guess. However, these studies should indeed have included the measurements of the amount of bacteria and the level of LPS in the media and demonstrated as the results in the paper, as this is a critical issue in this kind of studies.


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## kiny

Xiaofa Qin said:


> TNF-α has not served as an accomplice that helped the replication of bacteria inside the cell; rather TNF-α served as a signal that mobilized the macrophages to fight. I believe this scenario would make more sense. Thus the more bacteria grown in the media, the more production of the TNF-α, the more active of the macrophages, and the more bacteria could be found inside the cell. If this would be true, at least some of the bacteria we saw inside the cells would be virtually actively captured by the macrophages to destroy.


Thank you. In 2006 someone wrote this, and I have remembered it for 6 years because of the last line in their interpretation. 

http://www.ncbi.nlm.nih.gov/pubmed/16503465

"Local inflammatory reaction to inoculation with E coli was attenuated, as quantified by changes in bloodflow (ileal disease 50%, n=6, p=0.01; colonic disease 77%, n=6, p=0.0003). This response was mediated by nitric oxide in controls, was increased by sildenafil in patients, and was not related to CARD15 genotype.

INTERPRETATION:

In Crohn's disease, a constitutionally weak immune response predisposes to accumulation of intestinal contents that breach the mucosal barrier of the bowel wall, resulting in granuloma formation and chronic inflammation. Polymorphisms in CARD15 do not underlie this phenotype, but incapacitate the NOD2 pathway that can compensate for impairment of innate inflammation. Current treatment of secondary chronic inflammation might exaggerate the underlying lesion and promote chronic disease."


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## Xiaofa Qin

Thanks kiny for sharing this interesting article.


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## Xiaofa Qin

I started a discussion last month at several IBD-related LinkedIn groups including the European Crohn's and Colitis Organisation ECCO, CCFA (Crohn's & Colitis Foundation of America), IBD - Crohn's disease & Ulcerative Colitis – CCF, and IBD Research Foundation, entitled  “We should put a little bit more effort to find out the cause of inflammatory bowel disease”, in hoping to generate some in-depth discussion on the cause and etiology of IBD among the IBD professionals. It turned out only Mr. Michael Seres, a patient with Crohn’s disease, and two other non-IBD professionals gave some response. I had also submitted an abstract to the 2012 Advances in Inflammatory Bowel Diseases: Crohn's and Colitis Foundation's Clinical and Research Conference and the 8th European Crohn's and Colitis Organisation Congress of Inflammatory Bowel Diseases 2013, in hoping to have the chance exchanging information, evidences and views with IBD professions regarding the etiology of IBD, but the abstract was rejected by both of the conferences. I believe everybody knew a big problem in IBD is we still do not know its cause. However, it seems hardly any people who had the resource really had the urge and interest in finding out the cause of the remarkable increase in IBD.


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## Moe.

One day they'll get it and suffer. 
It there kids will get it and they'll suffer.

Round n round it goes. 
The cause the reason?
No one knows!

I can complain and whinge and whine
Or I can sit here and make a nursery rhyme. 

Sorry off topic.


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## CrohnGlobal

Your research is very interesting Xiaofa Qin, thank you! We allow you to translate it into French?


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## CrohnGlobal

We also note and believe there is not a single cause but different causes; several environmental interactions (mainly chemicals including junkfood, etc. sweeteners, additives, excipients, pharmaceutical, etc. overuse of antibiotics. stress, acidity, acidosis = inflammation) these environmental interactions inducing an imbalance in the homeostasis of the body, causing an imbalance within the microbiota, microbiota where there have not a single bacterium as seen, but interactions between several bacteria, yeasts, fungi, or ... as primary reason an imbalance of the microbiota .... The first main food microorganisms is sugars then nutrients... This is clearly a cascade of causes which leads to symptoms of IBD, different gradients, different sub-groups based on micro-organisms involved ... diagnoses (often late) based mainly on the findings of lesions, lesions are a result. Search for a single cause, we think it's like trying to make a snowman in summer heatwave...


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## wildbill_52280

Xiaofa Qin said:


> I started a discussion last month at several IBD-related LinkedIn groups including the European Crohn's and Colitis Organisation ECCO, CCFA (Crohn's & Colitis Foundation of America), IBD - Crohn's disease & Ulcerative Colitis – CCF, and IBD Research Foundation, entitled  “We should put a little bit more effort to find out the cause of inflammatory bowel disease”, in hoping to generate some in-depth discussion on the cause and etiology of IBD among the IBD professionals. It turned out only Mr. Michael Seres, a patient with Crohn’s disease, and two other non-IBD professionals gave some response. I had also submitted an abstract to the 2012 Advances in Inflammatory Bowel Diseases: Crohn's and Colitis Foundation's Clinical and Research Conference and the 8th European Crohn's and Colitis Organisation Congress of Inflammatory Bowel Diseases 2013, in hoping to have the chance exchanging information, evidences and views with IBD professions regarding the etiology of IBD, but the abstract was rejected by both of the conferences. I believe everybody knew a big problem in IBD is we still do not know its cause. However, it seems hardly any people who had the resource really had the urge and interest in finding out the cause of the remarkable increase in IBD.


Thanks for keeping us updated.

I also wonder why it has taken so long for any interest in fecal transplants for IBD when Thomas J Borody had his experiments published in i think 2003, that was ten years ago, and it is probably the most promising treatment out there. ill admit, we only just finished the microbiome project and know little about the intestinal flora and what can be considered healthy to choose the correct donor, that was one thing that may have been holding some people back from interest. but i have found 3 studys last year that will be completed this year, so thats promising.


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## Moe.

Now that mention it. I do not understand and if someone could clarify.
Fecal transplant work on crohn colitis and ulcerative colitis but not on crohn ileitis. 

Is there a give. Reason. In one case from borodys article 6 patients had no sign of uc for 13 years. That's a record for remission if it even is that.
Anyone's thoughts. I can link article if required.


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## Mark in Seattle

Thanks for your efforts Xiaofa to push researchers forward in identifying the cause(s) of IBD.


Personally, the thing that intrigues me the most is how IBD can be triggered so suddenly when people change their environment.  My disease course was mild for 10 years, and then within 5 months of moving to Seattle I found myself having gut problems which quickly resulted in the inability to get off my bed one morning, and the need for emergency surgery to remove diseased small bowel.  I recall corresponding with randynoguts, who mainly posts on a different website and has his own blog or at least he used to.  He told me that he was hit with CD when he went (I think) to Europe for his service in the armed forces.  And then when I read about immigrants who come from countries with a low IBD incidence, and then these folks get IBD when they come here, there's clearly something(s) insidious and no doubt ubiquitous in our environment.  When folks move geographically, they pick up new habits - dietary habits are what strike me first.  In addition to suspecting sweeteners, additives, and so forth, perhaps an additional causative factor could be new bacteria introduced...bacteria which an individual's lumen is not used to or does not recognize.  Randynoguts for example may have been exposed to many European bacterial strains that he normally did not come in contact with in America.  And given that the food chain now sources food from farther and more disparate corners of the globe, perhaps the importation of foreign bacteria strains may be a trigger as well?  I had thought of this because I get bad pain in my Crohn's spot if I eat even a single bite of the Kerrygold cheese which comes from Ireland; I tried it because the Kerrygold cows are grass-fed.  Maybe some Irish bacteria that disagrees with my American (dysbiotic) microbiota?


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## Mark in Seattle

CrohnGlobal, would you mind clarifying who you are or who you represent?  I understand you're French, and you remarked earlier about Nestle.  You've used the term "we" in your post, which makes me wonder whether you represent a group of some sort.


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## kiny

Xiaofa Qin said:


> European Crohn's and Colitis Organisation Congress of Inflammatory Bowel Diseases 2013, in hoping to have the chance exchanging information, evidences and views with IBD professions regarding the etiology of IBD, but the abstract was rejected by both of the conferences.


People have tried to find out who or what ECCO is, no one can tell us what it is. Not the first time someone on this forum thought it was an official organisation. It is not approved by the European union, it is fully funded by pharmaceutical companies, no one seems to have a clue who approved this organisation or why it exists. 

It has a lot of money and people have asked what this organisation actually is and which government in Europe has greenlighted it, no one can give an answer.

They use a lot of words that make it seem like this organisation is state funded or, that it's an official European organisation, that is it government approved or has links to the EU, it has none of those things, it seems to be fully privately funded.

Things like this baffle me, there is a very powerful organisation in Europe, with unlimited funds, that is talking for the people with crohn's disease, but not one government or person with IBD knows what this thing is.


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## Xiaofa Qin

Thanks all for the response and support. 

I felt there are some big problems in IBD research, likely even beyond. The great efforts are not dedicated to solve the problem based on dynamic reasoning, but rather great resource has been spent to fulfill some miraculous fantasy generated by those capable.  

As we know, IBD emerged and dramatically increased only for about a century, clearly suggesting factors in the environment have played the dominant role. However, tremendous efforts and resources have kept spending on genes and things within the body, with very little effort on finding out the causative factors in the environment. The identification of more and more risk genes for IBD in the last decade had served as examples of great achievements with many publications in the most prestigious journals [1]. However, the shadows behind these glories were well hidden that made hardly any people in the world even aware of their existence.   

As we know, the association between NOD2 (also called IBD1 or CARD15) and Crohn's disease (CD) was first published in 2001 in Nature [2, 3]. It has been celebrated as a big breaking through in IBD. At beginning, it had estimated that NOD2 itself could explain 15 – 20 % of the genetic risk of CD [4, 5]. Later, 32 CD risk loci were identified in 2008 through genome wide association study (GWAS) but the new calculation suggested the 32 loci all together may just explain about 20% of the genetic risk, in which only about 1 – 2 % can be attributed to NOD2, despite that NOD2 has been the gene with the biggest contribution [6]. As it was esteemed that the genes may contribute 50% of the overall risk, the 32 loci all together may explain about 10% of the overall risk of CD [6]. A recent study that included more than 75,000 cases and controls has revealed 163 risk loci for IBD, including 140 loci for CD and 133 loci for ulcerative colitis (UC) [7]. However,  they can only explain 13.6% of the overall disease risk for CD and 7.5% for UC [7]. Although more GWAS study would find more loci associated “significantly” with IBD, the association would be even weaker and the effect would be even smaller [8].

More importantly, those crucial genes identified by these studies seemed actually not that critical. The ultimate judgment of the importance of a gene would be to see how the disease develop after getting rid of the gene, which can be done by knockout a certain gene in the mice. In fact, shortly after finding NOD2 being an important risk gene for CD, NOD2 deficient mice were successfully generated, with the paper published in 2003 [9]. Surprisingly, it was found that mice lacking NOD2 were indistinguishable from controls and showed no signs of intestinal pathology. No NOD2 deficient mice had any obvious histological abnormalities in the colon, cecum, duodenum, or ileum. In 2006, GWAS  revealed autophagy-related gene 16-like 1 (ATG16L1) being a susceptible gene for CD [10] and it generated a new round of enthusiasm on the critical role of autophagy, microbial sensing, endoplasmic reticulum stress in IBD [11]. However, no spontaneous (naturally occurred) colitis was developed in knockout mice deficient of ATG16L1 [12]. In 2006, another GWAS also identified IL23R as a risk gene for IBD gene[13] and the IL-23/IL17 axis has been expected a crucial pathway in IBD and became another area of extensive research [14]. However, it was found that IL-17 knockout mice developed more severe colitis caused by dextran sulfate sodium [15]. In fact, the recent randomized, double-blind placebo-controlled trial regarding the effect of the anti-IL-17A monoclonal antibody on CD has to be discontinued prematurely due to the higher rates of adverse events [16]. So, should the results of these genetic research in IBD serve as an example of great success or rather the great difficulty to make an accurate assessment of the true nature of a disease that was caused by factors in the environmental by just analysis of the genes and other factors within the body without knowing its cause?  

Interestingly, this dubious hypothesis discussed here, based on evidence mainly collected from the literature during spare time and only accepted for publication by some low rank journals with the publishing fee paid by the author himself, was actually in good accordance with the results of the knockout mice. This hypothesis suggested a weakening of the mucus layer rather than the immune system or the gene being the root mechanism for IBD, which is strongly supported by the fact that mice either deficient of MUC2 [17], the main component of the mucus layer of the gut, or aberrant assembly of MUC2 [18], or just some defect in the mucin linked glycans [19] developed spontaneous colitis. However, MUC2 had not included in the 200 IBD associated genes identified by the multiple GWAS studies [7, 20]. You see, this vulgar hypothesis not only provided a simple explanation for many peculiar epidemiological features of IBD, it had also made a much better prediction on the importance of molecules associated with IBD than the many elegant genetic studies. Again, are they just coincidences? 

As Einstein said: “time has a sieve” that will eventually make a selection among those splendid and important and those insipid and bad. There have been a lot facts gathered in the last decade and definitely more will emerge that would eventually show us which path would more likely leads to a final solution for IBD such as the understanding of its cause and root mechanism and ultimately its cure and prevention. 

REFERENCES

1.	Visscher, P.M., et al., Five years of GWAS discovery. Am J Hum Genet, 2012. 90(1): p. 7-24. http://www.ncbi.nlm.nih.gov/pubmed/22243964

2.	Hugot, J.P., et al., Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature, 2001. 411(6837): p. 599-603. http://www.ncbi.nlm.nih.gov/pubmed/11385576

3.	Ogura, Y., et al., A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature, 2001. 411(6837): p. 603-6. http://www.ncbi.nlm.nih.gov/pubmed/11385577

4.	Marx, J., Biomedicine. Puzzling out the pains in the gut. Science, 2007. 315(5808): p. 33-5. http://www.ncbi.nlm.nih.gov/pubmed/17204619

5.	Torok, H.P., et al., Alterations of the CARD15/NOD2 gene and the impact on management and treatment of Crohn's disease patients. Dig Dis, 2003. 21(4): p. 339-45. http://www.ncbi.nlm.nih.gov/pubmed/14752224

6.	Barrett, J.C., et al., Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet, 2008. 40(8): p. 955-62. http://www.ncbi.nlm.nih.gov/pubmed/18587394

7.	Jostins, L., et al., Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature, 2012. 491(7422): p. 119-24. http://www.ncbi.nlm.nih.gov/pubmed/23128233

8.	Park, J.H., et al., Estimation of effect size distribution from genome-wide association studies and implications for future discoveries. Nat Genet, 2010. 42(7): p. 570-5. http://www.ncbi.nlm.nih.gov/pubmed/20562874

9.	Pauleau, A.L. and P.J. Murray, Role of nod2 in the response of macrophages to toll-like receptor agonists. Mol Cell Biol, 2003. 23(21): p. 7531-9. http://www.ncbi.nlm.nih.gov/pubmed/14560001

10.	Hampe, J., et al., A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet, 2007. 39(2): p. 207-11. http://www.ncbi.nlm.nih.gov/pubmed/17200669

11.	Kaser, A. and R.S. Blumberg, Autophagy, microbial sensing, endoplasmic reticulum stress, and epithelial function in inflammatory bowel disease. Gastroenterology, 2011. 140(6): p. 1738-47. http://www.ncbi.nlm.nih.gov/pubmed/21530740

12.	Saitoh, T., et al., Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature, 2008. 456(7219): p. 264-8. http://www.ncbi.nlm.nih.gov/pubmed/18849965

13.	Duerr, R.H., et al., A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science, 2006. 314(5804): p. 1461-3. http://www.ncbi.nlm.nih.gov/pubmed/17068223

14.	Sarra, M., et al., IL-23/IL-17 axis in IBD. Inflamm Bowel Dis, 2010. 16(10): p. 1808-13. http://www.ncbi.nlm.nih.gov/pubmed/20222127

15.	Yang, X.O., et al., Regulation of inflammatory responses by IL-17F. J Exp Med, 2008. 205(5): p. 1063-75. http://www.ncbi.nlm.nih.gov/pubmed/18411338

16.	Hueber, W., et al., Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut, 2012. 61(12): p. 1693-1700. http://www.ncbi.nlm.nih.gov/pubmed/22595313

17.	Van der Sluis, M., et al., Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology, 2006. 131(1): p. 117-29. http://www.ncbi.nlm.nih.gov/pubmed/16831596

18.	Heazlewood, C.K., et al., Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis. PLoS Med, 2008. 5(3): p. e54. http://www.ncbi.nlm.nih.gov/pubmed/18318598

19.	Fu, J., et al., Loss of intestinal core 1-derived O-glycans causes spontaneous colitis in mice. J Clin Invest, 2011. 121(4): p. 1657-66. http://www.ncbi.nlm.nih.gov/pubmed/21383503

20.	Elding, H., et al., Refinement in Localization and Identification of Gene Regions Associated with Crohn Disease. Am J Hum Genet, 2012. http://www.ncbi.nlm.nih.gov/pubmed/23246291


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## wildbill_52280

Xiaofa Qin, 

this might interest you.


ISME J. 2012 Dec 13. doi: 10.1038/ismej.2012.158. [Epub ahead of print]
*Butyrate-producing Clostridium cluster XIVa species specifically colonize mucins in an in vitro gut model.*
Van den Abbeele P, Belzer C, Goossens M, Kleerebezem M, De Vos WM, Thas O, De Weirdt R, Kerckhof FM, Van de Wiele T.
Source
Laboratory of Microbial Ecology and Technology (LabMET), Ghent University, Ghent, Belgium.
Abstract
The human gut is colonized by a complex microbiota with multiple benefits. Although the surface-attached, mucosal microbiota has a unique composition and potential to influence human health, it remains difficult to study in vivo. Therefore, we performed an in-depth microbial characterization (human intestinal tract chip (HITChip)) of a recently developed dynamic in vitro gut model, which simulates both luminal and mucosal gut microbes (mucosal-simulator of human intestinal microbial ecosystem (M-SHIME)). Inter-individual differences among human subjects were confirmed and microbial patterns unique for each individual were preserved in vitro. Furthermore, in correspondence with in vivo studies, Bacteroidetes and Proteobacteria were enriched in the luminal content while Firmicutes rather colonized the mucin layer, with Clostridium cluster XIVa accounting for almost 60% of the mucin-adhered microbiota. Of the many acetate and/or lactate-converting butyrate producers within this cluster, Roseburia intestinalis and Eubacterium rectale most specifically colonized mucins. These 16S rRNA gene-based results were confirmed at a functional level as butyryl-CoA:acetate-CoA transferase gene sequences belonged to different species in the luminal as opposed to the mucin-adhered microbiota, with Roseburia species governing the mucosal butyrate production. Correspondingly, the simulated mucosal environment induced a shift from acetate towards butyrate. As not only inter-individual differences were preserved but also because compared with conventional models, washout of relevant mucin-adhered microbes was avoided, simulating the mucosal gut microbiota represents a breakthrough in modeling and mechanistically studying the human intestinal microbiome in health and disease. Finally, as mucosal butyrate producers produce butyrate close to the epithelium, they may enhance butyrate bioavailability, which could be useful in treating diseases, such as inflammatory bowel disease.



Biochem Biophys Res Commun. 2007 May 11;356(3):599-603. Epub 2007 Mar 12.
*The short chain fatty acid, butyrate, stimulates MUC2 mucin production in the human colon cancer cell line, LS174T*.
Hatayama H, Iwashita J, Kuwajima A, Abe T.
Source
Molecular Biology Laboratory, Faculty of Bioresource Sciences, Akita Prefectural University, Akita 010-0195, Japan.
Abstract
The short fatty acid, butyrate, which is produced by intestinal anaerobic bacteria in the colon, has inhibitory activity on histone deacetylases (HDACs). Treatment of the human colon cancer cell line, LS174T, with 1-2 mM sodium butyrate stimulated MUC2 mucin production, as determined by histological PAS staining of carbohydrate chains of mucin, and confirmed at the protein and mRNA levels by immunoblotting with anti-MUC2 antibody and real-time RT-PCR, respectively. Increases in acetylated histone H3 in the LS174T cells treated with butyrate suggest inhibition of HDACs in these cells. Butyrate-stimulated MUC2 production in the LS174T cells was inhibited by the MEK inhibitor, U0126, implicating the involvement of extracellular signal-regulated kinase (ERK) cascades in this process. Proliferation of the LS174T cells was inhibited by butyrate treatment. Although apoptotic nuclear DNA fragmentation could not be detected, cell-cycle arrest at the G0/G1 phase in the butyrate-treated cells was demonstrated by flow cytometry. Thus butyrate, an HDAC inhibitor, inhibits proliferation of LS174T cells but stimulates MUC2 production in individual cells.


the butyrate producers are typically found to be either poorly represented or non existent in studies of the intestinal microbiota in crohns patients.
if there was ever some ingested substance with the power to disrupt these relationships,perhaps they may be responsible for colitis, chronic or otherwise. my intuition is telling me these are important, but i cant articulte all the precise reasons. maybe this is not so important, but you can decide.

edit- i think a word to define the relationship that might exist between the butyrate producing bacteria and its ability to upregulate muc 2 , which then makes it an even more hospitable environment, is an example of cyclical causation. maybe its better/more accurate to think of the bacteria as part of us, rather then, on top of us, outside of us.


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## kiny

Thanks for posting Xiaofa ~

I made a thread here about the lack of NOD2 mutation in the Asian CD population: http://www.crohnsforum.com/showthread.php?t=45141

My worry is that so much money is going to genetic studies and studies trying to unravel the human microbiome, they are super expensive studies that have no direct practical implications.

The genetic link in crohn's disease seems rather weak. The microbiome studies might lead to discoveries but decades will go by before they unravel the millions of commensals and how they relate to crohn's disease, to this day these studies have not helped a single person with crohn's disease and billions have been spent on them.

There are almost no etiology studies that go out there and look at the environment and behavioral patters of people who get crohn's disease, whatever is triggering this disease is out there, it's not in the genes nor in the microflora I think. Genetic susceptibility to crohn's disease in exact twins with genetic markers is sub 50 percent.

Even the murine model that is used where colitis in KO mice is induced with DDS has very little to do with crohn's disease, the inflammation in crohn's disease is transmural and deep and is nothing like colitis mice at all.


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## Mark in Seattle

I've been trying to eat black beans, which are supposed to be a substrate for butyrate-producting bacteria.  I may be mistaken, but I've gotten the impression that butyrate is more of an angle relating to UC than CD.


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## wildbill_52280

Mark in Seattle said:


> I've been trying to eat black beans, which are supposed to be a substrate for butyrate-producting bacteria.  I may be mistaken, but I've gotten the impression that butyrate is more of an angle relating to UC than CD.



i have read that rye produces quite a bit of more butyrate then most other grains. 

i have also just recently read that the majority of butyrate producers make butyrate from  acetate and lactate made from other microorganisms, this is know as crossfeeding.


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## Xiaofa Qin

Thanks wildbill_52280 for sharing those interesting articles and thanks kiny for sharing the thoughts. I have totally the same opinion as kiny described in the post (#100). As for research on the microbiome, I also felt the assessment of each gut bacteria by means like genetic analysis seemed not a feasible approach. Actually, I had written a small paper on this with what I thought several years ago (Qin X. With the great complexity unveiling, can we still decipher the interaction between gut flora and the host in inflammatory bowel disease to find out the mechanism and cause? How? Inflamm Bowel Dis. 2008 Nov;14(11):1607-8). 

I found the notion proposed by Mark in Seattle in the previous post (#95) that the development of IBD in the immigrants might be caused by exposure to some new bacteria an interesting new explanation. But as for the remarkable increase of IBD in the developed countries along with the improved hygiene, it seems more likely to be caused by change of the bacteria ecosystem within the body rather than in the environment.


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## wildbill_52280

kiny said:


> Thanks for posting Xiaofa ~
> 
> I made a thread here about the lack of NOD2 mutation in the Asian CD population: http://www.crohnsforum.com/showthread.php?t=45141
> 
> My worry is that so much money is going to genetic studies and studies trying to unravel the human microbiome, they are super expensive studies that have no direct practical implications.


the genetic studies, i do not think they are a waste. if it had become the case that we identified a true genetic basis for the disease, better treatments would have followed. and it would have been considered a great success. But perhaps you mean in consideration of properly interpreting the existing evidence to determine what strategies might yielded quicker results, then perhaps a more complete investigation to identify some environmental toxin exposure woudl have found a common cause then i suppose it could have turned out differently.
So now we know where the answers arent, so we have eliminated some possibilitys and are certain the answer lies somewhere else, and that is progress, but not success. 

Does finding the cause tell us how to treat currently existing cases?
probably not, but it would sure help avoid creating new ones. different strategies will provide different benefits for different people then it seems.



> The genetic link in crohn's disease seems rather weak. The microbiome studies might lead to discoveries but decades will go by before they unravel the millions of commensals and how they relate to crohn's disease, to this day these studies have not helped a single person with crohn's disease and billions have been spent on them.


i agree decades could go before any benefits are realized. 
but i would have to say that knowledge about how these bacteria work has already benefited me. if i didnt know how bacteria fermented short chain fatty acids from certain dietary fibers mainly soluble fibers, which i agree are very basic facts and maybe not a direct result from the microbiome project, it has given me insight as to the benefits of a high fiber diet can do for crohns disease, i eat about 1250 of my 1800-1900 calories a day from oats, wheat and beans, i attribute these whole grains to staying relatively complication free for 4 years now, never been in the hospital and never had any surgery, in fact, medication free as well, but that is not solely due to a high fiber diet, but lack of complication i believe are due to high fiber diet the more i know about these bacteria, the better. i acknowledge this only my testimony and not a scientific demonstration, therefore perhaps it is purely chance i have done so well doing the things i do and does not apply to other crohns cases, and the consumptions of whole grains has nothing to do with my success. in all sense of rationality, its likely got something to do with it though.

im not sure about the billions for the microbiome project, its more in the 300-400 millions i believe. While The united states defense budget is in the *600 billion*'s, hows that for comparison of a waste.

http://www.foxbusiness.com/technolo...-us-defense-spending-edges-toward-completion/




> There are almost no etiology studies that go out there and look at the environment and behavioral patters of people who get crohn's disease, whatever is triggering this disease is out there, it's not in the genes nor in the microflora I think. Genetic susceptibility to crohn's disease in exact twins with genetic markers is sub 50 percent.
> 
> Even the murine model that is used where colitis in KO mice is induced with DDS has very little to do with crohn's disease, the inflammation in crohn's disease is transmural and deep and is nothing like colitis mice at all.


yes,i agree disease models suck. but thats where the microbiome project would come into use i believe, the better defined the disease becomes, the better models we have for it. EDIT- consider this, learning how to eliminate distinct bacterial species so that the flora are identical to the pathological changes in ibd, and seeing if that would be sufficient to create a form of chronic colitis, we cant do that without knowing alot more about the bacteria.


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## Xiaofa Qin

Thanks wildbill_52280 for sharing the thoughts. I think everybody understand and appreciate the great achievements in genetic research since last century. Actually, I had communicated with Dr. James D. Watson, the co-discoverer of the double helix structure of DNA more than two decades ago when I was a postgraduate in China with discussions on his DNA model. 

I do not agree with the notion that it is a trivial thing to find out the cause of disease. We may develop some new biologics that is more effective (probably also more expensive) than the anti-TNF-alpha antibodies currently under use. However, without knowing the cause, I am afraid this kind of treatment may still just suppress the symptoms rather than get rid of the root of the disease and thus achieve the true cure that is without the need for incessant medication. The effective prevention would also depend on finding out its cause. Without knowing the cause, many things such as the effect of short chain fatty acids would only remain the guess.  

I think no body against genetic research, but rather recommended a balanced effort. We should realize that everything has its limitations. For a dramatically increasing disease like IBD, in my opinion, finding out its cause in the environment would be just as important as finding out the risk genes, as demonstrated by the many facts described in the previous post (#98). I felt IBD professionals should put more effort finding out its cause. Is that normal a new theory with a unified hypothesis on the cause and mechanism as well as the relationship between ulcerative colitis and Crohn’s disease is fervently discussed here, but not by IBD professionals or at the IBD conferences?


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## Mark in Seattle

Xiaofa Qin said:


> But as for the remarkable increase of IBD in the developed countries along with the improved hygiene, it seems more likely to be caused by change of the bacteria ecosystem within the body rather than in the environment.


Xiaofa,

Do you believe that we are "losing our microbes", perhaps with each successive generation?  You're arguing in favor of the hygiene hypothesis, essentially then, right?


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## Xiaofa Qin

I think we would have to face the fact that IBD emerged and dramatically increased in modern society along with the improved hygiene. However, the “hygiene hypothesis” and I have a totally different explanation for this increase. The “hygiene hypothesis” proposed that the increases in the autoimmune and allergic diseases in modern society are due to the reduced exposure of the immune system to microbes and thus the lack of education at the early stage, resulting in an "aberrant" immune reaction later. Tremendous efforts (like current research in IBD) have been taking to find out what is going wrong. In contrast, I suspected that the increased immune response as seen in these diseases is just a natural reaction to the increased infiltration of bacterial and dietary components in the gut due to the damage of the gut barrier by factors such as the poorly inactivated digestive proteases, as the result of reduction in gut bacteria (Qin X. What caused the increase of autoimmune and allergic diseases: a decreased or an increased exposure to luminal microbial components? World J Gastroenterol. 2007 Feb 28;13(8):1306-7. http://www.wjgnet.com/1007-9327/full/v13/i8/1306.htm).


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## mf15

Xiaofa Qin is of course on the right track I believe.  But we must look prior to about 1920 or so for the cause of IBD.  MAP,CMV,chlorination,freezing food,canning or a million other things that happened, perhaps something that was protective and we are no longer eating. Even the worm theory.  This is all pre antibiotic,pre food additives,many industrial chemicals,Wesson oil 1899,Crisco 1922,who knows. Since I have never eaten saccharin I have to discount that in my case of UC.  Chlorination may have started around 1911 but have to do more research on that.
Here is a good IBD history in case you missed it.
We also know that fecal transplant can put some UC people into remission.
It is also interesting to note that prior to about 1920 or so there was little cancer and MI was unheard of,is there a connection.
Old Mike
http://onlinelibrary.wiley.com/doi/10.1002/ibd.3780010103/pdf

Here is what people ate during the civil war,quite interesting. Meat and grease.

http://scholar.lib.vt.edu/theses/available/etd-05262005-122146/unrestricted/CivilWarDiet.pdf


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## Xiaofa Qin

Thanks Old Mike for sharing the thoughts. Indeed, million things may be changed along with the modernization; each of them may be correlated somehow with the changes in IBD at certain time point and thus presented as a possible connection. So what should we do? Give up or continue? Can we still find those truly responsible? How? 

I felt the current situation of IBD is somehow like a long unsolved complicated case of crime. There are many tips and suspects; the crime remains unsolved usually not because there are too many but rather none of the suspects really match the evidence of the crime scene. The same would be true for IBD with the many suspected agents as described in the introduction section of the paper and vividly discussed in this forum.  

Luckily, the crime can still usually be solved, no mater it is committed by just an individual or groups of gangs, but this can usually only be achieved by finding out the specific match, like DNA rather than some general evidences like the type of blood. 

We are talking about the recent increase of IBD. In fact, the pattern of increases is quite different even among the development countries. As shown in Figure 4 in the paper discussed here, it showed a dramatic increase of IBD in Brisbane, Australia during middle 1990s but started decrease since early 2000s. However, in Oslo, Norway, a dramatic increase of IBD started since early 2000s. This would be the kind of specific evidence needed to track down the criminal. These increases seems quite unlikely to be explained by many currently suspected factors such as the genes, smoking, sunshine, nutrients, refrigeration, or even a further improvement in the sanitary condition, but I found many of these increases occurred shortly after the approval of sucralose in the different countries like Canada, Australia, New Zealand, Norway, and US. It also predicted the remarkable increase of IBD in the children in Ireland that were reported shortly after the publication of this paper (http://adc.bmj.com/content/97/7/590/reply#archdischild_el_15773). 

As for saccharin, I also had wondered if and to what extent it would be linked to IBD. This had driven me looking into the history of IBD and saccharin. It is a painstaking process that had taken me more than a decade so far. As shown in the paper, it covered from the earliest of reports of clustered cases of ulcerative colitis in London since 1888 and the earliest marketing and favorite use of the German made saccharin in UK since 1887, through the multiple reports of the leveling off or decrease of IBD during 1980s in many countries and the finding of carcinogenicity and attempted ban on saccharin in later 1970s, with included a brief description of wide spread use of saccharin along with World War I. The more evidence I found, there seems more to support rather against the possible link. Despite that, without a vigorous test, they are just the suspects like the many others. We can definitely bring in more suspects. However, I think we should remove dietary chemicals like saccharin and sucralose from the list of suspects for IBD only after we have found out those with a more perfect and specific match and pinned down as the real criminal.


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## Xiaofa Qin

I was informed by the Journal of Crohn’s and Colitis that the manuscript I submitted entitled "Have genome-wide association studies or knockout mice more reflected the true nature of inflammatory bowel disease?", a topic that was discussed in the previous post (#98), has been accepted for publication.  It seems a little bit odd that such a crucial issue is brought up by a spare time IBD researcher rather the many those engaged in genetic research of IBD. Hope it may generate some in-depth and insightful thinking that may lead to a more efficient approach toward the solution of IBD.


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## kiny

Congrats, I hope it gets published soon. I wish it was not elsevier because that limits the exposure of the paper to people with crohn's disease, but I realise it's not that easy to publish papers.

Regarding NOD2, I was surprised to read how many "normal" people run around in Europe with NOD2 mutations without any issues. Within that group of people with NOD2 mutations there is only a fraction of people who have crohn's disease.

I was more surprised that in countries within Europe where NOD2 mutation is highest per capita, they do not have more crohn's disease. On an individual basis a person has higher chance of catching crohn's disease with a NOD2 mutation, but as a populous this isn't reflected.

Geographic location easily trumps genetic predisposition when you take into account the most common loci like NOD2 and ATG16L1.


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## Mark in Seattle

Congrats Xiaofa.  You're a diligent guy.  I appreciate your efforts, and hope this publication benefits you, as well as the IBD community.


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## Xiaofa Qin

Thanks kiny and Mark for the kind congrats. 

As for NOD2, many studies have well documented that NOD2 has been the risk gene having the strongest association with Crohn’s disease. Despite that, as pointed by kiny, NOD2 not only failed to show an association with CD in Asian as demonstrated in the multiple studies listed in thread by kiny (http://www.crohnsforum.com/showthread.php?t=45141), it also failed to show a correlation in the western countries, as demonstrated in the study by Hugot JP, et al (Prevalence of CARD15/NOD2 mutations in Caucasian healthy people. Am J Gastroenterol. 2007 Jun;102(6):1259-67. http://www.ncbi.nlm.nih.gov/pubmed/17319929), which had included countries from three continents: Europe (France, Germany, UK, Italy, Belgium, Finland), Northern America (US and Canada) and Australia. Again, this would suggest some factors to be identified make the effect of even the strongest gene minimal, just like its minimization on the effect of smoking and antibiotics as discussed in the previous posts. We need finding out these factors responsible.


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## Xiaofa Qin

Just found this study presented at the 2007 Digestive Disease Week (DDW) by Dr. Steven B. Ingle and colleagues at Mayo Clinic, entitled “Increasing Incidence and Prevalence of Inflammatory Bowel Disease in Olmsted County, Minnesota, During 2001-2004” (Gastroenterology 132 (4 suppl): A19-A20, 2007). 

Here are the results:


> The age- and sex-adjusted incidence rate for ulcerative colitis in 2001-04 was 12.5 cases per 100,000 person-years (95% confidence interval [CI], 9.4-15.6), compared to an incidence of 10.7 per 100,000 (8.7 - 12.6) in 1991-2000. The age- and sex-adjusted incidence rate for Crohn's disease in 2001-04 was 12.9 per 100,000 (9.7-16.1), compared to an incidence of 9.0 per 100,000 (7.2 - 10.8) in 1991-2000.


Here is the conclusion:


> Although incidence rates of Crohn's disease and ulcerative colitis had remained relatively stable in Olmsted County between 1970 and 2000, the incidence of both conditions appears to have increased somewhat over the past 5 years.


As we know, Mayo Clinical had been the place with the earliest reports and treatments of clustered IBD (ulcerative colitis) in the United States, with the reporting of 117 cases of UC treated there during 1915 to 1918 (http://books.google.com/books?hl=en&lr=&id=pIkfAAAAIAAJ&pg=PA180#v=onepage&q&f=false) and 693 cases between 1923-1928 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2183453/). Mayo Clinic has been one of the best-known leading hospitals in the world for the treatment of IBD. So their diagnosis would be highly reliable. 

Frankly, this result is not surprising to me. Again, this increase occurred shortly after the approval of sucralose in the US in 1998, just as predicted in this paper. Without a more vigorous test, we cannot say this is definitely caused by sucralose. But a sudden increase again after 30 years stable would be a valuable clue that may help finding out the right suspects and nailing down the real culprit .


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## wildbill_52280

here is some additional support

J Toxicol Environ Health A. 2008;71(21):1415-29. doi: 10.1080/15287390802328630.
*Splenda alters gut microflora and increases intestinal p-glycoprotein and cytochrome p-450 in male rats.*
Abou-Donia MB, El-Masry EM, Abdel-Rahman AA, McLendon RE, Schiffman SS.
Source
Department of Pharmacology, Duke University Medical Center, Durham, North Carolina 27708, USA. donia@duke.edu

Abstract

Splenda is comprised of the high-potency artificial sweetener sucralose (1.1%) and the fillers maltodextrin and glucose. Splenda was administered by oral gavage at 100, 300, 500, or 1000 mg/kg to male Sprague-Dawley rats for 12-wk, during which fecal samples were collected weekly for bacterial analysis and measurement of fecal pH. After 12-wk, half of the animals from each treatment group were sacrificed to determine the intestinal expression of the membrane efflux transporter P-glycoprotein (P-gp) and the cytochrome P-450 (CYP) metabolism system by Western blot. The remaining animals were allowed to recover for an additional 12-wk, and further assessments of fecal microflora, fecal pH, and expression of P-gp and CYP were determined. At the end of the 12-wk treatment period, the numbers of total anaerobes, bifidobacteria, lactobacilli, Bacteroides, clostridia, and total aerobic bacteria were significantly decreased; however, there was no significant treatment effect on enterobacteria. Splenda also increased fecal pH and enhanced the expression of P-gp by 2.43-fold, CYP3A4 by 2.51-fold, and CYP2D1 by 3.49-fold. Following the 12-wk recovery period, only the total anaerobes and bifidobacteria remained significantly depressed, whereas pH values, P-gp, and CYP3A4 and CYP2D1 remained elevated. These changes occurred at Splenda dosages that contained sucralose at 1.1-11 mg/kg (the US FDA Acceptable Daily Intake for sucralose is 5 mg/kg). Evidence indicates that a 12-wk administration of Splenda exerted numerous adverse effects, including (1) reduction in beneficial fecal microflora, (2) increased fecal pH, and (3) enhanced expression levels of P-gp, CYP3A4, and CYP2D1, which are known to limit the bioavailability of orally administered drugs.


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## Xiaofa Qin

Thanks wildbill for the post. This is just the article I first saw in early last year that led me to suspect the possible link between sucralose and IBD (as described in the previous post #28 in this thread).


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## Xiaofa Qin

In my paper (Fig. 4, http://www.ncbi.nlm.nih.gov/pubmed/22553395) and previous posts (#109 and #114 in this thread) I showed some evidence regarding the remarkable increases of IBD shortly after the approval of sucralose in western countries like Canada, the US, Australia, New Zealand, Norway and Ireland. As we know, the heavy use of sucralose in the western countries has made it an increasing environmental concern for its effects on the aquatic organisms in the rivers and lakes (Tollefsen KE, Nizzetto L, Huggett DB. Presence, fate and effects of the intense sweetener sucralose in the aquatic environment. Sci Total Environ. 2012 Nov 1;438:510-6). In fact, sucralose was also approved by Asia countries like Japan, South Korea, and China around 2000. Surprisingly, a recent study found that sucralose has become the top contaminants among the many pharmaceuticals, household chemicals, and pesticides even in China. It would be interesting to know how this has linked to the recent increase of IBD in these countries.

Here is the article (http://www.ncbi.nlm.nih.gov/pubmed/22845779)



> Environ Sci Technol. 2012 Aug 21;46(16):8680-8. Epub 2012 Jul 30.
> 
> Organic micropollutants in rivers downstream of the megacity Beijing: sources and mass fluxes in a large-scale wastewater irrigation system.
> 
> Heeb F, Singer H, Pernet-Coudrier B, Qi W, Liu H, Longrée P, Müller B, Berg M.
> 
> 
> Abstract
> 
> The Haihe River System (HRS) drains the Chinese megacities Beijing and Tianjin, forming a large-scale irrigation system severely impacted by wastewater-borne pollution. The origin, temporal magnitudes, and annual mass fluxes of a wide range of pharmaceuticals, household chemicals, and pesticides were investigated in the HRS, which drains 70% of the wastewater discharged by 20 million people living in Beijing. Based on Chinese consumption statistics and our initial screening for 268 micropollutants using high-resolution mass spectrometry, 62 compounds were examined in space and time (2009-2010). The median concentrations ranged from 3 ng/L for metolachlor to 1100 ng/L for benzotriazole and sucralose. Concentrations of carbendazim, clarithromycin, diclofenac, and diuron exceed levels of ecotoxicological concern. Mass-flux analyses revealed that pharmaceuticals (5930 kg/year) and most household chemicals (5660 kg/year) originated from urban wastewaters, while the corrosion inhibitor benzotriazole entered the rivers through other pathways. Total pesticide residues amounted to 1550 kg/year. Per capita loads of pharmaceuticals in wastewater were lower than those in Europe, but are expected to increase in the near future. As 95% of the river water is diverted to irrigate agricultural soil, the loads of polar organic micropollutants transported with the water might pose a serious threat to food safety and groundwater quality.


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## Xiaofa Qin

Some people wondered why the inflammation of ulcerative colitis (UC) is limited in the mucosa, while in Crohn’s disease (CD) the inflammation is transmural that can be seen in all layers of the gut. This would be a very basic and yet important question but hardly any textbooks or articles on IBD gave an explanation. In fact, the paper discussed here has actually contained a very simple explanation. I have depicted the overall hypotheses for the cause and mechanism of IBD including both UC and CD in Figure 5 in the paper (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3332284/figure/F5/ ). It suggested that both UC and CD are caused by weakening of gut barrier. However, the large amounts of bacteria in the colon made the recruitment of neutrophils and formation of crypt abscess as the main manifestation of UC, while the infiltration of antigens and dietary particles in the small and large intestine has mainly caused the recruitment of macrophages that led to the formation of granulomas as the main manifestations in CD. With a life span of just a couple of days, neutrophils are the fast reaction army of the body and will be dispatched to the very front and fight vigorously there with the enemy until die. However, macrophages are the cleaner and order keeper inside the body, with a basic duty to cleared up debris like the dead cells. They have a life span of months and can fulfill their job by eating the debris, digesting them, moving around, and picking up again for quite a while. However, things like dietary particles and multiple species of bacteria such as Mycobacterium, Salmonella, Listeria and Shigella are beyond the ability of macrophage to digest. But the macrophages may have carried and moved them quite inside before they caused the cells to die. Then the particles or bacteria will be released and picked up by other macrophages and moved further inside. Eventually, the macrophages will realize that they just cannot get rid of the intruder and call in more macrophages and lymphocytes to quarantine them. This is how the granulomas were formed (http://en.wikipedia.org/wiki/Granuloma ). In my opinion, UC is more like the bacterial pneumonia ( http://en.wikipedia.org/wiki/Bacterial_pneumonia ) with the involvement of mainly neutriphils and the inflammation mainly inside the alveoli, while CD is more like some pneumoconiosis (caused by inhalation of dusts) such as silicosis or berylliosis ( http://radiographics.rsna.org/content/26/1/59.full) or tuberculosis of the lung with the involvement of mainly macrophages and manifested as glanulomatous inflammation, destruction of the tissue, extensive proliferation of fibroblasts and formation of fibrosis, etc. I think this may also attributed to the genetic, epidemiological and other aspects of the similarities and discrepancies between UC and CD as discussed in the paper (in page 1716-1717, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3332284/pdf/WJG-18-1708.pdf)


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## mf15

Xiaofa: I am still up in the air about your theory, I read that B glucuronidase
is related to increased colon cancer risk. Can you explain the problem as to inhibition reducing cancer and inhibition causing IBD.
http://www.homeopathicdoctor.ca/GSD...sessments/CDSA_2/CDSA2_SuppGd/CDSA2_BetaG.pdf

There are of course many more references to the above.

It seems a way to increase b glucuronidase is to increase colon pH, I have also read an abstract where in UC there is reduced bicarbonate levels in the colon.

There also seem to be antibodies directed against b glucuronidase in IBD.
http://www.ncbi.nlm.nih.gov/pubmed/8115839

veggies inhibit.
http://jn.nutrition.org/content/132/6/1341.full

meat increases
http://www.ncbi.nlm.nih.gov/pubmed/22364273

bilirubin colon cancer confounding info
http://lib.bioinfo.pl/paper:15382069

Another possible reason besides saccharin,might be the increased consumption of certain vegetables in modern times,of course this would not explain why all vegetarians dont get IBD,or there is not high incidence in countries like India.
XIAOFA: I am starting to believe that you are on the right track.
The question is how do increase uncongugated bilirubin in the colon,protein and pH.  We also know that UC usually starts in the rectum/distal colon,where the mucus layer is thinest.
What about bacterial protease,as opposed to digestive protease causing the
problem.
http://www.mendeley.com/catalog/bacterial-proteases-ibd-ibs/#page-1

bacteria dds mucus layer penetration,could the initial mechanism for UC
be this simple,bacteria breach the mucus layer,resulting in UC.
However the cause of the reduced mucus layer thickness/viscoity
remains to be determined.
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0012238

from this is seems some protease is necessary to expand the mucus volume
please comment
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3035142/

sialic acid degrading enzymes from bacteria
http://www-05.all-portland.net/cs/074/0071/0740071.pdf
Thanks
Old Mike


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## Xiaofa Qin

Thanks Old Mike for sharing the thoughts and info. The core of my hypothesis is that the primary cause of IBD is the over digestion of gut barrier by the poorly inactivated proteases (most may from the pancreas, but some may be from the bacteria) due to the inhibition of gut bacteria by dietary chemicals along with the improved hygiene. This is initiated by the finding that digestive proteases are inactivated by unconjugated but not conjugated bilirubin. It is well known that bilirubin secreted from the bile into the lumen is mainly in the conjugated form, which can be deconjugated by beta-glucuronidase enriched in gut bacteria. Yes, this enzyme may have also involved in the formation of some carcinogens. This would just reflect the many complicated interactions of the body and environment, just like smoking is protective for ulcerative colitis but a risk for many other diseases including Crohn’s disease. Yes, many patients with ulcerative colitis have the antineutrophil antibodies (ANCA), with a large portion being the antibody against beta-glucuronidase. As this enzyme has been one of the main enzymes released by neutrophils at the site of inflammation, I personally suspected that this enzyme may be beneficial and its inactivation by the antibodies may have somehow contributed to the pathogenesis of the disease. 

Multiple studies showed that meat increased while vegetables and fruits decreased the risk of IBD, although the effects are minimal. But we have to face these fact. A simple explanation in line with this unified hypothesis discussed here would be that meat will increase while vegetarians would reduce the production of digestive proteases. Here is a paper showing these effects: Bozkurt T, Haberich FJ. Physiological studies of exocrine pancreatic secretion in conscious rats. 7th communication: short-term kinetics of adaptation of digestive enzymes to different nutritional stimuli. Z Gastroenterol. 1985;23(5):257-66 (http://www.ncbi.nlm.nih.gov/pubmed/2417422 ). In fact, bilirubin is a metabolite of heme (the molecule makes the blood red) through a two-step reaction: first heme is metabolized to biliverdin, then biliverdin is further metabolized to bilirubin. Biliverdin is water-soluble and also regarded as less toxic, which has been excreted from the body as the end metabolite of heme in many herbivores like rabbit, nutrias (rodents that eat water plants), sloths, some birds and tilapia, regardless of the stage of evolution. I suspected that the inactivation of digestive proteases by deconjugated bilirubin would be the possible evolutionary driving force for bilirubin or biliverdin predominance in animals (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2095646/ ). I personally believe the relationship among gut bacteria, proteases, mucus, gut barrier and IBD would be worthy of further study and we can only get a more clear picture and definite answers through these studies.


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## mf15

Thank you Dr.
It would seem to me that a diet void of artificial sweeteners,and low in vegetables that contain glucarate,might have an effect on UC.

I might suspect the wide spread inclusion in the diet of certain vegetables and fruits that may not have been generally in the western diet prior to about
1920 may have a great effect on UC,if your theory is correct.

This on cancer,seems to be somewhat dangerous to eat too much meat/fat.
http://cancerres.aacrjournals.org/content/37/10/3533.full.pdf

Inhibition of tryptase release from colon mast cells
http://www.wjgnet.com/1007-9327/10/332.pdf




Old Mike


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## Xiaofa Qin

Again, the core of my hypothesis is the impaired inactivation of digestive proteases rather than the activity of beta-glucuronidase. I do not find evidence suggesting vegetables and fruits may have caused such a problem. In fact, I suspect that human IBD would be more like the IBD in pet dogs and cats, carnivores in nature, rather than Johne’s disease in cattle (Qin X. What is human inflammatory bowel disease (IBD) more like: Johne's disease in cattle or IBD in dogs and cats? Inflamm Bowel Dis. 2008 Jan;14(1):138). As you mentioned in the previous post, people in the developing countries would be more likely consuming less meat and protein rather than vegetables and grains (carbohydrates). To find out the real main culprit for IBD, we not only need to look out more suspects but also rule out those unlikely. I kept recommending checking out the possible link between saccharin and sucralose just because it seems fits more specific features of IBD. As saccharin and sucralose are very stable and most of them just excreted without further metabolism, their possible link with IBD may be easily checking out by just conducting an analysis of their existence in the feces or urine of patients versus controls. However, it seems nobody with the resource to do this has the interest in this hypothesis. Shortly after the publication of this paper, I have emailed a copy to each member of the Epidemiology and Natural History Task Force of the International Organization of Inflammatory Bowel Disease (IOIBD) advocating them checking out this possibility. They just published a paper regarding the geographical variability and environmental risk factors in inflammatory bowel disease (Ng SC, et al. Geographical variability and environmental risk factors in inflammatory bowel disease. Gut. 2013 Apr;62(4):630-49. http://www.ncbi.nlm.nih.gov/pubmed/23335431), without bothering to mention the existence of such a hypothesis. Recently, I submitted a manuscript as a letter to the editor entitled “Dietary chemicals like saccharin and sucralose should not be omitted by epidemiologists as the possible important causative factors for inflammatory bowel disease”, but was rejected. Here I would like to share it with the people in this forum.

************************************************
I read with interest the meta-review by the Epidemiology and Natural History Task Force of the International Organization of Inflammatory Bowel Disease (IOIBD) regarding the geographical variability and environmental risk factors in inflammatory bowel disease (IBD).1 It discussed the variation of IBD between and within countries and over time as well as a wide range of possible environmental risk factors such as smoking, appendectomy, diets, antibiotics, westernisation of lifestyle and industrialization, urbanisation of societies, socioeconomic status, hygiene, pollution, etc. However, it remained failed to provide a coherent scenario regarding the cause and mechanism of IBD, as even those factors with the strongest associations such as smoking and appendectomy hardly fit the temporal and geographical features of IBD. 

More than a decade ago, a series of findings led me to suspect that dietary chemicals like saccharin may have played an important causative role in IBD, through its inhibition on gut bacteria and the resultant impairment of the possible bilirubin deconjugation-mediated inactivation of digestive proteases and the digestive damage of the protective mucus layer and the underlying gut tissue.2 It provided a simple explanation for many puzzles of IBD such as its emergence around the beginning of last century, its dramatic increase since 1950s, and the leveling off or even decrease of IBD around 1980s as seen in multiple studies. Recently, I further found that sucralose, the new generation of artificial sweetener, might also be linked to IBD through a similar mechanism as saccharin, which provided further explanation for the peculiar increase of IBD not only in the developing but also in the developed countries that can hardly be explained by any of the many currently suspected environmental factors. A further pursuit on this eventually led me coming up with a unified hypothesis on the etiology of IBD, including the cause and mechanism of IBD, as well as the relationship between ulcerative colitis and Crohn’s diseases.3 In my opinion, although many factors may involve in the eventual occurrence of IBD in an individual, a few factors like saccharin and sucralose may have played a predominant role. This may somehow like the relationship between smoking and lung cancer: although lung cancer can also be caused by multiple other factors like radon and air pollution and only a few smokers developed into lung cancer that may dependent on the genetic, dietary, and many other factors, still smoking alone is responsible for over 90% of lung cancers even in the countries with strict restrictions on smoking like the US. 

For more than a decade, I have contact multiple national and international agencies and IBD professionals advocating checking out the possible link between dietary chemicals like saccharin and sucralose and IBD, but failed to raise any action. In fact, I have also emailed my paper to all those list on the Epidemiology and Natural History Task Force of IOIBD, but they seems to be very skeptical about it and even do not bother to mention the existence of such a hypothesis in the paper. We have spent multiple millions in analyzing as many as 75,000 IBD patients and controls in the multiple genome wide association studies (GWAS) which, in my opinion, generated more puzzles rather than answers for IBD.4 Both saccharin and sucralose are very stable and just passed through the body and has become the main environmental contaminants not only in the western countries but also in countries like China. I advocate here again for those with the resource for IBD research to do an analysis of urines or feces to check out this possible link between dietary chemicals like saccharin and sucralose and IBD.  

REFERENCES
1. Ng SC, Bernstein CN, Vatn MH, et al. Geographical variability and environmental risk factors in inflammatory bowel disease. Gut 2013.
2. Qin XF. Impaired inactivation of digestive proteases by deconjugated bilirubin: the possible mechanism for inflammatory bowel disease. Med Hypotheses 2002;59:159-63.
3. Qin X. Etiology of inflammatory bowel disease: a unified hypothesis. World J Gastroenterol 2012;18:1708-22.
4. Qin X. Have genome-wide association studies or knockout mice more reflected the true nature of inflammatory bowel disease? J Crohns Colitis.  Published Online First: 8 February 2013. DOI: 10.1016/j.crohns.2013.01.013.


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## mf15

Xiaofa Qin: Not sure if you referenced this article,you may fine it of interest.
Old Mike

Enzymic Activity in Ileostomy Effluent with reference to the Characteristic Flora
J. G. H. Ruseler-Van-Embden, J. Kool, L. M. C. Van Lieshout, M. P. Hazenberg


http://www.microbecolhealthdis.net/index.php/mehd/article/view/7668/9008


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## Xiaofa Qin

Hi, Old Mike:

This is really a very interesting article. Thank you so much for sharing it. 

This study suggests that, under normal condition, the small intestine has high protease activity but low glycosidase activity, while the large intestine has high glycosidase activity but low protease activity. A detrimental degradation of mucus only occurred when large amounts of these two enzymes become coexist, such as increased bacterial glycosidase in the small intestine or impaired inactivation of digestive proteases in the large intestine as caused by dysbiosis. This would be just the scenario as depict in Figure 6 of the paper discussed here (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3332284/figure/F6/ ) as well as a paper I published early (Qin X. Synergic effect of bacterial glycosidases and digestive proteases on mucus degradation and the reduced risk of inflammatory bowel disease-like gut damage in both germ-free and poor hygiene conditions. Inflamm Bowel Dis. 2008;14(1):145-6).

Thanks again for sharing the paper. 

Xiaofa


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## mf15

Xiaofa: Being from China you may have great insight into this mechanism.
For now I am assuming your theory is correct,but how do we fix the problem.
One way it seems is Soy,I did this 10-11 years ago with Tempeh and some soy milk but perhaps not enough. I now find that tempeh dose not contain BBI. I probably did this after I found your first paper.
From the second paper it seems soy milk from the USA contains BBI which seems to be heat stable but not fermentation stable.
As you may know soy contains both Kuntz and Bowman-Birk Inhibitor (BBI )protease inhibitors and perhaps others. From this paper you can see the effect.
I am currently just re-starting my literature searching on this subject after 15 years.
I will add links to this thread as I find them.
What bothers me from the paper is that the BBI did not lower non colitic rat/mouse fecal protease levels,but lowered TNBS induced increase in protease levels. This may be good/not sure.
It is also interesting that I see an uptick in the literature from say about 
2011 on protease and IBS and especially IBS-D.
Also need to determine the mg of BBI which equates to, inhibit 1 mg of bovine pancreatic chymotrypsin.
I have passed by other studies on BBI and UC,will get back to it.
Hopefully you can provide other thoughts on colon protease inhibition,
that will not inhibit small intestine protease to a great extent,but will inhibit colon protease. Not sure how this might work,inhibition of digestive protease in the small intestine does not seem to be a good idea.
I do know if I drink too much soy milk I get gassy. Perhaps the extract is a 
better solution to the problem.
Old Mike

A Low Dose of Fermented Soy Germ Alleviates Gut Barrier Injury, Hyperalgesia and Faecal Protease Activity in a Rat Model of Inflammatory Bowel Disease
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498131/

BBI in some soy foods.
http://cdn.intechopen.com/pdfs/19747/InTech-Lunasin_a_cancer_preventive_seed_peptide.pdf

some insight amounts
http://ajcn.nutrition.org/content/68/6/1406S.full.pdf
http://cebp.aacrjournals.org/content/9/1/43.full

in this human trial they used 800 CI units of BBIC
http://link.springer.com/article/10.1007/s10620-007-9840-2#

well 2000mg BBIC=200 ci units,that is quite a bit,8 grams BBIC
http://www.pharmcast.com/Patents100/Yr2004/July2004/072704/6767564_MultiSclerosis072704.htm

here is the patent on how to make BBIC
http://www.google.com/patents/US5217717

does not seem that difficult,use regular soybean flour,which of couse is not defatted,dont believe it will make a difference,bu the fat might prevent the water soluble fraction from disoliving. You can buy defatted flour in bulk.
Make a slurry with water,add some vinegar,filter,through a cone coffee filter.
Keep the water part,you could try adding acetone and then filter and keep the precipitate,or then just dry down the water. A crude BBIC should be present.
The instructions in the patent are somewhat vague. Of course you have no idea of the BBI concentration in the concentrate.

human soy milk urine testing
http://cebp.aacrjournals.org/content/9/7/741.full

finally foud it the BBI content of soy flour can be as high as 5.5mg/g
1g of textured soy protein contains 0.48mg BBI

so a pound of soy flour could contain up to about 2500mg or 2.5 grams
you can see why they use the soy flour, I suspect difficult to eat pounds of it,rather gassy.
I might add this seems to be impractical,too bad the government had made
BBI a drug.
There must be another way to inhibit colon protease,perhaps an asian style diet,high starch lowerd protein,trying to find info on proteasse output if on a high starch diet. Another problem is that mast cells release protease.

If you think about the way UC starts it is distal,,however in the proximal colon the bacterial load is low and the digestive protease is high,and the mucus layer is thick. However disitally the mucus layer is thin,the bacterial load is high,and normally the protease content should be low.  This also might mean that distally we are also dealing with bacterial protease,which is a real problem.




Old Mike


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## Xiaofa Qin

Thanks Old Mike for checking out and sharing the lots of information. 

Without a more vigorous test, even myself do not know how much this hypothesis would be correct. Hope it would not be true. Otherwise we would have already lost more than a decade for a more effective prevention and treatment.  

I indeed learnt before BBIC is a potent protease inhibitor that also showed inhibition on the development of multiple cancers. Here is a clinical trial regarding the effect of BBIC on ulcerative colitis, showing some benefits (Lichtenstein GR, et al. Bowman-Birk inhibitor concentrate: a novel therapeutic agent for patients with active ulcerative colitis. Dig Dis Sci. 2008 Jan;53(1):175-80). But as you say, it seems that taking large amount of soy products may not be a good way of inactivating digestive proteases in the large intestine, as it may also impair the digestion of proteins from the diet (in addition to gassy). Therefore, targeted delivery of some small molecule inhibitors to the lower intestine would be a more ideal way for this purpose. I have to point out that the increased activities of digestive proteases and over digestion of the mucus layer may probably have played a more important role in the initiation of the disease. Once the weakening of gut barrier allowed the infiltration of significant amounts of gut bacteria and its products, the infection would become the main driving force for the persistent inflammation, just like the infection of a wound after a cut. The increased existence of adhesive and invasive E. coli (AIEC) and other bacteria in Crohn’s disease and the crypt abscess in ulcerative colitis would suggest antibiotics should have some effect. I suspected that the impaired inactivation of digestive proteases may have confounded the efficacy of antibiotics (Qin X. Impaired inactivation of digestive proteases: a factor that may have confounded the efficacy of antibiotics aimed at reducing the exposure to luminal bacteria and their components. Am J Gastroenterol. 2008 Nov;103(11):2955-6. http://www.ncbi.nlm.nih.gov/pubmed/19032485 ). Right now, the treatment of IBD still mainly focuses on suppression of the inflammation, which seems mainly alleviated the symptoms rather than gets out the roots of the diseases. The prolonged inflammation has caused a reduction or depletion of goblet cells. I believe the restoration of the number and full function of goblet cells should be added as a big marker and goal for the treatment of IBD. After the gut barrier function restored to normal, I think then the commensal flora rather than the protease inhibitor should be used to keep the gut normal. I am just an amateur IBD researcher and this is just my personal opinion.


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## mf15

Xiaofa:Thank you for your thoughts.
I have gotten through about 200 medline abstracts on BBI so far.
It seems to be safe,about 50% is absorbed into the circulation from ingested amounts,which might lead to other systemic benefits.

I find this of interest. In the other UC forum I read many swear by a diet of spinach and sunbutter,sunbutter is like peanut butter but instead it is ground sunflower seeds.  Taste good also.
Anyhow it seems that sunflower contains the most powerfull BBI.
Old Mike
http://www.ncbi.nlm.nih.gov/pubmed/12621047

raw potato also seems to contain lots of inhibitors,believe cooking destorys them, potato juice can be used to heal perianal irritation from excess protease in the stool.
http://www.ncbi.nlm.nih.gov/pubmed/15086363

mast cell tryptase
http://www.ncbi.nlm.nih.gov/pubmed/21173247

this approach may not be safe,seems to cause problems in rats
http://link.springer.com/article/10.1007/BF01092012#page-1


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## Xiaofa Qin

Old Mike: thank you for the great effort you take and sharing the info.  

Yes, there are many studies and publications on BBI before. By the end of the paper published in 2008 regarding the clinical trial of BBIC on ulcerative colitis (Lichtenstein GR, et al. Bowman-Birk inhibitor concentrate: a novel therapeutic agent for patients with active ulcerative colitis. Dig Dis Sci. 2008 Jan;53(1):175-80),  it mentioned that a larger clinical trial was underway. Do not know the trial is still ongoing or stopped by some reason.


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## mf15

Xiaofa:Sorry I can not find anything on other BBI UC trials,perhaps they found a problem
as in the rat study of potato protease inhibitors above.  A question might be how much non fermented soybean is in the asian diet,and is long term low level BBI consumption
protective.  We know IBD incidence in asia is low but increasing,perhaps due to westernization of diet.
Another interesting thought is what is going on in Sweden with UC.
http://www.ncbi.nlm.nih.gov/pubmed/23491313
Old Mike
this paper seems to indicter soy BBI is safe
http://ajcn.nutrition.org/content/68/6/1406S.full.pdf
looks like 35-55 mg bbi/100g soymilk,looks like 30mg enough to start to prevent cancer. From above paper.
http://cebp.aacrjournals.org/content/9/7/741.full

Believe will revisit soy milk,if I can stand the gas.
Raw potato may be some dangerous due to solanine content.

A new way to get bbi is to soak live soybeans in warm water for a few hours the bbi is excreated into the water,I do not know 
how much bbi /pound of beans.
Old Mike


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## Xiaofa Qin

I know soy products like tofu and soybean sprouts are among the common dishes in East Asian. Do not know if this may have contributed to the relatively low incidence of IBD even in the developed countries or regions like Japan, Singapore and Hong Kong. But I feel IBD seems more likely to be caused by increased intake or exposure to some bad staff rather than low intake of some good staff, such as the recent increase of UC in Sweden as you mentioned in your post above (Sjöberg D, et al. Incidence and natural history of ulcerative colitis in the Uppsala Region of Sweden 2005-2009 - Results from the IBD Cohort of the Uppsala Region (ICURE). J Crohns Colitis. 2013 Mar 8. [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/23491313). Frankly, this increase is not surprising to me. Again, this increase occurred shortly after the approval of sucralose by European Union in 2004. It would be just like the sudden increase of Crohn's disease in Oslo, Norway during 2005-2007 (Perminow G, et al. A characterization in childhood inflammatory bowel disease, a new population-based inception cohort from South-Eastern Norway, 2005-07, showing increased incidence in Crohn's disease. Scand J Gastroenterol. 2009;44(4):446-56) that was included in my paper and shown as Figure 4E. Yes, the increase of UC in Uppsala, Sweden but CD in Oslo, Norway would be a brain-wrenching puzzle for those who believe UC and CD are totally different diseases. However, this is not a problem for me. As depicted in Figure 5 in my paper regarding the overall hypothesis on the cause and mechanism of IBD, a milder inhibition of gut bacteria will be first shown up as UC characterized with the infiltration of bacteria, recruitment of neutrophils and formation of crypt abscess. However, a further reduction in gut bacteria will result in the infiltration of dietary particles and antigens and the involvement of macrophages becoming the main problem and thus a shift from UC to CD. This notion is in accordance with the finding published in 2009 that the concentration of sucralose in the surface river water of Oslo had been 312 ng/L, while the highest concentration of sucralose in seven Sweden cities (Alvkarleby, Norrkoping, Stockholm, Flottsund, Emsforo, Asbro, Alelyckantested) was just 76 ng/L (Loos R, et al.  Sucralose screening in European surface waters using a solid-phase extraction-liquid chromatography-triple quadrupole mass spectrometry method. J Chromatogr A. 2009 Feb 13;1216(7):1126-31). 

It would be great if anyone may provide an explanation better than this.


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## mf15

Xiaofa: You might find this of interest.
I am trying to look into saccharin consumption in Sweden and this poped up.
Will also try to find saccharin in ground water.  Seems sweeteners are getting into tap water.
Ubiquitous Occurrence of the Artificial Sweetener Acesulfame in the Aquatic Environment: An Ideal Chemical Marker of Domestic Wastewater in Groundwater
http://pubs.acs.org/doi/abs/10.1021/es900126x

only small amount of saccharin but dont know the usage at the time of this study.
http://link.springer.com/article/10.1007/s00216-009-2881-y?LI=true#page-1

http://www.ncbi.nlm.nih.gov/pubmed/12623659

some consumption history
http://monographs.iarc.fr/ENG/Monographs/vol73/mono73-24.pdf

http://pubs.acs.org/doi/abs/10.1021/es1031272

Taken together this might be enough information to at least infer that 
saccharin is to some extent in drinking water,and I would guess that back  around 1920 there was perhaps more,due to lack of sewage/water treatment
plants.  It is in my toothpaste,have to find a brand without,but trying to find toothpaste without any artificial sweetener is difficult.  In the past I have switched to just baking soda,but for some reason my teeth become sensitive.
Old Mike


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## Xiaofa Qin

Thanks Old Mike for checking out and sharing the info. I added a little more discussion and info in the previous post (#130). Although IBD may be caused by many factors, a true contribution of each factor may depends on the extent of consumption, the strength of their toxic effects on the target, and how much can really reach the target (like the bacteria in the lower gut). I suspect that the artificial sweeteners may be capable of causing a big impact on the population due to the wide use. However, I think the small amount of saccharin in the toothpaste, if not swallowed, probably would  not be enough to cause a big problem on gut bacteria.


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## mf15

Xiaofa:Here is PROOF,a long forgotten study from Japan,no other meds except protease inhibitor, and it induced remission. This is unbelieveable.

Treatment of Ulcerative Colitis with Camostat Mesilate, A Serine Protease Inhibitor


https://www.jstage.jst.go.jp/article/internalmedicine1992/32/4/32_4_350/_pdf


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## Xiaofa Qin

Thanks Old Mike for sharing the article. The results are amazing but not surprising. It would be just what may (should) happen according to the hypothesis discussed here. Unfortunately, it is just case report. It would be worthwhile to conduct some randomized, double-blind, placebo-controlled clinical trial for a more accurate assessment.


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## mf15

Xiaofa: This should be enough to prove at least that inhibiting proteases in the colon will induce remission,the case report and the BBIC trial.
At any rate here might be why there are no more BBIC trials.
The company who made the BBIC was taken over and the new management is not interested in BBIC.
Go to the insert and read the last paragraph.
Never the less I am excited to have found the Camostat report,hopefully natural protease inhibitors also work as well,and that the synthetic drug is not many times more effective/powerfull than the natural compounds.
Old Mike
http://link.springer.com/chapter/10.1007/978-94-007-6214-5_11#

here is an article on trypsin inhibitors in the colon UC included
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1869860/pdf/amjpathol00050-0024.pdf


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## Xiaofa Qin

Thanks Old Mike for checking out and sharing the info. Hope new clinical trials will be conducted and new drugs (treatments) may develop that may get rid of the root of the disease and lead to a real cure of IBD without the need of lifelong medication.


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## sir.clausin

Amen to that, a cure would be what we need not more meds that only suppress the disease.


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## Xiaofa Qin

I found a thread in this forum started by D Bergy entitled “Most medical research false?”. I think it would be not accurate to say most of medical research false. However, in my opinion, there are some fundamental problems in medical research that is far beyond just the bias caused by the funding from some private companies and a declaration of Conflict of Interest in the publication can solve.  

Right now, most of funding in medical research is still from the government. However, the grant application is very competitive and only a small portion can succeed. To get the funding, the most important thing would be to show the significance of the study. For most of the disease the cause is simple and sometimes may be transient, but the response of the body is usually very complex that is accompanied by changes of many molecules, process, or resistance to pathogens. However, most of these changes are secondary. Just like the self rotation of the earth can be (and had been) easily interpreted as the whole universe being turning around the earth, an abnormality followed a disease can be easily presented in the application as the center of the problem, and those who are good at doing so would be more likely to get the funding. As the result, more funding may go to the exploration of some fantasy rather than finding out the simple solution of the fundamental problem, just like the current situation that most of the funding for research on diseases caused by some environmental agents like IBD has been used in studies on genes but hardly any on finding out the causative factors in the environment. For the publication of the study in a good journal and renewal of the grant, the results was also more likely to be interpreted in a fashion of fantastic, complex and mysteries rather than in a way of plain, simple, and more likely. A response may be presented as the driving force. The consequence may be presented and the cause. The failure may be presented as achievements. Then a fantasy becomes the mainstream authoritative thoughts and fashion of further study. Therefore we got a lot of vivid and detailed observations but many are rather just local and superficial; we constructed a lot elegant theories but many are erroneous and misleading, just like the superb theory of Ptolemy depicting how the universe moved around the earth that fooled us for more than a thousand of years. On the other hand, it also made the likely true explanation become heresy. The discrepancy between the human and animals further jeopardized the efficiency to reach the ultimate goal of the effective treatment and prevention of diseases through medical research. A direct manifestation of its consequence would be the extreme low rates of success in clinical trials. According to a paper published recently in Proceedings of the National Academy of Sciences of the United States of America (Seok J, et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci USA. 2013 Feb 26;110(9):3507-12. ) “Murine models have been extensively used in recent decades to identify and test drug candidates for subsequent human trials. However, few of these human trials have shown success. The success rate is even worse for those trials in the field of inflammation, a condition present in many human diseases. To date, there have been nearly 150 clinical trials testing candidate agents intended to block the inflammatory response in critically ill patients, and every one of these trials failed.” Inflammation has been one of the main areas of medical research, with enormous investment and numerous publications and theories. Yes, 0/150 of success in clinical trials, that is the efficacy of our medical research. This kind of failure in medical research caused harms not only to the society but also to the pharmaceutical companies. It cost these companies hundreds of millions or even billions to develop a new drug and led them struggling for survive. However, this high cost will eventually end up as the high price of the drugs and the tremendous burden on the patients, the health insurance company, and the society. It would have also greatly delayed the development of some more effective treatments for diseases.


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## Mark in Seattle

So Xiaofa, do you.have an alternate research funding system in mind?


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## wildbill_52280

Xiaofa Qin said:


> I found a thread in this forum started by D Bergy entitled “Most medical research false?”. I think it would be not accurate to say most of medical research false. However, in my opinion, there are some fundamental problems in medical research that is far beyond just the bias caused by the funding from some private companies and a declaration of Conflict of Interest in the publication can solve.
> 
> Right now, most of funding in medical research is still from the government. However, the grant application is very competitive and only a small portion can succeed. To get the funding, the most important thing would be to show the significance of the study. For most of the disease the cause is simple and sometimes may be transient, but the response of the body is usually very complex that is accompanied by changes of many molecules, process, or resistance to pathogens. However, most of these changes are secondary. Just like the self rotation of the earth can be (and had been) easily interpreted as the whole universe being turning around the earth, an abnormality followed a disease can be easily presented in the application as the center of the problem, and those who are good at doing so would be more likely to get the funding. As the result, more funding may go to the exploration of some fantasy rather than finding out the simple solution of the fundamental problem, just like the current situation that most of the funding for research on diseases caused by some environmental agents like IBD has been used in studies on genes but hardly any on finding out the causative factors in the environment. For the publication of the study in a good journal and renewal of the grant, the results was also more likely to be interpreted in a fashion of fantastic, complex and mysteries rather than in a way of plain, simple, and more likely. A response may be presented as the driving force. The consequence may be presented and the cause. The failure may be presented as achievements. Then a fantasy becomes the mainstream authoritative thoughts and fashion of further study. Therefore we got a lot of vivid and detailed observations but many are rather just local and superficial; we constructed a lot elegant theories but many are erroneous and misleading, just like the superb theory of Ptolemy depicting how the universe moved around the earth that fooled us for more than a thousand of years. On the other hand, it also made the likely true explanation become heresy. The discrepancy between the human and animals further jeopardized the efficiency to reach the ultimate goal of the effective treatment and prevention of diseases through medical research. A direct manifestation of its consequence would be the extreme low rates of success in clinical trials. According to a paper published recently in Proceedings of the National Academy of Sciences of the United States of America (Seok J, et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci USA. 2013 Feb 26;110(9):3507-12. ) “Murine models have been extensively used in recent decades to identify and test drug candidates for subsequent human trials. However, few of these human trials have shown success. The success rate is even worse for those trials in the field of inflammation, a condition present in many human diseases. To date, there have been nearly 150 clinical trials testing candidate agents intended to block the inflammatory response in critically ill patients, and every one of these trials failed.” Inflammation has been one of the main areas of medical research, with enormous investment and numerous publications and theories. Yes, 0/150 of success in clinical trials, that is the efficacy of our medical research. This kind of failure in medical research caused harms not only to the society but also to the pharmaceutical companies. It cost these companies hundreds of millions or even billions to develop a new drug and led them struggling for survive. However, this high cost will eventually end up as the high price of the drugs and the tremendous burden on the patients, the health insurance company, and the society. It would have also greatly delayed the development of some more effective treatments for diseases.



WOW. 

excellent post by the way, and you are hitting upon some things i have noticed myself and questions i have had for some time.




regarding the issue of non transferability of animal models of inflammation to humans, this was something i started to realize when thinking about the nature of scientific reasoning itself, many times it is very analogical and some of the theoretical knowledge we gain may be completely pointless. one time i read a study of compounds to identify anti-inflammatory effects, it identified capsacin to be the best compound, so i got some hot peppers and correctly set of a good experiment with a control period and the first day the inflammation became way worse, it was an in vitro study i really didnt expect things to work out great, but that led me to veiw in vivo as more promising, but even  information i have tried with in vivo experiments have not worked. Not only was capsaicin/whole hot pepper not an inert/inactive substance, it intensified the inflammation, that's how wrong and inaccurate the information from the study actually was.

after thinking about traditional medicine systems i realized that there was this vast amount of knowledge gained about plants and their medicinal properties for disease, observations over periods of thousands of years by chinese and ayruvedic medicine that were all conducted in vivo, there is likely many promising herbs from these systems for the human body for treating diseases, of course others have realized the same thing, not trying to claim this as originally mine or anything like that, like realizing/understanding this in my own mind.


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## Xiaofa Qin

Mark in Seattle said:


> So Xiaofa, do you.have an alternate research funding system in mind?


Not yet. I indeed feel we have some big problem in the current funding system. For instance, I believe I have more thorough and deep thinking on IBD than many IBD professionals and that is how I can construct this unified hypothesis on the etiology of IBD. However, due to the lack of direct research on IBD, I was scored by the reviewers very low as the investigator that would be enough to fail any application. 

Despite that, I feel a bigger problem still lies in the current atmosphere and culture of medical research than the funding system. The great progress and achievements in genetic research in last century made people have a nearly religious belief in genetic analysis. Research on genes is definitely crucial, but everything has its limitations. Hope it will not cost too much and take too long to make people realize that. Currently, most people would believe the cure of IBD largely relying on deciphering the 200 genes we already found and much more genes that will be found, despite that we still do not know how NOD2, the most important and distinctive gene, is linked to IBD after more than a decade of its finding. However, a simple and easy solution might be just fecal transplant, or some more effective probiotics, or protease inhibition. Personally, I believe the real reduction in IBD would largely depends on finding out the causative factor(s) in the environment rather than just research on genes and cytokines (Qin X. How can we really reduce the morbidity of inflammatory bowel disease - Research on genes and cytokines, or find out the causative factors in the environment? J Crohns Colitis. 2009 Dec;3(4):315).



wildbill_52280 said:


> after thinking about traditional medicine systems i realized that there was this vast amount of knowledge gained about plants and their medicinal properties for disease, observations over periods of thousands of years by chinese and ayruvedic medicine that were all conducted in vivo, there is likely many promising herbs from these systems for the human body for treating diseases, of course others have realized the same thing, not trying to claim this as originally mine or anything like that, like realizing/understanding this in my own mind.


Thanks wildbill_52280 for sharing your thought and story. Although I grew up in China, frankly, I was not very confident in traditional medicine at beginning. But this was changed after I found the inhibition of digestive protease by the unconjugated bilirubin and pursed further. 

The gallstone of the ox (also called Calculus Bovis in academic, or Niuhuang in Chinese) was described in “Shennong Bencao Jing” (Divine Farmer’s Materia Medica Classic, the first book of Chinese herbal medicine written two thousand years ago) as a superior medicine and has been one of most precious medicine in China. For instance, Angong Niuhuang Wan (Calm the Palace Pill with Cattle Gallstone) can be more than $100 per pill. It is reported having life-saving effects for critically ill patients. Here is a story regarding a Hong Kong TV hostess who was hit by a train and declared brain dead in London but got a full recovery after being brought back and treated in China. In fact, the main component of cattle gallstone is unconjugated bilirubin, formed due to the infection of the biliary system and precipitation of deconjugated bilirubin in the bile by beta-glucuronidase from the bacteria. I believe bilirubin would be the indispensable component of cattle gallstone (Qin XF. Bilirubin would be the indispensable component for some of the most important therapeutic effects of Calculus Bovis (Niuhuang). Chin Med J (Engl). 2008 Mar 5;121(5):480), through mechanisms such as the inhibition of digestive proteases. Definitely, there would be many valuable staff in the traditional medicine we may explore.


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## mf15

Xiaofa:Here is another possible mechanism.
H0-1
http://www.ncbi.nlm.nih.gov/pubmed/15803024


HO-1 induction,will make CO and bilirubin

http://www.wjgnet.com/1007-9327/14/6122.pdf
UC and CO

http://www.ncbi.nlm.nih.gov/pubmed/16365149

http://www.ncbi.nlm.nih.gov/pubmed/21444764

http://onlinelibrary.wiley.com/doi/10.1111/j.1746-6342.2006.00051.x/abstract

http://www.medscape.com/viewarticle/775152

http://www.medicalgasresearch.com/content/2/1/23

http://link.springer.com/article/10.1007/s10620-009-1112-x#

http://www.ncbi.nlm.nih.gov/pubmed/23266559

http://www.ncbi.nlm.nih.gov/pubmed/22943587

http://www.ncbi.nlm.nih.gov/pubmed/22300078

lipoic acid also induces

http://www.ncbi.nlm.nih.gov/pubmed/16123320

iron deficiency will inhibit,zinc protoporphyrin is formed and will inhibit H0-1

http://en.wikipedia.org/wiki/Zinc_protoporphyrin

http://www.biomedcentral.com/1471-2407/8/197

Low iron in the blood leads to zinc protoporphyrin formation which inhibits HO-1.

Seems we are caught in some form of biochemical trap.
Just suppose we bleed then become anemic,and then we cannot induce H0-1 because we are anemic,we continue to bleed and become more anemic,and induce less and less H0-1.
I know I am anemic,and many with UC are also anemic. I hate to take iron pills they seem to make me wose,but will now force myself to take iron,will also take lipoic acid
which induces HO-1. Will see where this goes.
Hope I was somewhat clear with the mechansim of what is taking place.
Old Mike


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## Xiaofa Qin

Thanks Old Mike for checking out and sharing these articles. Multiple studies showed that HO-1 is induced at the site of inflammation or injury, with beneficial effects to the body. 

I am just a researcher but not a doctor. I just suggest to be prudent when trying something out, especially for those seemingly making things worse.


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## mf15

Another review suggesting the use of protease inhibitors.
Old Mike
http://www.ncbi.nlm.nih.gov/pubmed/23567293


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## Xiaofa Qin

Thanks Old Mike for checking out and sharing this interesting article.

Xiaofa


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## Grungel

I want to put this idea to you all. Check available data on milk consumption per capita for different countries, for example in Europe, and number of IBD cases. It gives some idea. There seem to be a very good correlation between theese numbers. Why make this so hard? I took away milk and sugar from my diet 8 years ago, after fighting Crohn's for two years. I actually followed SCD diet for two years after, with not a single cheat, not a single time i ate something out of the diet. Im a very disciplined guy..  I have been well ever since, no medicines whatsoever. Thats why i even had the idea. For me it seems kind of obvious that problems in bowel are caused by what you put into it. Nightshades might play a role as well during the leaking from an oversensitive bowel, at least. 

Just my few cents.


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## mf15

Grungle: Thanks for the input,I have have UC since 1980,tried SCD 3 times,also no dairy,no nightshade,no sugar,and many other alternative approaches. Still have UC.
Old Mike


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## Xiaofa Qin

Grungel said:


> I want to put this idea to you all. Check available data on milk consumption per capita for different countries, for example in Europe, and number of IBD cases. It gives some idea. There seem to be a very good correlation between theese numbers. Why make this so hard? I took away milk and sugar from my diet 8 years ago, after fighting Crohn's for two years. I actually followed SCD diet for two years after, with not a single cheat, not a single time i ate something out of the diet. Im a very disciplined guy..  I have been well ever since, no medicines whatsoever. Thats why i even had the idea. For me it seems kind of obvious that problems in bowel are caused by what you put into it. Nightshades might play a role as well during the leaking from an oversensitive bowel, at least.


Thank Grungel for sharing the thoughts and experience. To my knowledge, multiple studies back to 1980s found increased intake of refined sugar in patients with Crohn’s disease (here are some of the studies). However, the enthusiasm receded when some controlled trials failed to show a benefic with the restricted use of sugar  (Ritchie JK, et al. Controlled multicentre therapeutic trial of an unrefined carbohydrate, fibre rich diet in Crohn's disease. Br Med J (Clin Res Ed). 1987 Aug 29;295(6597):517-20), especially the poor correlation between the Crohn’s disease and refined sugar consumption (Sonnenberg A. Geographic and temporal variations of sugar and margarine consumption in relation to Crohn's disease. Digestion. 1988;41(3):161-71). However, I have not noticed any vigorous research between the milk consumption and IBD. Your post interested me to have a look on this and found out a ranking list of countries by milk consumption per capita). However, I cannot perceive a good correlation between the milk consumption per capita and the incidence of IBD. For instance, according to a study on the incidence of IBD across Europe (Shivananda S, et al. Incidence of inflammatory bowel disease across Europe: is there a difference between north and south? Results of the European Collaborative Study on Inflammatory Bowel Disease (EC-IBD). Gut. 1996 Nov;39(5):690-7), Ioannina in Greece has the lowest incidence of Crohn's disease. However, according to the list, Greece is among the countries with the highest milk consumption per capita. On the other hand, although countries like Canada and New Zealand have the highest incidence of IBD, their milk consumption are much lower than countries with very low incidence of IBD such as Lithuania (Kiudelis G, et al. Incidence of inflammatory bowel disease in Kaunas region, Lithuania. Medicina (Kaunas). 2012;48(8):431-5) or Romania (Gheorghe C, et al. Epidemiology of inflammatory bowel disease in adults who refer to gastroenterology care in Romania: a multicentre study. Eur J Gastroenterol Hepatol. 2004 Nov;16(11):1153-9). It would be great if you would share your evidence and analysis for the good correlation between milk consumption per capita and incidence of IBD. Anyway, glad to know you have been in long remission without any medication, which would suggest IBD patients may indeed recover to full health.


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## wildbill_52280

Grungel said:


> I want to put this idea to you all. Check available data on milk consumption per capita for different countries, for example in Europe, and number of IBD cases. It gives some idea. There seem to be a very good correlation between theese numbers. Why make this so hard? I took away milk and sugar from my diet 8 years ago, after fighting Crohn's for two years. I actually followed SCD diet for two years after, with not a single cheat, not a single time i ate something out of the diet. Im a very disciplined guy..  I have been well ever since, no medicines whatsoever. Thats why i even had the idea. For me it seems kind of obvious that problems in bowel are caused by what you put into it. Nightshades might play a role as well during the leaking from an oversensitive bowel, at least.
> 
> Just my few cents.


you likely have a mild to moderate case of ibd, which can be easily controlled by removing lactose and sucrose and following the SCD. the guidelines to the SCD are to remove/reduce lactose and sucrose to starve bacteria, as well as some select starches/complex carbs. it is also possible that by avoiding milk, you avoid coming in contact with MAP bacteria, which can sometimes survive pasteurization according to some studies. but this may not be the only intracellular bacteria that may be involved in crohn's disease, there may be others. IBD seems to generally be defined as, a lowered ability to eradicate  pathogenic bacteria, likely due to some degree of preceding dysbiosis. the severity of dysbiosis from damaged intestinal flora, and the type of bacteria you may come in contact with, will generally explain the differences in ibd cases, in my opinion.


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## Xiaofa Qin

A scientist at a scientific institution contacted me to discuss my hypothesis on the possible link between sucralose and IBD, and also informed me a blog at Evidence Based IBD (http://evidencebasedibd.blogspot.com/2013/03/artificial-sweeteners-and.html ) with comments and critiques on the proposed hypothesis, and interested to hear my response. I wrote a response there and would also like to have more in-depth discussions here if anybody interested.


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## Xiaofa Qin

There are several studies published recently that may be of some interest. One study showed that the incidence of IBD in the children in Shanghai, China increased 12-folds from 2001-2010 (Wang XQ, et al. Inflammatory bowel disease in Chinese children: a multicenter analysis over a decade from Shanghai. Inflamm Bowel Dis. 2013 Feb;19(2):423-8. http://www.ncbi.nlm.nih.gov/pubmed/23340680 ). It seems this recent increase in IBD in Asian cannot be simply explained by the development in the economy. For instance, in another retrospective hospital study on the pediatric IBD in the already highly developed Singapore (Chu HP, Logarajah V, Tan N, Phua KB. Paediatric inflammatory bowel disease in a multiracial Asian country. Singapore Med J. 2013 Apr;54(4):201-5. http://www.sma.org.sg/UploadedImg/files/SMJ/5404/5404a1.pdf ) , there was either zero or only one case of IBD during 1996 –2001, but multiple cases started to emerge since 2002, with 8 cases in 2008. Interestingly, this increase occurred again shortly after the approval of sucralose in Singapore in 1999 and the opening of the $198 million sucralose plant in 2007 (http://www.chemweek.com/regions/sou.../Tate-and-Lyle-Opens-Singapore-Unit_6383.html ). I do not want to explain everything by the hypothesis I proposed and exclude the many other possibilities, but the co-incidences kept on popping up. Does anyone have any better explanations we can share? Hope people may find out the reason.


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## Xiaofa Qin

Here is another interesting article published recently: Messer JS, et al. The Crohn's disease: associated ATG16L1 variant and Salmonella invasion. BMJ Open. 2013 Jun 20;3(6). It showed that mutation or deficiency of the Crohn’s disease - associated core autophagy gene ATG16L1 conferred protection from bacterial invasion and infection.


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## helena101

Xiaofa Qin, 
The last article you posted a link to, I am not sure I understand... I thought the genetic variants associated with crohn's facilitated bacterial infection, so is this study suggesting that the opposite may be true? it seems there is still a very long way to go before they figure out what causes IBD.


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## kiny

There's nothing beneficial about having autophagy defects (NOD2 / ATG16L1 / IRGM / VDR). Defects in xenophagy result in severely decreased ability to deal with both bacteria and viruses.

Defects in autophagy means defects in the lysosome, it's an essential part of actually clearing an intracellular organism.

Defects in autophagy also results in a host of problems during starvation.

People with crohn's disease have not just one defect in autophagy, they have multiple, NOD2, ATG16L1, IRGM and VDR are all involved in autophagy.

To ignore autophagy in crohn's disease is to ignore the only concrete evidence we have about this disease, which is:

*-people with autophagy defects have a far higher chance of getting crohn's disease than others*

Not only that, people with those defects have a more severe form of crohn's disease than those that do not.

Autophagy is a major major part of dealing correctly with infections.


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## kiny

good synopsis


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## kiny

Xiaofa Qin said:


> It showed that mutation or deficiency of the Crohn’s disease - core autophagy gene ATG16L1 conferred protection from bacterial invasion and infection.


By saying that, to me it seems like you're casually suggesting that impaired autophagy is somehow beneficial, which it isn't, especially not in relationship to crohn's disease.

Autophagy is an* essential* part of the host's defense against bacteria and viruses.

Impared autophagy has been shown to be detrimental on more than one occasion.

http://onlinelibrary.wiley.com/doi/10.1111/j.1462-5822.2009.01381.x/pdf

And, as has also been shown, defects in autophagy genes results in more severe crohn's disease.

And, as also been shown, defects in ATG16L1, increase your chance of infection, with E Coli, H. pyroli, mycobacteria, and a host of other pathogens.

http://www.ncbi.nlm.nih.gov/pubmed/22885761

http://www.ncbi.nlm.nih.gov/pubmed/21978003

Impaired cytokine response to Viral infections related to ATG16L1:

http://www.ncbi.nlm.nih.gov/pubmed/8292306

And, as also has been shown, a major reason for the still increased mortality rate in people with crohn's disease, is infections.

More interestingly, the mortality rate of UC due to infections, is lower, who, surprisingly, don't have an ATG16L1 predisposition.


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## Xiaofa Qin

Thanks helena101 and kiny for the posts. Yes, I think the article I posted early (in post #152) related to a fundamental question:  Is IBD like Crohn’s disease caused by an OVER REACTION or DEFICIENCY of the immune system? I know most of the many recent magnificent studies that are published in some of the most prestigious scientific journals, authored by hundreds of elite professionals and achieved by hundreds of millions of funding pointed to uncontrolled infection as the possible cause, with evidences such as: 1) there is a link between CD and NOD2, while NOD2 has been an intracellular receptor recognizing muramyl dipeptide (MDP) existing in certain kinds of bacteria; 2) there is a link between CD and genes related to autophage like ATG16L1, while autophage is related to the destruction and clearance of pathogens inside the cells; 3) there is a striking overlap between susceptibility loci for IBD and mycobacterial infection, as shown by the large scale genome wide association study that involves dozens of thousands of patients and controls; 4) there were increased detection of the adhesive and invasive E. coli (AIDE), Mycobacterium avium paratuberculosis (MAP), enterovirus, etc, in gut tissue of the patients; and 5) as stated by kiny in the previous posts, there is increased infection of bacteria and virus in mutations or deficiency of NOD2 or autophage genes and Crohn’s patients. However, on the hand, we would also have to face another hard fact: suppression of the immune system by anti TNF-alpha antibody and other agents has been the most effective treatment for CD but they increased the risk of infections by bacteria, fungi, and virus, and even of cancer. With these contradiction, I think we may need a more thorough and insightful thinking of the different “facts”to get into the true nature behind these phenomena. In my opinion, the miracle efficacy of the immune suppression agents by far overweighed the other claims, and CD is more likely caused by the over reaction rather the deficiency of the immune system. This notion is in accordance with the finding by Hedl M, Li J, Cho JH, and Abraham C (Chronic stimulation of Nod2 mediates tolerance to bacterial products. Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19440-5) that chronic stimulation of the normal NOD2 resulted in tolerance to bacterial products while the Crohn's disease-relevant NOD2 mutation is associated with deficient in this ability of tolerance that leads to escalated inflammation. Thus, as stated in this unified hypothesis discussed here, I believe the weakening of the gut barrier would be the root mechanism of the disease and the increased risk in the mutants of the NOD2 and autophage genes is not due to uncontrolled growth and infection of bacteria or virus but rather the over reaction to the increased infiltration of microbes (live and dead), their debris or metabolites, or antigens from the food, as the result of the deficient in tolerance to the chronic exposure.


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## kiny

Xiaofa Qin said:


> However, on the hand, we would also have to face another hard fact: suppression of the immune system by anti TNF-alpha antibody and other agents has been the most effective treatment for CD but *they increased the risk of infections by bacteria*, fungi, and virus


I agree and disagree.

You're right for example for tuberculosis, that's why people before they get infliximab, get a mantoux test, infliximab can exacerbate latent tuberculosis.

But, I will show you this isn't the case for all mycobacteria. For example:

http://www.ncbi.nlm.nih.gov/pubmed/22398081

(I posted the full study some time ago)

Infliximab is detrimental to the survival of MAP for example.

It measurably decreased the amount of MAP within 24 hours in a dose dependent manner.


Another thing is that AIEC (invasive E Coli) induces TNF-alpha from monocytes in the blood. There's quite a number of bacteria that invoke an immune response and actually thrive in it. AIEC is one of them.

*Infliximab actually induces apoptosis of those monocytes by binding to TNF-alpha on the cell wall.*


Infliximab seems to bind to TNF-alpha on the cell wall, and it seems to induce apoptosis of certain *active* leukocyte, it's possible that infliximab is an antimicrobial agent against certain intracellular bacteria or viruses, especially ones that would exploit autophagy.

Not only that, 6mp, seems to be doing that same thing.

Corticosteroids on the other hand don't do this. While they're able to reduce inflammation, they are not inducing apoptosis of active leukocytes. Is that why they're not as effective as 6mp or infliximab? Who knows.

There are also anti-iniflammatory agents, like etanercept, that also decrease TNF-alpha, but they do not help for crohn's disease at all. The only difference between etanercept and infliximab, is that etanercept does not bind to TNF-alpha on the cell wall inducing apoptosis.

Etanercept does work for other inflammatory diseases, it does not work for crohn's disease, and it reduces the amount of TNF-alpha, by the exact same dose dependent manner as infliximab. *The only difference is that infliximab induces apoptosis and etanercept does not.*


Also, some bacteria are fast dividing and some are extremely slow dividing. TB is very fast dividing compared to say MAP.  That's why culturing TB takes a short time, and culturing MAP can take months.

Just to use MAP, the time between infection with MAP of a ruminant and actual clinical symptoms of paratuberculosis, are years apart.

A tnf-alpha blocker would have very different effects on different infections.


There's also a laundry list of anti-inflammatory agents that work for inflammatory and autoimmune diseases that do not work for crohn's disease. Crohn's disease has an extremely limited amount of anti-inflammatories that work. There's only a handful of agents that help crohn's disease, if you look at other diseases there are 40+ treatments that work. And with the exception of corticosteroids, I believe all of the agents that work for crohn's disease induce apoptosis of active leukocytes (6mp, infliximab, humira), are anti-viral (immunoglobulin), or are macrolides or quinolones (antibiotics that are cell-penetrating).


Also, it should be noted that these anti-inflammatory agents and cytokine blockers were actually first used for infections, to stop the destructive inflammation, to stop organ and nerve damage.

Viral and bacterial infections often result in organ and nerve damage, caused by inflammation. Actually the destructive inflammation of intestinal TB is extremely similar to that of crohn's disease.

Stopping the destructive inflammation in an infected patient is often the priority, the actual clearance of the bacteria is done after the inflammation is controlled. Again, to avoid organ damage and nerve damage.


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## kiny




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## 723crossroads

Did anyone ever think possibly it could be from chemicals in our water? To me that makes more sense. Way back, there was very little pollution to the water and thus no chemicals added. Then along came factories and the water is full of crap. Then we add tons of chlorine and other harmful chemicals to kill the crap and we are all getting sick with cancer ,IBD's etc.... Any thoughts along these lines besides mine?


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## wildbill_52280

723crossroads said:


> Did anyone ever think possibly it could be from chemicals in our water? To me that makes more sense. Way back, there was very little pollution to the water and thus no chemicals added. Then along came factories and the water is full of crap. Then we add tons of chlorine and other harmful chemicals to kill the crap and we are all getting sick with cancer ,IBD's etc.... Any thoughts along these lines besides mine?


water quality is always an issue. 

but if this were the case with IBD, it would become very obvious after the research was done. so it is so unlikely this is the case after you look at all the data we have collected so far.

the pattern for IBD is high rates in industrialized developed nations, up to 70 times compared to places like rural china. so yes it likely has something to do with some toxin in the environment. This could include many different substances, like the one proposed in the paper of this threads original post, sacharrin, and now sucralose. Now taking multiple courses of antibiotics are showing to be good candidates for the possible toxin, as western medicine doesnt exist in non developed countries.

Also there is a pattern of more cases the further from the equator we get, suggesting vitamin d may play a large role. this may play some protective role against dysbiosis in its role in production of antimicrobial peptides that are secreted in mucus membranes, so vitamin d deficit may just make dysbiosis worse, so when you get a powerful hit of antibiotics, your chances of damaging intestinal bacteria permanantly are greater, raising risk for IBD.

multiple factors involved in developing this disease. diet alone may even be enough to cause dysbiosis leading to IBD. that's the least likely route i believe though.


----------



## kiny

723crossroads said:


> Did anyone ever think possibly it could be from chemicals in our water? To me that makes more sense. Way back, there was very little pollution to the water and thus no chemicals added. Then along came factories and the water is full of crap. Then we add tons of chlorine and other harmful chemicals to kill the crap and we are all getting sick with cancer ,IBD's etc.... Any thoughts along these lines besides mine?


Maybe the _*broad street pump*_ story interests you if you haven't read it yet.

There's quite a number of good studies that show clustering of crohn's disease cases.

Also a number of studies that show crohn's disease clustering in families with unrelated bloodlines.


----------



## 723crossroads

Thanks you guys.


----------



## Xiaofa Qin

Thanks all for the posts, and thanks kiny for sharing the thoughts and info. 



kiny said:


> I agree and disagree.
> 
> You're right for example for tuberculosis, that's why people before they get infliximab, get a mantoux test, infliximab can exacerbate latent tuberculosis.
> 
> But, I will show you this isn't the case for all mycobacteria. For example:
> 
> http://www.ncbi.nlm.nih.gov/pubmed/22398081
> 
> (I posted the full study some time ago)
> 
> Infliximab is detrimental to the survival of MAP for example.
> 
> It measurably decreased the amount of MAP within 24 hours in a dose dependent manner.
> 
> 
> Another thing is that AIEC (invasive E Coli) induces TNF-alpha from monocytes in the blood. There's quite a number of bacteria that invoke an immune response and actually thrive in it. AIEC is one of them.
> 
> *Infliximab actually induces apoptosis of those monocytes by binding to TNF-alpha on the cell wall.*
> 
> 
> Infliximab seems to bind to TNF-alpha on the cell wall, and it seems to induce apoptosis of certain *active* leukocyte, it's possible that infliximab is an antimicrobial agent against certain intracellular bacteria or viruses, especially ones that would exploit autophagy.
> 
> Not only that, 6mp, seems to be doing that same thing.


I read through the paper you listed above (Bach H, Rosenfeld G, Bressler B. Treatment of Crohn's disease patients with infliximab is detrimental for the survival of Mycobacterium avium ssp. paratuberculosis within macrophages and shows a remarkable decrease in the immunogenicity of mycobacterial proteins. J Crohns Colitis. 2012 Jun;6(5):628-9.). I am also very impressed by the title. However, the paper did not provide an explanation for the possible mechanism, and it is also beyond my imagination as how infliximab can cause the death of MAP. Apoptosis is the programmed cell death that almost all the cells within our body naturally die ( http://en.wikipedia.org/wiki/Apoptosis). The apoptosis induced by infliximab seems also just through the common routines such as the caspase-dependent pathway as suggested in the studies in your previous post (#159 in this thread). If MAP succumbed along with this natural death of the cells, how can they cause the persistent inflammation seen in CD. According to the paper, the significant decrease in the survival of MAP in the macrophages treated with infliximab only started to show up at 48 hour but not at 24 hour. In my opinion, a more likely explanation would be the treatment with infliximab caused accelerated apoptosis of the macrophages, probably through its binding with the tmTNF-alpha on the cell wall as stated in your post, resulting in the release of MAP from the dead cells into the culture media, rather than the real killing of MAP. This is a very short paper without detailed description of the methods and procedures of the experiment, thus this is just my guess. However, some more meaningful and clinically relevant in vivo studies indeed showed that immunosuppression will result in exacerbated but not alleviated infection of MAP and damage of the tissue, just the same as tuberculosis. Large amounts of Mycobacterium paratuberculosis became showed up in the feces, gut tissue or even liver in mice (Follett DM, Czuprynski CJ. Cyclophosphamide and prednisolone exacerbate the severity of intestinal paratuberculosis in Mycobacterium paratuberculosis monoassociated mice. Microb Pathog. 1990 Dec;9(6):407-15) or chicken (Valente C, et al. Use of an experimental chicks model for paratuberculosis enteritis (Johne's disease). Vet Res. 1997 May-Jun;28(3):239-46) treated with immunosuppressive agents like cyclophosphamide and prednisolone. Still, MAP got eliminated from the body and became undetectable even in the immunodepressed chicks after a few months (Here is the link to the full text), in contrast to the Crohn’s disease in human that lasted forever, 

I also felt the notion that the high efficacy of the immune suppression agents like inflixmab and 6-MP is largely due to their bactericidal activity on MAP a fascinating idea, but I just wonder how this miracle occurred. A study (Greenstein RJ, et al. On the action of methotrexate and 6-mercaptopurine on M. avium subspecies paratuberculosis. PLoS One. 2007 Jan 24;2(1):e161) showed that although 6-MP have some inhibition on the growth of MAP, its activity is still much lower than some antibiotics like clarithromycin (4 ug/ml 6-MP versus 0.5 ug/ml clarithromycin to cause 80% growth inhibition of the bacteria). For the treatment of IBD, 6-MP is usually used in a dose below 100 mg/day and lasted for several weeks. However, in the study by Selby W, et al. (Antibiotics in Crohn's Disease Study Group. Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn's disease. Gastroenterology. 2007 Jun;132(7):2313-9), even clarithromycin used at 750 mg/day, along with 450 mg/day rifabutin and 50 mg/day clofazimine to treat the patients with Crohn’s disease for up to two years failed to show evidence of sustained benefit. I just cannot image how 6-MP, with much less bactericidal capability and used at a much lower dose and in such a short period can achieve the effective treatment for Crohn’s disease through the claimed killing of MAP.

We live in the age of information explosion. It also generated massive clouds of false information that made it a big challenge to find out those pieces of evidences that bared clues of the truth. Hope these discussions may sharp our vision and clear out thoughts. I think we share the same goal – to find the truth and solve the mystery. Thanks again for sharing the thoughts and info.


----------



## kiny

Xiaofa Qin said:


> Apoptosis is the programmed cell death that almost all the cells within our body naturally die


Thanks.

Right, except in places of high inflammation...where netosis and autophagy induced necrosis happens instead.

Any form of disregulated autophagy, induction or subversion, is going to lead to big problems, because it will result in tissue damage.

I believe autophagy is really important in crohn's disease, bacteria found in people with crohn's disease are able to interact with the autophagy process (especially invasive E coli), and those gene mutations which lead to predisposition of crohn's disease are all related to the autophagy process. (ATG16L1, NOD2, IRGM, VDR)

You can't say autophagy without mentioning intracellular bacteria and viruses.

I think the idea that crohn's disease is primarily related to bacterial or viral involvement, is not only reasonable, it's really hard to suggest that a type of infection is not involved.

To get all those monocytes and especially lymphocyes to home in on the gut, you need a spark, you need something that starts the fire. You need an APC, you need a trigger.

Two things can do this, an autoantigen...which has never been found with any consistency in crohn's disease (you'd also have indiscriminate inflammation all over the organ, which isn't the case in crohn's disease)...or you need an antigen in the form of a bacteria or virus.


----------



## Xiaofa Qin

kiny said:


> To get all those monocytes and especially lymphocyes to home in on the gut, you need a spark, you need something that starts the fire. You need an APC, you need a trigger.
> 
> Two things can do this, an autoantigen...which has never been found with any consistency in crohn's disease (you'd also have indiscriminate inflammation all over the organ, which isn't the case in crohn's disease)...or you need an antigen in the form of a bacteria or virus.


As illustrated in my paper, I believe that the weakening of gut barrier and increased infiltration of toxic components like lipopolysaccharides (LPS) and the Muramyl dipeptide (MDP) containing peptidoglycan of bacteria might be the primary trigger of the inflammation. As we know, the gut contains large amounts of LPS (also called endotoxin) that can kill the host thousands of times over, and the long evolution has equipped the body with an innate immune system with defense cells like macrophages being able to launch promptly a vigorous instinct response to low doses of LPS. Thus the inflammation of the gut can be started and continued without any antigen. 

Here I would like to provide a unified explanation regarding the relationship among NOD2, autophagy, immune suppression, etc, and CD based on the massive conflicting evidences available. 

I believe everybody may get CD, once the gut became enough leaky (by mechanisms such as the increased degradation of the protective mucus layer, etc) that allowed enough toxic luminal components to get in. As both LPS and peptidoglycan are main cell wall components of gut bacteria and both also have high potency to active immune cells, they may be two key bioactive agents responsible. As the molecular weight of MDP has been less than 500 and the molecule of LPS still much small than the whole bacteria, they would be much easer to penetrate the gut barrier. 

According to the references, LPS and MDP seems worked synergistically to cause the inflammation, through their binding with TLR4 on the surface and NOD2 in the cytoplasm, respectively, of the macrophages. Under normal condition, the binding of MDP to NOD2 not only caused increased production of proinflammatory cytokines like TNF-alpha and IL-1 beta, but also anti-inflammatory cytokines like IL-10 that may have served as the mechanism to control as demonstrated by the induction of tolerance after repeated exposure. 

Although studies showed reduced production of pro-inflammatory cytokines and bactericidal capability with CD-associated NOD2 mutation, studies have also revealed that these mutants have reduced production of IL-10 and loss of tolerance to chronic exposure. I believe the later may be more clinical relevant and the loss of tolerance rather than an uncontrolled infection would be the main reason for the increased risk of NOD2 mutation. This is in accordance with the fact that people never see large amounts of bacteria in the mucosa of CD patients as MAP in the mucosa of Johne’s disease. The increased detection in CD patients of some bacteria by highly sensitive methods like PCR may have just reflected the increased permeability. 

As the binding of MDP with NOD2 and the series of reactions after that occurred in the cytoplasm, I suspected that the link between CD and some defect in autophagy may be caused by the delayed degradation of the MDP and NOD2 complex and other active components through autophagy rather than increased infection of the cell by bacteria. 

This provided an explanation to the critical question as why potent suppression of immune system resulted in healing (both clinical and mucosal) rather than exacerbation of CD.  

The above is just my personal opinion.


----------



## kiny

I need to go over your paper again because I truly don't understand everything you're saying, I lack the knowledge to understand everything.

What I do know is that your theory does not exclude infection. Any change in intestinal homeostasis would allow a pathogen to exploit it.

I wish some studies incorporated early events of crohn's disease more. Early endoscopic events are inflammation of peyer's patches.

These are the earliest events in new crohn's disease, a rare endoscopic picture of a germany study.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3396064/







In C you can see structurally a completely unaffected lumen wall with completely intact mucosal layer, what you do see is lymphatic involvement, red rings around lymphoid follicles in the terminal ileum.

This is a very unaffected bowel, compared to someone with advanced crohn's disease this looks like it's cured, the only thing that's noticeable is the inflammation, the inflamed follicle. It's a very early stage of crohn's disease.

Peyer's patches are bacterial sensors, they sip bacterial content, pathogenic content, with their M cells. They're miniature lymph nodes. They're most present in the terminal ileum and beginning of colon, *coincidentally where the majority of people have crohn's disease.*

Random coincidence? Fat chance.

AIEC (invasive E Coli) actually invades through the peyer's patches.

Another question, why do many people in their teens get crohn's disease....diet? random unexplained event?

Peyer's patches (intestinal lymphatic system) is most active during teenage years:









Ignoring the bacterial and infectious component in crohn's disease, considering the moutain of evidence, genetic, clinical, limited response to antibiotics, is * really* hard to justify at this point.


----------



## Xiaofa Qin

As we discussed in some early posts, I also believe that infection by bacteria may have contributed significantly to the pathogenesis of the disease, especially when the prolonged inflammation has caused such a damage that allowed the luminal bacteria easily get in. However, I suspected that the sustained inflammation is mainly caused by the continuous infiltration of toxic luminal components, not only the live bacteria (probably multiple strains in nature) but also their debris like LPS and peptidoglycan, rather than UNCONTROLLABLE tenacious infection of certain species of bacteria. 

As we know, the Peyer’s patch has less goblet cells and thinner mucus layer (http://www.ncbi.nlm.nih.gov/pubmed/7054025 ) and enriched with inflammatory cells, thus would be more vulnerable and sensitive. It would be no surprising that the inflammation started at these sites. 

I admired the great passion and enthusiasm you and many others in this forum put trying to find the root of this disease. Hope our efforts will eventually get some meaningful results.


----------



## wildbill_52280

really hate to interrupt your discussion, but the issues in crohn's goes far beyond inflammation trigger by lps through a leaky gut. leaky gut is controlled through butyrate via its influenced in intestinal tight junction proteins. 

and here a recent report of how butyrate produced from butyric acid bacteria also regulates the inflammatory process. 
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032841

just about every core process of this disease can be traced back to probiotic bacteria, and the disruptions in these bacteria indicated true cause. control the inflammation, cure the disease, and the bad bacteria will be unable to thrive any longer.

yea this is just another plug for fecal transplants.


----------



## Xiaofa Qin

Here is a study just got published recently (Midtvedt T, et al. Increase of faecal tryptic activity relates to changes in the intestinal microbiome: analysis of Crohn's disease with a multidisciplinary platform. PLoS One. 2013 Jun 20;8(6):e66074. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3688706/ ). It indeed measured butyric acid and other short chain fatty acids in the faeces of patients with Crohn’s disease and controls, but did not show significant difference (with butyric acid being actually higher in patients than controls:  28.4 and 18.2 mmol/kg, respectively). In contrast, it showed a significant increase of faecal tryptic activity that seems related to the decrease in Bacteroides, with more than 92% of the microbiota being virtually the same between the patients and controls. I am excited about this finding as it is in accordance with my hypothesis that the impaired inactivation of digestive proteases may be the primary cause of IBD, and it seems this problem might be corrected by inoculation just one species of bacteria, rather the random, poorly-defined faecal transplantation.


----------



## wildbill_52280

Xiaofa Qin said:


> Here is a study just got published recently (Midtvedt T, et al. Increase of faecal tryptic activity relates to changes in the intestinal microbiome: analysis of Crohn's disease with a multidisciplinary platform. PLoS One. 2013 Jun 20;8(6):e66074. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3688706/ ). It indeed measured butyric acid and other short chain fatty acids in the faeces of patients with Crohn’s disease and controls, but did not show significant difference (with butyric acid being actually higher in patients than controls:  28.4 and 18.2 mmol/kg, respectively). In contrast, it showed a significant increase of faecal tryptic activity that seems related to the decrease in Bacteroides, with more than 92% of the microbiota being virtually the same between the patients and controls. I am excited about this finding as it is in accordance with my hypothesis that the impaired inactivation of digestive proteases may be the primary cause of IBD, and it seems this problem might be corrected by inoculation just one species of bacteria, rather the random, poorly-defined faecal transplantation.



as always, im intrigued. 

quickly tho,the study states, 





> However, 4.6% of microbes found in controls were lacking in CD patients.



some issues i have are small sample size, but not to crucial.
I do recall reports of higher short chain fatty acids/butyrate at times compared to controls as well, so that is not new to me. i'm aware of conflicting reports in science. Even still this study points to disrupted microbiota, what differs from other studies is the bacteria that is disrupted and the mechanisms which ibd arises. at the moment it makes me consider for the first time other mechanisms by which IBD could occur through other bacteria being disturbed, rather then the butyrate producing bacteria. 

I will consider this new information more completly tomorrow.

thank you.


----------



## Xiaofa Qin

I just submitted a paper to the Journal of Crohn’s and Colitis entitled “Does the association with NOD2, autophagy and some pathogens really mean Crohn’s disease is caused by uncontrolled infection?”, and I was informed the paper has been accepted for publication. Apparently, the journal comprehends the notion that Crohn’s disease is more likely caused by escalated immune reaction to the increased infiltration of luminal bacteria and their debris rather than deficiency of the immune system and uncontrolled infection being reasonable, not ridiculous.


----------



## kiny

Xiaofa Qin said:


> I just submitted a paper to the Journal of Crohn’s and Colitis entitled “Does the association with NOD2, *autophagy* and some pathogens really mean Crohn’s disease is caused by uncontrolled infection?”, and I was informed the paper has been accepted for publication.
> Apparently, the journal comprehends the notion that Crohn’s disease is more likely caused by escalated immune reaction to the increased infiltration of *luminal bacteria* and their debris rather than deficiency of the immune system and uncontrolled infection being reasonable, not ridiculous.


That's a lot of assumptions, it goes completely against current evidence, and you run into a host of issues by blaming the gut flora and ignoring autophagy:

-you'd have to explain why the first signs of crohn's disease is inflammation of the peyer's patches, peyer's patches sip pathogens with their M cell, not the indingenous luminal bacteria

-you're ignoring the thousands of autophagy papers and papers that show autophagy genes like NOD2, ATG16L1 and IRGM *are* involved in crohn's disease, all related to control of ...shockingly....intracellular bacteria, not the indigenous gut flora

-you're ignoring the fact that people with those mutated autophagy genes actually have a worse disease than those who do not

-you'd have to explain how indigenous luminal bacteria "infiltrate"...they don't, indigenous luminal bacteria don't infiltrate into the submucosa

-you'd have to explain why the immune reaction is transmural, the indigenous flora isn't capable of doing that

-you'd have to explain why people get fistulas, the indigenous flora isn't capable of doing that

-you'd have to explain why the disease is patchy, if it was the indigenous flora causing an immune reaction you'd have inflammation everywhere

-you'd have to explain the granuloma, not caused by the indigenous flora

-you have to explain why classic crohn's disease is regional in the terminal ileum, a pathogen explains this, luminal bacteria do not

-you have to explain why the disease would be in the ileum instead of the colon, the colon has a way higher bacterial load...but there's no inflammation there for many people with crohn's disease

-you're simply ignoring evidence at this point, you're ignoring NOD2 and autophagy

-you're ignoring the fact crohn's disease doesn't look like an immune response against the indigenous flora, it looks like.....intestinal TB, in fact it looks a whole lot like intestinal TB, from the transmural inflammation, to the patchy lesions, to the granuloma, what it doesn't look like at all, is UC

-you're ignoring the wealth of clinical evidence that AIEC is involved

-this would be the first disease in history where the body is unable to control the indigenous gut flora

-and the most important one, never has there been an immune response found against the indigenous flora, you actually need to find the immune response against the flora, not just guess that's it's there. You keep wondering if an infection is involved or not, you ignore the fact there is an immune response found against AIEC and MAP, and you're going with a theory that lacks any evidence of an immune response.

The reason I don't believe in the idea that our own body is somehow attacking our indigenous flora, and that luminal content is somehow infiltrating so deep into tissue that it's causing transmural inflammation and fistulas is because it makes no sense and it's not based on any evidence.


----------



## wildbill_52280

Xiaofa Qin said:


> I just submitted a paper to the Journal of Crohn’s and Colitis entitled “Does the association with NOD2, autophagy and some pathogens really mean Crohn’s disease is caused by uncontrolled infection?”, and I was informed the paper has been accepted for publication. Apparently, the journal comprehends the notion that Crohn’s disease is more likely caused by escalated immune reaction to the increased infiltration of luminal bacteria and their debris rather than deficiency of the immune system and uncontrolled infection being reasonable, not ridiculous.



what a wonderful question that needs to be properly addressed. 

"what do these observations mean?" and what is its significance in crohns/IBD in regards to causation.



i do believe a more significant issue in crohn's is immune reaction to inflitration of luminal bacteria, which includes pathogens as well. Rather, then nod2, which fails to predict crohn's and only seems related to severity of disease progession. Also more important then intracellular bacteria issues and here is one major reason why i believe this.

By simply considering the anatomy of the intestine: pathogens have to get past the layer intestinal flora/bacteria that covers the epithelium first and foremost. we need to explain how they do that before they(aeic/MAP), can invade a macrophage. next explain how they invaded the epithelium, the integrity of which is highly dependant upon the bacterial flora to maintain tight junction permeability, via short chain fatty acids and other mechanisms/signals that originate from the flora. 

All this seems to point in the direction of the flora being disrupted. Which would explain the remarkable results from fecal microbiota transplants. We still need to explain this data as well, why does a fecal transplant seem to eliminate all disease in patients without any drugs? there is a very good question. perhaps the answer is because correcting dysbiosis reverses the disease.


----------



## kiny

Xiaofa Qin said:


> I just submitted a paper to the *Journal of Crohn’s and Colitis*. Apparently, *the journal comprehends the notion that Crohn’s disease is more likely caused by escalated immune reaction* to the increased infiltration of luminal bacteria and their debris rather than deficiency of the immune system and uncontrolled infection being reasonable, not ridiculous.


Have you wondered why this journal is biased though?

Have you wondered why this journal is against biosimilars?

Have you wondered why half of this journal's publications are about medical trials?

*These are the companies who publish the journal*. Who do you think is going to lose billions of dollars if crohn's disease turns out to be an infectious disease that is curable?

Publishing in ECCO is not the same as getting something published in Nature or PlosOne, they are a highly biased journal, they shouldn't even be called a journal imo, they're a front for big pharma, that's why they're against biosimilars.







This is the same journal that allowed the _Weapons of Mass destruction
_ article to be posted that did didly squat to help us as patients.

I feel the same way Kuenstner does.

Publications need to be in OUR interest, not in the interest of being right or wrong because person A is too stubborn to acknowledge person B and person B too stubborn to acknowledge person A, our lives are on the line, not the ones of researchers or big pharma.

For a person with crohn's disease, autoimmune disease targeted at the gut flora or infections disease, is the difference between being on drugs for the rest of our lives or a *disease being curable*.

AIEC / MAP / Campylobacter are NOT just of academic importance, if there's a pathogen behind the disease it means the disease is an infection, and it means it's curable.

I have no issues with people who want to discuss this or challenge this notion, but I have 0 respect when people ignore evidence, since our lives are on the line.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3142597/


----------



## kiny

And the idea that crohn's disease is an infectious disease is not new, Dalziel in *1913*, who was the first person I know of who accurately published accounts of people with chronic enteritis, decades before it was named Crohn's disease by Burrill Crohn, suggested it because of it's clinical similarities to intestinal TB. The granuloma and transmural inflammation are highly reminiscent of intestinal TB.

Why this disease has ever been called an autoimmune disease is beyond my comprehension, never has there been an autoantigen found in crohn's disease that is targeting epithelial cells like in UC. The disease is patchy and localised to the terminal ileum in the majority of people.

Dalziel in 1913 would have found the notion that crohn's disease was a reaction against our own flora ridiculous, and 100 years later the notion is still just as ridiculous as it was back then.


The evidence that we suddenly lost tolerance to our gut flora and somehow, magically, our immune system decided to attack our own indigenous intestinal flora: *0 papers*

The evidence that autophagy, immune deficiency and an intracellular pathogen are involved: *thousands of papers*. And this includes concrete genetic evidence, which supports that autophagy is a major component in this disease.


----------



## Xiaofa Qin

kiny posted several long posts. Frankly, I would like to discuss with people with reasoning, but have no interest to argue with people over arbitrary allegations. You raised a lot of questions. In fact, you can find my answers to most of these questions in my paper or my previous posts.  



kiny said:


> That's a lot of assumptions, it goes completely against current evidence, and you run into a host of issues by blaming the gut flora and ignoring autophagy:


You should realize that the paper is in fact dealing with the possible relationship among NOD2, autophagy, pathogens and Crohn’s disease with up to date evidences. How can I ignore autophagy?



kiny said:


> -you'd have to explain why the first signs of crohn's disease is inflammation of the peyer's patches, peyer's patches sip pathogens with their M cell, not the indingenous luminal bacteria


As stated in post 168” As we know, the Peyer’s patch has less goblet cells and thinner mucus layer (http://www.ncbi.nlm.nih.gov/pubmed/7054025 ) and enriched with inflammatory cells, thus would be more vulnerable and sensitive. It would be no surprising that the inflammation started at these sites.” The inflammation would be started once the mucus layer became thinner enough to let just the debris rather the whole bacteria get in, at a stage the surface seems still intact as shown in the area of red ring in your post #167.  



kiny said:


> -you're ignoring the thousands of autophagy papers and papers that show autophagy genes like NOD2, ATG16L1 and IRGM *are* involved in crohn's disease, all related to control of ...shockingly....intracellular bacteria, not the indigenous gut flora
> 
> -you're ignoring the fact that people with those mutated autophagy genes actually have a worse disease than those who do not


As shown in the title in the paper as well as the post 166, I am not ignoring autophagy and NOD2, but provided some new explanation to the massive conflicting evidences.   



kiny said:


> -you'd have to explain how indigenous luminal bacteria "infiltrate"...they don't, indigenous luminal bacteria don't infiltrate into the submucosa


In fact, the indigenous bacteria in gut lumen can get into the mucosa, into the lymph, into blood and many organs under many situations like the alcoholic and non-alcoholic liver disease, cirrhosis, pancreatitis, shock, burn, etc, even without the apparent damage of the gut like in IBD. Here is a paper:  Berg RD. Bacterial translocation from the gastrointestinal tract. J Med. 1992;23(3-4):217-44.   



kiny said:


> -you'd have to explain why the immune reaction is transmural, the indigenous flora isn't capable of doing that


Read my post #118, I have a detailed description there. I have also submitted a manuscript entitled “Why damage is limited to the mucosa in ulcerative colitis while transmural in Crohn’s disease?” to World Journal of Gastrointestinal Pathophysiology and it has been accepted for publication (another journal of conspiracy?). This is an open assess journal and hopefully people can see it soon. 



kiny said:


> -you'd have to explain why people get fistulas, the indigenous flora isn't capable of doing that


Fistula would be just a further development of the tranmural damage, read my post #118.



kiny said:


> -you'd have to explain why the disease is patchy, if it was the indigenous flora causing an immune reaction you'd have inflammation everywhere


The inflammations usually occurred at places where the feces stayed longer ( https://en.wikipedia.org/wiki/Crohn's_disease ), and the inflammation became greatly alleviated after diversion of the luminal content. This would suggest the inflammation are largely caused by the toxic components in gut lumen, rather than an uncontrolled growth of AIEC, MAP, etc, in the macrophages and mucosa.  



kiny said:


> -you'd have to explain the granuloma, not caused by the indigenous flora


As illustrated in my paper, increased infiltration of bacteria, their debris, or even dietary particles all can cause granuloma. 



kiny said:


> -you have to explain why classic crohn's disease is regional in the terminal ileum, a pathogen explains this, luminal bacteria do not


How does a pathogen explain this? Because the mucosa at terminal ileum is different from the other sites? Again, it would be the prolonged stay of the feces and high pressure here due to the existence of the ileocecal valve that gave bacteria the chance to penetrate into the mucosa and became flourished there.



kiny said:


> -you have to explain why the disease would be in the ileum instead of the colon, the colon has a way higher bacterial load...but there's no inflammation there for many people with crohn's disease


As illustrated in my paper (Fig. 5), I believe the largely macrophage mediated Crohn’s disease occurred when relative sterile. Otherwise, large amounts of neutrophils will be recruited and manifested as ulcerative colitis. You should realize that Crohn’s Disease just at the colon has become the dominant type in multiple recent studies. For instance, in Stockholm County, Sweden, colonic CD increased from 15% during 1959-1964 to 32% during 1980-1989, and further to 52% during 1990-2001. My paper provided some explanation. 



kiny said:


> -you're simply ignoring evidence at this point, you're ignoring NOD2 and autophagy


This is the third time of the same accusal. I am tired to reply. 



kiny said:


> -you're ignoring the fact crohn's disease doesn't look like an immune response against the indigenous flora, it looks like.....intestinal TB, in fact it looks a whole lot like intestinal TB, from the transmural inflammation, to the patchy lesions, to the granuloma, what it doesn't look like at all, is UC


As stated in my post 118 and the paper to be published, I actually felt CD would be more like tuberculosis and pneumoconiosis in that they mainly involve macrophages and formation of glanulomas. 



kiny said:


> -you're ignoring the wealth of clinical evidence that AIEC is involved


Back to November last year, in response to your post #73, I have clearly stated that I do not think AIEC is innocent bystander (see post #74). In the recent post #168, I referred you to that post again to clarify my opinion. I am not ignoring it. 



kiny said:


> -this would be the first disease in history where the body is unable to control the indigenous gut flora
> 
> -and the most important one, never has there been an immune response found against the indigenous flora, you actually need to find the immune response against the flora, not just guess that's it's there. You keep wondering if an infection is involved or not, you ignore the fact there is an immune response found against AIEC and MAP, and you're going with a theory that lacks any evidence of an immune response.


As stated in my post #166, “the gut contains large amounts of LPS (also called endotoxin) that can kill the host thousands of times over, and the long evolution has equipped the body with an innate immune system with defense cells like macrophages being able to launch promptly a vigorous instinct response to low doses of LPS. Thus the inflammation of the gut can be started and continued without any antigen.” 



kiny said:


> The reason I don't believe in the idea that our own body is somehow attacking our indigenous flora, and that luminal content is somehow infiltrating so deep into tissue that it's causing transmural inflammation and fistulas is because it makes no sense and it's not based on any evidence.


In fact, even under normal condition, the body secretes large amounts (3 - 5 g/day) of antibodies (Ig A) into the lumen of the gut. This may make no sense to you but is a critical mechanism of front-line defense of the body (Fagarasan S, Honjo T. Intestinal IgA synthesis: regulation of front-line body 
defences. Nat Rev Immunol. 2003 Jan;3(1):63-72). As stated above, the indigenous gut bacteria can be translocated deep into the mucosa and other organs under many situations even with less damage of the gut. There are a lot of evidences.

As you stated, the notion of infection is not new. In fact, from the very beginning, infectious agents had been suspected as the cause and extensively studied. Most people finally gave up this notion due to the failure of the anti-infection treatment. Apparently, a cure would largely depend on finding out the real cause and root mechanism of the disease, which would in turn depends on careful analysis and insightful reasoning of all the evidences.


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## kiny

Xiaofa Qin said:


> As stated in post 168” As we know, the Peyer’s patch has less goblet cells and thinner mucus layer (http://www.ncbi.nlm.nih.gov/pubmed/7054025 ) and enriched with inflammatory cells, thus would be more vulnerable and sensitive. It would be no surprising that the inflammation started at these sites.” The inflammation would be started once the mucus layer became thinner enough to let just the debris rather the whole bacteria get in, at a stage the surface seems still intact as shown in the area of red ring in your post #167.


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3049390/

I think this is what is going on. The PP are mini lymph nodes, they aren't just inflamed, they are activated, they would be the APC trigger that's need to cause an inflammatory cascade, and AIEC has been shown to invade them.


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## kiny

Xiaofa Qin said:


> Most people finally gave up this notion due to the failure of the anti-infection treatment.


most? http://www.crohnsforum.com/showthread.php?t=52198

I don't know why you recognise AIEC in CD but then say people have given up on the theory of infection. AIEC is an infection, it infects macrophages and enters deep inside transmural tissue thanks to it's fimbriae.


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## kiny

Xiaofa Qin said:


> How does a pathogen explain this? Because the mucosa at terminal ileum is different from the other sites?


Pathogens all have a niche in the body. When a cow gets infected with MAP, it goes straight to the terminal ileum. Why? Because, that's why, pathogens are site specific, they find a niche that allows them to prosper.

Why is H pylori in the stomach? Because.

Why is C diff in the colon? Because.

Why the terminal ileum in crohn's disease? Because it has peyer's patches I'm thinking.


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## sir.clausin

You guys are very knowledgeable, I am following this thread with huge interest.


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## Xiaofa Qin

Thanks sir.clausin and many others for the interest. Here I would like to share another personal story. 

Not long ago, I found a paper published in Journal of Pediatric Gastroenterology and Nutrition regarding the incidence of inflammatory bowel disease in northern Stockholm (Malmborg P, et al. Increasing incidence of paediatric inflammatory bowel disease in northern stockholm county,  2002-2007. J Pediatr Gastroenterol Nutr. 2013 Jul;57(1):29-34).  Interestingly, it showed a sudden decrease of Crohn’s disease (CD) from about 10 per 100,000 during 2002 - 2004 to 7 during 2005 – 2007, but an increase in ulcerative colitis (UC) from about 1 per 100,000 during 2002 - 2004 to 4 during 2005 – 2007, with hardly any change of total IBD during these two periods. This surprised me as a study by Perminow, G et al showed a sudden increase of Crohn’s disease during 2005 – 2007 in South-Eastern Norway (Perminow G, et al. A characterization in childhood inflammatory bowel disease, a new population-based inception cohort from South-Eastern Norway, 2005-07, showing increased incidence in Crohn's disease. Scand J Gastroenterol. 2009;44(4):446-56), which I have included in my paper (see Fig. 4E) and explained as the approval of sucralose by the European Union (EU) in 2004.  I was greatly puzzled by the opposite change of CD between these two neighboring countries of EU as well as the opposite change of CD and UC in Stockholm during the same period. I told myself the cause of IBD would be indeed very complex and there is no way to get an easy answer. 

However, when I check a little bit further, I found some interesting information. Although EU approved sucralose in 2004, it also reduced the maximum permitted level for cyclamate in soft drinks from 400 mg/l to 250 mg/l in the same year. I further found that cyclamate is heavily used in countries like Sweden (Ilbäck NG, et al. Estimated intake of the artificial sweeteners acesulfame-K, aspartame, cyclamate and saccharin in a group of Swedish diabetics. Food Addit Contam. 2003 Feb;20(2):99-114) that may be  far beyond the acceptable daily intake (ADI) in some children, while the use of cyclamate in the neighboring Norway is near zero (Husøy T, et al. Reducing added sugar intake in Norway by replacing sugar sweetened beverages with beverages containing intense sweeteners - a risk benefit assessment. Food Chem Toxicol. 2008 Sep;46(9):3099-105). On the other hand, a study conducted in 2007 found high concentrations of sucralose in the surface water near cities like Oslo, Norway, but much lower concentrations in cities in Sweden (Loos R, et al. Sucralose screening in European surface waters using a solid-phase extraction-liquid chromatography-triple quadrupole mass spectrometry method. J Chromatogr A. 2009 Feb 13;1216(7):1126-31). These suggest Norway would be more greatly affected by the new approval of sucralose by EU in 2004 but Sweden would be more greatly affected by the reduced maximum permitted level for cyclamate the same year. Thus the mysterious simultaneous decrease of CD and increase of UC at Stockholm turned out to be a vivid test for my hypothesis that CD and UC are virtually two manifestations of the same morbidity rather than two different diseases (Qin X. Etiology of inflammatory bowel disease: a unified hypothesis. World J Gastroenterol. 2012 Apr 21;18(15):1708-22) and a shift can occur along with the intensity of exposure. I submitted a paper to the journal that it is accepted and got published recently (Qin X. How to explain the discordant change of ulcerative colitis and Crohn's disease in adjacent or even the same regions and time periods. J Pediatr Gastroenterol Nutr. 2013 Jul 16. [Epub ahead of print]). 

Time and again, I have asked myself how valid my hypothesis could be. That have driven me to check all the way back to the earliest literatures and found the clustering of UC cases since 1888 and the first marketing of saccharin in 1887. It is the many co-incidences like above that makes me strongly feel we should check out the possible link between those dietary chemicals and IBD. Yes, there are numerous hypotheses: improved hygiene, cold chain, sunshine, vitamin D, MAP, AIEC, worms, and many others. Each hypothesis would have to be tested against the many peculiar changes in IBD epidemiology. Time will eventually tell us how valid and how important each hypotheses would be.


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## kiny

since you like epidemiology studies, there's tens of studies like this showing clustering






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## Xiaofa Qin

Thanks kiny for sharing the info. These are very interesting studies. There would be always a reason for a phenomenon, and the answer could be very simple once we solved the mystery.


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## Xiaofa Qin

The clustering of a disease in a family may be caused by both genetic and environmental factors. However, the occurrence of Crohn’s disease in the father and 4 of the 8 children as reported (Joossens M, et al. Contribution of genetic and environmental factors in the pathogenesis of Crohn's disease in a large family with multiple cases. Inflamm Bowel Dis. 2007 May;13(5):580-4) fits perfectly into the pattern of some inherited genetic disorders such as the autosomal dominant disorder in which the father carried a copy of the risk gene or the autosomal recessive inheritance in which the father carried two copy and the mother carried one copy of the risk gene. The authors suspected a major environmental factor, largely because they did not find the known genetic susceptibility factors. The problem is, as discussed in my early post (see post #98), although we have identified 200 risk genes for IBD, the really crucial genes seemed out of the radar. No spontaneous colitis occurred in knockout mice deficient of either NOD2 (Pauleau, A.L. and P.J. Murray, Role of nod2 in the response of macrophages to toll-like receptor agonists. Mol Cell Biol, 2003. 23(21): p. 7531-9) or ATG16L1 (Saitoh, T., et al., Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature, 2008. 456(7219): p. 264-8). In fact, loss of NOD2 in IL-10 knockout mice resulted in significant amelioration of chronic colitis (Jamontt J, et al. Nucleotide-binding oligomerization domain 2 signaling promotes hyperresponsive macrophages and colitis in IL-10-deficient mice. J Immunol. 2013 Mar 15;190(6):2948-58), and Atg16L1-deficient mice cleared bacteriuria more rapidly and thoroughly than controls (Wang C, et al. Atg16L1 deficiency confers protection from uropathogenic Escherichia coli infection in vivo. Proc Natl Acad Sci U S A. 2012 Jul 3; 109(27): 11008-13). In contrast, spontaneous colitis developed in mice either deficient of MUC2 (Van der Sluis, M., et al., Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology, 2006. 131(1): p. 117-29), the main component of the mucus layer of the gut, or aberrant assembly of MUC2 (Heazlewood, C.K., et al., Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis. PLoS Med, 2008. 5(3): p. e54), or just some defect in the mucin linked glycans (Fu, J., et al., Loss of intestinal core 1-derived O-glycans causes spontaneous colitis in mice. J Clin Invest, 2011. 121(4): p. 1657-66). This had led me writing the paper entitle “Have genome-wide association studies or knockout mice more reflected the true nature of inflammatory bowel disease?” that has been published in Journal of Crohn’s and Colitis. 

Although clustering cases of a disease can be caused by both genetic and environmental factors, for the clustered cases in a family like above, I think more tests should be done on other genes like MUC2, etc, rather than just the glamorous ones like NOD2 and those related to autophagy.


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## kiny

I don't think the clustering is a coincidence. There might be undiscovered genetic predispostions...but really...we're talking an epidemic at this point.

10 new cases in Canada per day, crohn's disease has surpassed diabetes there. Around 1 in 150 people in canada now have crohn's disease. (a quarter of a million people in a country of 30 million) This is set to rise. The disease is much more destructive in newly diagnosed children.

This is not just genes, something is going on in the environment. I think the genes give clues, but there are people getting this disease regardless of any genetic make-up, it's rising way too fast.

UC is actually pretty stable in many countries. While crohn's disease keeps going up, especially in Asian nations. They are not at all linked to each other.

They will have to start paying attention to this disease, the economic cost of both the treatment and the people who can't work is massive.

Another interesting thing about Canada and Western Europe, immigrants from regions with low crohn's disease rates, get it at rates higher than the local population once they immigrated.


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## sir.clausin

Ok, so I can not shut up, because I was thinking this last night. This is what makes me Believe it´s an infection of some sort, because a friend of mine moved from Iran to Sweden a couple of years ago, and only one year after living here *BAM* Crohns disease in the ileum. 

And what really scares me is, that I read somewhere in a local Swedish Magazine that Sweden have the largest numbers of Crohns patient (newly diagnosed) IN THE WORLD! So what makes Sweden unique?! The only obvious reason I can Think of is....milk. Milk consumption in Sweden is very high, second only to Finland. But that might not be the whole truth, but anyways...I can´t be that hard to figure out what makes people get it here so easily...I wish we knew. I don´t Believe in the genes-thingy, too many is getting this shitty disease.


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## kiny

Xiaofa Qin, tell me what you think about this. 

http://www.ncbi.nlm.nih.gov/pubmed/23850724


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## Xiaofa Qin

kiny said:


> I don't think the clustering is a coincidence. There might be undiscovered genetic predispostions...but really...we're talking an epidemic at this point.
> 
> 10 new cases in Canada per day, crohn's disease has surpassed diabetes there. Around 1 in 150 people in canada now have crohn's disease. (a quarter of a million people in a country of 30 million) This is set to rise. The disease is much more destructive in newly diagnosed children.
> 
> This is not just genes, something is going on in the environment. I think the genes give clues, but there are people getting this disease regardless of any genetic make-up, it's rising way too fast.
> 
> UC is actually pretty stable in many countries. While crohn's disease keeps going up, especially in Asian nations. They are not at all linked to each other.
> 
> They will have to start paying attention to this disease, the economic cost of both the treatment and the people who can't work is massive.
> 
> Another interesting thing about Canada and Western Europe, immigrants from regions with low crohn's disease rates, get it at rates higher than the local population once they immigrated.


My early post (#185) was actually talking about the occurrence of Crohn’s disease in the father and his 4 of the 8 children as referred by your early post (#183) that fits into the pattern of some inherited genetic diseases. As for the epidemic of IBD since last century, I think we share the same feeling that some environmental factors would have played the predominant role. I believe a really reduction in IBD would largely depend on finding out these causative factors in the environment (Qin X. How can we really reduce the morbidity of inflammatory bowel disease - Research on genes and cytokines, or find out the causative factors in the environment? J Crohns Colitis. 2009 Dec;3(4):315). It would be indeed worrisome for the rapid increase of IBD in Asia. Appallingly, as shown by a recent study by the Asia-Pacific Crohn's and Colitis Epidemiology Study, Guangzhou, China has an even higher incidence of IBD than the more developed neighboring Hong Kong and Macau; Sri Lanka, Malaysia, and Indonesia also showed a similar, or even higher incidence of IBD compared to the much more developed Singapore. It would suggest the causative agents are spreading into the developing countries. I submitted a paper to Gastroenterology entitled “Is the gap between the developed and developing countries in the incidence of inflammatory bowel disease disappearing?” to raise this alarm, and this paper has been accepted for publication.


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## Xiaofa Qin

sir.clausin said:


> Ok, so I can not shut up, because I was thinking this last night. This is what makes me Believe it´s an infection of some sort, because a friend of mine moved from Iran to Sweden a couple of years ago, and only one year after living here *BAM* Crohns disease in the ileum.
> 
> And what really scares me is, that I read somewhere in a local Swedish Magazine that Sweden have the largest numbers of Crohns patient (newly diagnosed) IN THE WORLD! So what makes Sweden unique?! The only obvious reason I can Think of is....milk. Milk consumption in Sweden is very high, second only to Finland. But that might not be the whole truth, but anyways...I can´t be that hard to figure out what makes people get it here so easily...I wish we knew. I don´t Believe in the genes-thingy, too many is getting this shitty disease.


It would be very interesting for the MILK theory in Sweden, as all the link between milk and Crohn’s disease has pointed to the contamination of the milk by Mycobacterium avium subsp. paratuberculosis (MAP) from the cattle with Johne’s disease. However, as discussed in the early post (see post #31), according to document by some government agency, Sweden had hardly any uncontrolled MAP infection in the herds (see Sternberg Lewerin S et al. Control of paratuberculosis in Sweden).  Are you suggesting the poor accuracy of these documents or some new pathogens in the milk other than MAP? Anyway, thanks for sharing the thoughts and story.


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## Xiaofa Qin

kiny said:


> Xiaofa Qin, tell me what you think about this.
> 
> http://www.ncbi.nlm.nih.gov/pubmed/23850724


Sorry for the delayed response. I have some other things to do. I read this paper. To my understanding, the so called allelic imbalance refers to a difference in the expression of a risk gene versus the normal gene, thus may somehow reflected the intensity of the risk, but not the mechanism and nature of the risk. Therefore, the increased NOD2 expression by the Newcastle Disease Virus seems more related to the pathogenesis or etiology of IBD. However, increased NOD2 expression can be caused not only by some infectious agents like bacteria or virus, but also some non-infectious agents like organic dusts (Poole JA, et al. Organic dust augments nucleotide-binding oligomerization domain expression via an NF-{kappa}B pathway to negatively regulate inflammatory responses. Am J Physiol Lung Cell Mol Physiol. 2011 Sep;301(3):L296-306). NOD2 knockout mice demonstrated increased expression of some pro-inflammatory cytokines like IL-6, along with higher degree of airway inflammation induced by the dust. This is in accordance with my notion that Crohn's disease and pneumoconiosis may share some similarities in pathogenesis as discussed in my early posts (see post 118). It is the highly effective treatments of CD by the immune suppression agents but significantly increased risk of infection to bacteria, fungi, and virus that made me suspected that NOD2 and autophagy may be related to CD through the tolerance and degradation of the increasingly infiltrated luminal bacterial debris like LPS and peptidoglycan by inflammatory cells like macrophages, more than the killing and clearance of the live microbes. I submitted a paper entitled “How NOD2 and autophagy may be related to Crohn’s disease? A view shifted from live microbes to luminal bacterial debris” to Journal of Crohns and Colitis to express my view, and it was accepted for publication. This is just my personal opinion.


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## wildbill_52280

Xiaofa Qin said:


> My early post (#185) was actually talking about the occurrence of Crohn’s disease in the father and his 4 of the 8 children as referred by your early post (#183) that fits into the pattern of some inherited genetic diseases. As for the epidemic of IBD since last century, I think we share the same feeling that some environmental factors would have played the predominant role. I believe a really reduction in IBD would largely depend on finding out these causative factors in the environment (Qin X. How can we really reduce the morbidity of inflammatory bowel disease - Research on genes and cytokines, or find out the causative factors in the environment? J Crohns Colitis. 2009 Dec;3(4):315). It would be indeed worrisome for the rapid increase of IBD in Asia. Appallingly, as shown by a recent study by the Asia-Pacific Crohn's and Colitis Epidemiology Study, Guangzhou, China has an even higher incidence of IBD than the more developed neighboring Hong Kong and Macau; Sri Lanka, Malaysia, and Indonesia also showed a similar, or even higher incidence of IBD compared to the much more developed Singapore. It would suggest the causative agents are spreading into the developing countries. I submitted a paper to Gastroenterology entitled “Is the gap between the developed and developing countries in the incidence of inflammatory bowel disease disappearing?” to raise this alarm, and this paper has been accepted for publication.


although i do not agree with everything stated here, i see the possibility of perhaps some bacteria which might travel around or something which could find a susceptible host. i'm wondering if it could originate from a more developed country or something, i do recall them finding strange bacteria in ibd patients, sorry i'm lacking the sharpness today on the terminology, but i believe it was bacteria that are termed superbugs/antibiotic resistant or something like that.

sorry, really bad theory/hypothesis on my part here, but just thought id say something related.


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## wildbill_52280

Xiaofa Qin said:


> It would be very interesting for the MILK theory in Sweden, as all the link between milk and Crohn’s disease has pointed to the contamination of the milk by Mycobacterium avium subsp. paratuberculosis (MAP) from the cattle with Johne’s disease. However, as discussed in the early post (see post #31), according to document by some government agency, Sweden had hardly any uncontrolled MAP infection in the herds (see Sternberg Lewerin S et al. Control of paratuberculosis in Sweden).  Are you suggesting the poor accuracy of these documents or some new pathogens in the milk other than MAP? Anyway, thanks for sharing the thoughts and story.


i would like to say about this idea is that before i was officially diagnosed with crohns disease, for about 1.5 years prior i had been almost entirely dairy free on some fad diet related to helping my acne, therefore i only ate cheese that had been cooked @ 500 something degrees, as i only ate pizza on occasion. 

but my symptoms didnt really start until i tried going back to milk, although this could have simply been the lactose, and still possibly other things like eating spinach where i would also may have acquired some pathogens. i can say a month after going back to milk, i only had a few glasses for a week tho mind you, didnt fully go back yet, i then started to develop objective symptoms of crohns, in addition to just feeling like crap after a round of amoxicillin which i believe was what really made me susceptible to crohns, but the bacteria to really start the inflammation may have come from the milk i consumed. 

sorry about all the details but i tried my damnest over the years to recall every event prior to getting crohns so i could understand this disease. hopefully my testimony helps a bit.


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## mf15

Xiaofa: They are starting to get the idea.
Old Mike
http://medicalxpress.com/news/2013-08-pathways-inflammatory-bowel-diseases.html


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## kiny

I don't know where they got the _1 in 250 people in Europe with IBD_.

If that's correct, Europe has a population of 750 million. That means 3 million people in Europe alone have IBD.

No wonder Humira is the best selling drug in the world.

They really need to come up with better medication and a cure. In Canada crohn's disease surpassed diabetes I heard.

1 in 100 have IBD there I read.


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## rollinstone

the more and more people getting crohns I think is due to different causes, after all, what is the tell tale diagnostic tool, chronic inflammation of a biopsy underneath a microscope? this inflammation is bound to have multiple causes, whether micro bacterium to disbiosis related, who knows.


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## Xiaofa Qin

Thanks all for the posts.



mf15 said:


> Xiaofa: They are starting to get the idea.
> Old Mike
> http://medicalxpress.com/news/2013-08-pathways-inflammatory-bowel-diseases.html


Thanks Old Mike for referring me the EU-funded project IPODD ('IBD: proteases offer new targets for drug discovery'). It is an interesting study. They looked into the matrix metalloproteases (MMPs) within the tissue as well as the proteases from gut bacteria, but, unfortunately, not the digestive proteases like trypsin and chymotrypsin. In my opinion, impaired inactivation of these pancreatic proteases probably played a more important, primary causative role, as proposed in the paper I published more than a decade ago (Qin XF. Impaired inactivation of digestive proteases by deconjugated bilirubin: the possible mechanism for inflammatory bowel disease. Med Hypotheses. 2002 Aug;59(2):159-63). Anyway, it would be a good thing people are starting to get some idea in this area.


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## mf15

Qin: I see you are always thinking on this subject.
Thank You, for your efforts.
Old Mike
http://www.ncbi.nlm.nih.gov/pubmed/23946890


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## Xiaofa Qin

mf15 said:


> Qin: I see you are always thinking on this subject.
> Thank You, for your efforts.
> Old Mike


Thanks Old Mike. With millions of people suffering from such devastating diseases as Crohn’s disease and ulcerative colitis, I felt obligated to warn the world what I perceived as the possible cause and glad to participate in the challenging exploration for the possible mechanism.


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## Xiaofa Qin

Frankly, I frequently feel frustrated, as it was more than a decade ago that I perceived IBD could be simply resulted from the inhibition of gut bacteria by dietary chemicals like saccharin, etc, and the resultant damage of gut barrier by the poorly inactivated digestive proteases (Qin XF. Impaired inactivation of digestive proteases by deconjugated bilirubin: the possible mechanism for inflammatory bowel disease. Med Hypotheses. 2002 Aug;59(2):159-63. http://www.ncbi.nlm.nih.gov/pubmed/12208202 ). Since then, I have taken great efforts advocating to check out this possibility. However, it failed to raise any attention and action. In contrast to this, although the emergence and dramatic increase of IBD in last century clearly suggested environmental factors would have played the predominant role, the finding of the link between NOD2 and Crohn’s disease at about the same time was treated as a big breaking through in IBD and followed by many studies. 

Now, with large amounts of evidences generated in the last decade, we would be able to have a more clear vision and judgment.

In the last decade, NOD2 has been extensive studied. However, we still do not know how NOD2 is linked to Crohn’s disease. More intriguingly, it found no correlation between the distribution of NOD2 mutation in the population and the incidence of Crohn’s disease even in the western countries, suggesting the minimal effect even this most highly related risk gene. Meanwhile, the extensive studies have found another 200 IBD-related genes, which can still only explain a small portion of the variation that have been claimed at beginning capable of being explained by NOD2 alone. In addition, it is found that gut microbiota contains genes that are 100 times of the human genome. Now it projects a promising future that a breaking through might be achieved after decoding the many risk genes found and more to be found, the gut microbiota, and their interactions with the environment.  

Thus, I and the main stream presented two totally different scenarios: I feel I, as a spare time IBD researcher and without any funding on IBD, may have virtually solved the mystery of IBD more than a decade ago, while the main stream presented an extremely complex IBD that may need billions, if not trillions, and decades, if not centuries, to decipher it. 

I feel my hypothesis prevailed the many others in that it provided a simple explanation for many puzzles on IBD that encompass epidemiology such as its emergency around the beginning of last century, the dramatic increase in countries like the United States since 1950s, the temporary level off in later 1970s, the recent worldwide increase, and the similarities and discordances between CD and UC; pathology such as the limited damage of UC but transmural damage in CD; and genetics such as the relationship among NOD2, autophagy genes, and CD. 

I have been pretty frustrated, just like I feel seeing pretty clearly some kids get drowned in the shallow water but I was blocked to reach them. There are many people around but none paid the attention. There are also many lifeguards but they kept digging into the mud with their advance equipments that generated a lot of turbidity, making the vision more and more blurry. Under such a situation, what I can do is just shouting again and again, pointing to the direction I perceived they should check. Each manuscript is just a reflection of this effort. Following is the list of some of them. 


Qin X. Does the association with NOD2, autophagy and some pathogens really mean Crohn’s disease is caused by uncontrolled infection? Journal of Crohn’s Colitis. 2013 Aug 13 [Epub ahead of print]
Qin X. How NOD2 and autophagy may be related to Crohn's disease? A view shifted from live microbes to luminal bacterial debris. Journal of Crohn’s Colitis. 2013 Aug 19 [Epub ahead of print]
Qin X. Have genome-wide association studies or knockout mice more reflected the true nature of inflammatory bowel disease? Journal of Crohn’s Colitis. 7(5):419-20, 2013. 
Qin X. Why damage is limited to the mucosa in ulcerative colitis while transmural in Crohn’s disease? World Journal of  Gastrointestinal  Pathophysiology. 4(3): 63-63, 2013.
Qin X. How to explain the discordant change of ulcerative colitis and Crohn's disease in adjacent or even the same regions and time periods. Journal of Pediatric Gastroenterology and Nutrition. 2013 Jul 16. [Epub ahead of print] 
Qin X. Is the gap between the developed and developing countries in the incidence of inflammatory bowel disease disappearing? Gastroenterology 2013 (accepted)
Qin X. Etiology of inflammatory bowel disease: a unified hypothesis. World Journal of Gastroenterology 18(15):1708-22, 2012. 
Qin X. Food additives: possible cause for recent remarkable increase of inflammatory bowel disease in children. Journal of  Pediatric  Gastroenterology and  Nutrition. 54(4):564, 2012.
Qin X. The possible cause for the rapid rise in incidence of Irish paediatric inflammatory bowel disease. Arch Dis Child. 2012 May 16. [eLetter] 
Qin X. What caused the recent worldwide increase of inflammatory bowel disease: Should sucralose be added as a suspect? Inflamm Bowel Dis. 17(10):E139, 2011. 
Qin X. What made Canada become a country with the highest incidence of inflammatory bowel disease: Could sucralose be the culprit? Can J Gastroenterol 25(9):511, 2011
Qin X. The effect of dietary chemicals on gut bacteria and IBD demands further study. Journal of Crohn’s Colitis. 5(2):175, 2011. 
Qin X. How can we really reduce the morbidity of inflammatory bowel disease — Research on genes and cytokines, or find out the causative factors in the environment? Journal of Crohn’s Colitis  3(4):315, 2009.  
Qin X.  Can meat and protein really increase, while vegetables and fruits decrease the risk of inflammatory bowel disease? How? J Crohn’s Colitis 3:136, 2009
Qin X. What caused the extra high incidence of inflammatory bowel diseases in the industrialized countries in the west – lack of some nutrients or increased intake of some harmful agents? Inflammatory Bowel Diseases. 15: 319, 2009 
Qin X. Impaired inactivation of digestive proteases: a factor that may have confounded the efficacy of antibiotics aimed at reducing the exposure to luminal bacteria and their components. American Journal of Gastroenterology. 103: 2955-2956, 2008.
Qin X. With the great complexity unveiling, can we still decipher the interaction between gut flora and the host in inflammatory bowel disease to find out the mechanism and cause? How? Inflammatory Bowel Diseases. 14: 1607-1608, 2008. 
Qin X. Has Crohn's disease really occurred anywhere in the digestive tract? Inflammatory Bowel Diseases.  140):1461-2, 2008.
Qin X.  Gut microbiota: A new aspect that should be taken into more consideration when assessing the toxicity of chemicals or the adverse effects and efficacy of drugs. Regulatory Toxicology and Pharmacology. 51, 251, 2008.
Qin X.  Reduced production of digestive proteases and the efficacy of enteral and parenteral nutrition on inflammatory bowel disease. Inflammatory Bowel Diseases. 14, 871, 2008.
Qin X. Synergic effect of bacterial glycosidases and digestive proteases on mucus degradation and the reduced risk of inflammatory bowel disease-like gut damage in both germ-free and poor hygiene conditions. Inflammatory Bowel Diseases. 14, 145-146, 2008.
Qin X.  What is human inflammatory bowel disease (IBD) more like: Johne's disease in cattle or IBD in dogs and cats? Inflammatory Bowel Diseases. 14, 138, 2008.
Qin X. Inactivation of digestive proteases: another mechanism that probiotics may have conferred a protection. American Journal of Gastroenterology. 102: 2109, 2007.
Qin X. Inactivation of digestive proteases by deconjugated bilirubin: The possible evolutionary driving force for bilirubin or biliverdin predominance in animals. Gut. 56, 1641-1642, 2007.
Qin X.  Is the incidence of inflammatory bowel disease in the developed countries increasing again? Is that surprising? Inflammatory  Bowel Diseases. 13, 804-805, 2007. 
Qin X. What caused the increase of autoimmune and allergic diseases: a decreased or an increased exposure to luminal microbial components? World Journal of Gastroenterology. 13, 1306-1307, 2007. 
Qin X.  Inactivation of digestive proteases: another aspect of gut bacteria that should be taken into more consideration. World Journal of Gastroenterology. 13, 2390-2391, 2007. 
Qin X. Primary sclerosing cholangitis and inflammatory bowel disease: where is the link? American Journal of Gastroenterology. 102, 1332-1333, 2007. 
Qin X. High incidence of inflammatory bowel disease with improved hygiene and failure to get human-like IBD in laboratory animals. World Journal of Gastroenterology. 13, 3271, 2007. 
Qin X. Inhibition of gut bacteria by dietary chemicals and the hygiene hypothesis. Annals of  Allergy, Asthma and Immunology. 98, 602, 2007.  
Qin, X. Impaired inactivation of digestive proteases by deconjugated bilirubin: the possible mechanism for inflammatory bowel disease. Medical Hypotheses, 59, 159-163, 2002.


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## rollinstone

I assure you your work is appreciated more than you know, you really are a great person for the research you've done and im so glad people like you exist, i can't thank you enough, I am really hopeful that they make a break through soon with FT therapy restoring gut bacteria, my disease seemed to be onset by long term doxycycline use, i believe that destroyed the healthy bacteria creating an extreme disbiosis or even extinction of beneficial bacteria.


----------



## Xiaofa Qin

Thanks Joshuaaa for the warm words. It encourages me to continue my efforts. I believe IBD is preventable, but at first we need finding out the causative factors in the environment. IBD would also be curable. In my opinion, this may largely rely on at first restore the gut barrier function, then followed by the restoration of normal gut flora.


----------



## wildbill_52280

Xiaofa Qin, 

is this of any significance to you?



> Bacteroides is the only group of bacteria known to be able to inactivate pancreatic trypsin. Faecal tryptic activity was high in CD patients, and inversely correlated to the levels of Bacteroides.


abstract http://www.ncbi.nlm.nih.gov/pubmed/23840402


----------



## mf15

Really good find Wildbill. So good it might complete the circle.
Here is another example for UC,same thing lowered bacteroides
http://www.ncbi.nlm.nih.gov/pubmed/21073731

You might want to look at this thread I have on oxygen in the colon how
it might relate to this,and perhaps provide an answer. Seems like all this
ties together.  Inflammation,generates more oxygen in the colon iNOS/possible excess nitrates in diet,obligate anaerobes/bacteriodes die, trpsin/protease is not deactivated,facultative anaerobes grow and invade,more inflammation,tissue destruction. 
Or excess nitrate in diet,might start the whole mess off.
Old Mike 
http://www.crohnsforum.com/showthread.php?p=694401#post694401

here is something on saccharin and gut bacteria
http://www.ncbi.nlm.nih.gov/pubmed/2420077


----------



## Xiaofa Qin

Thanks wildbill_52280 and Old Mike for sharing the info and thoughts. 

As stated in the paper I published several years ago (Qin X. With the great complexity unveiling, can we still decipher the interaction between gut flora and the host in inflammatory bowel disease to find out the mechanism and cause? How? Inflamm Bowel Dis. 2008 Nov; 14(11):1607-8), I felt it would be an extremely difficult task in attempting to find out the mechanism and cause of IBD by comparing the abundance of each of the dozens of thousands species of gut bacteria in patients versus controls, then analyzing the unique features that each bacterial species possesses and the specific profile of response by the host that each bacterial species elicits. In contrast, in my opinion, the overall effect of this dysbiosis, such as the increased activity of digestive proteases in the lower gut, would be more easily assessed and may also be in fact more directly related to the pathogenesis of the disease; and this detrimental effect of dysbiosis may be easily corrected by certain strains of bacteria such as Bacteroides mentioned in wildbill_52280’s post (#203) and discussed in my earlier post (#170).


----------



## mf15

Here is the problem,as far as a bacteroides as a probiotic.
Is FT the only solution,or can we somehow regrow our own.
http://www.drmyhill.co.uk/wiki/Prob...ose_following_antibiotics_and_gastroenteritis

somewhat better article
http://www.drpompa.com/Health-Tips/probiotics-digestive-problems-digestive-disease.html

in the past I used to eat some dirt but was afraid of getting some pathogen from say rabbit poo,but perhaps

if you dig down you might be ok. You don't actually have to swallow the dirt,just hold it in your mouth and swallow the saliva.



Another way is perhaps with fermented cabbage,but a slightly different take.

You would have to have a fermentation lock,like they use to make wine to exclude oxygen,then some type of straw arrangement that is also sealed,once you get lots of bacteria going,suck out all the juice.

I suspect you can only due this once,since air would have to be let in to get the juice out of the straw,unless of course you use nitrogen to pressurize the container while drinking.

Then again you might just be able to drink the juice real fast without exposing it to too much oxygen.



There has got to be a way around this,hopefully by reducing iNOS and ROS the obligate anaerobes will grow better.


----------



## Xiaofa Qin

Bacteroides may be easily grown in media (Eley A, Greenwood D, O'Grady F. Comparative growth of Bacteroides species in various anaerobic culture media. J Med Microbiol. 1985 Apr;19(2):195-201). If Bacteroides indeed benefits, an efficient way would be to grow it in vitro, then make a targeted delivery to the lower intestine such as the colon (Chourasia MK, Jain SK. Pharmaceutical approaches to colon targeted drug delivery systems. J Pharm Pharm Sci. 2003 Jan-Apr;6(1):33-66).


----------



## Xiaofa Qin

In fact, the capability of inactivating digestive proteases seems just belonged to some very special strains of bacteria. For instance, a study showed that trypsin can be inactivated by Bacteroides distasonis E9 but not Bacteroides distasonis D4 (Ramare F, et al. Inactivation of tryptic activity by a human-derived strain of Bacteroides distasonis in the large intestines of gnotobiotic rats and mice. Appl Environ Microbiol. 1996 Apr;62(4):1434-6). Thus, as for the effective inactivation of digestive proteases, it may probably be achieved by targeted delivery of just a small amount of the right bacteria.


----------



## mf15

Here is an older paper on mucus and protease in the colon,not sure
if it has been referenced yet. It is cached so it does not format quite right.
Old Mike
Link


----------



## Xiaofa Qin

Thanks Old Mike for sharing the paper. It clearly demonstrated a similar scenario regarding the synergistic effect of digestive proteases and bacterial glycosides on mucus degradation. But the unified hypothesis discussed here further proposed that the increased proteases activity might be the result of poor inactivation due to the reduction of gut bacteria by dietary chemicals like saccharin and sucralose along with the improved hygiene condition in modern society. Thus it provided a possible ultimate explanation for the mystery of IBD.    

Here I would like to share some updates. 

I noticed a long-standing Special Requests for Proposals at Broad Foundation asking grant applications to look into the “Differences in IBD incidence between developing and developed countries” (http://broadmedical.org/funding/overview.html).  I recently submitted a Letter of Interest entitled “Some food additives as the possible main cause of differences in IBD incidence between developing and developed countries” as the first step of the application, but was soon rejected. This is the third time I tried applying some grant from Broad Foundation. The first one was in late 2001, shortly after I found that saccharin may be an important causative factor for IBD, and the second one was in 2008 after I published a series of paper with further evidence showing the possible link and mechanism. All of them were rejected. 

I saw a recently published paper in the journal of Inflammatory Bowel Disease showing the climbing incidence of pediatric IBD in the United States from 1997 to 2009 (Debruyn JC, et al. Nationwide Temporal Trends in Incidence of Hospitalization and Surgical Intestinal Resection in Pediatric Inflammatory Bowel Diseases in the United States from 1997 to 2009. Inflamm Bowel Dis 2013 Oct;19(11):2423-32). As demonstrated in Figure 2 and Figure 3 of my paper, it showed leveling off or even decreases in IBD in the United States as well as many other developed countries during later 1970s and early 1980s. I collect a series of more evidences suggesting the new round of accelerated increase of IBD in the US started since around early 2000s. For instance, in the conclusion of the paper by Ingle SB et al, it stated that “Although incidence rates of Crohn's disease and ulcerative colitis had remained relatively stable in Olmsted County between 1970 and 2000, the incidence of both conditions appears to have increased somewhat over the past 5 years” (Ingle SB, et al. Increasing Incidence and Prevalence of Inflammatory Bowel Disease in Olmsted County, Minnesota, During 2001-2004. Gastroenterology 2007;132:A19-A20). The Figure below shows the result of another study by Sewell JL et al (Hospitalizations are increasing among minority patients with Crohn's disease and ulcerative colitis. Inflamm Bowel Dis 2010;16:204-7), we can see the jump of IBD in Asians in the United States at the beganing of this new Millenium, suggesing a sudden introduction of some risk agents in their life. I feel people should pay great attention to this kind of peculiar changes, as the ultimate cause may just hide behind them. I submitted a letter to the editor to raise the concern, but it was also rejected. Again, the remarkable increase of IBD in early 2000s in the US shortly after its approval of sucralose in 1998. No matter it would be sucralose or something else, we need doing something to find its cause. Unfortunately, it seems hardly any people really interested to put some efforts on this.


----------



## mf15

Thank you Xiaofa: Interesting info. You might find this paper also very interesting.
I believe that this is the same basic mechanism for UC, but in UC perhaps many different
agents may accomplish the same end result. 
Old Mike
link


----------



## AJC - Australia

Thank you to the main contributors to this thread.
It is epic!

When I look at the map of the 'incidence of crohns' globally, 







England and America are the higest incidence.
It makes sense that it would spread from England to Europe via migration.
What is interesting is Australia and South Africa - mostly English people left England and went to these countries. 
Maybe it is the English genetic that left England and went to America that assisted in making crohn's rampant in America moreso than anywhere else.

My question is - what are they doing in England, America, South Africa, Australia and all of Europe that they are not doing in Russia, India, Japan, China?

It kind of rules out smoking - because the chinese, japanese, russians, indonesians all smoke like chimneys.

anti-biotics : everyone uses antibiotics these days...?

assuming you have the 'gene' - it must be something in the environment of these countries which is setting it off...and it is very hard to go past foods.

do the russians, africans, chinese, japanese, indonesians and asians drink cows milk? I have no idea

do the russians, africans, chinese, japanese, indonesians and asians eat white bread?

white rice?

they all drink coca cola - so we can probably rule out sugar!

there must be a common link....

it frustrates me that between all of us we cannot work it out.

The technology is incredible right here that we can all communicate...

I personally think that it is something to do with genetics, anti-biotics overuse and diet...


But god i wonder about this chart....the global incidence....all those south africans came from england.....all the australians came from england....all the americans....sorry, came from england.....it must have started in England....what did england pioneer in food consumption???


----------



## Xiaofa Qin

mf15 said:


> Thank you Xiaofa: Interesting info. You might find this paper also very interesting.
> I believe that this is the same basic mechanism for UC, but in UC perhaps many different
> agents may accomplish the same end result.
> Old Mike
> link


Thank you Old Mike for sharing the info. I found it very interesting. 




happy poo poo said:


> But god i wonder about this chart....the global incidence....all those south africans came from england.....all the australians came from england....all the americans....sorry, came from england.....it must have started in England....what did england pioneer in food consumption???


Yes, it is a very good question as why countries like Australia and South Africa but not many countries in Europe shared a similar patter of IBD as England. In fact, I have started the paper discussed here with the section entitled “Large commercial marketing of saccharin in 1887 and the emerge of clustered cases of ulcerative colitis since 1888, started from the United Kingdom”, which is further extended with three sub-sections: 1) The discovery of saccharin in 1878 from coal tar and its large-scale production and marketing since 1887; 2) The favorite use of saccharin in United Kingdom since 1887 but dislike or ban of saccharin in Germany and most of the other Western countries in the early years; 3) Emergence of clustered cases of ulcerative colitis since 1888, started from United Kingdom. In my opinion, this phenomenon probably is not related to gene (people in UK would be just originated from Europe) or the general food staff like bread or meat, but rather the attitude to some food additives such as saccharin originated from the coal tar.


----------



## mf15

Xiaofa: As you can see from the Pollen paper now that you have read it,that
the mucus is first degraded by protease,then the pollen can penetrate the mucus barrier
once this happens the immune system is then activated.
Whether the weakened mucus barrier in the gut is due to active digestive protease,bacterial protease,food mucus breachers,chemicals or toxins, or all of the above.
The same basic mechanism is taking place in the nasal passages and the gut,
the mucus is somehow breached and the antigens pollen/bacteria can present themselves to the immune system.
What bothers me is that non allergic people also have their nasal mucus breached but their
immune response does not cause allergies.
Both myself and my son have no allergies,yet both have UC.
By brother and daughter have pollen allergies but do not have UC.
Such a puzzle.
Old Mike


----------



## Xiaofa Qin

Yes, it seems nothing is straightforward and absolute in the real world. I saw your posts in another thread regarding polyethylene glycol (PEG) as a mucus breacher in the diet. PEG can easily penetrate the mucus layer largely because it shares some similar chemo-physical properties as mucus. As such, PEG has been used in some studies as surrogates for mucus and it actually showed some protective effect on things such as the ethanol-mediated mucosal injury of the stomach, etc.  

Here are some studies:

Gutiérrez-Cabano CA. Protection by intragastric polyethylene glycol 400 in rat stomach against ethanol damage involves alpha2-adrenoceptors. Dig Dis Sci. 2000 Jan;45(1):105-9.


Wu L,et al. High-molecular-weight polyethylene glycol prevents lethal sepsis due to intestinal Pseudomonas aeruginosa. Gastroenterology. 2004 Feb;126(2):488-98.


----------



## mf15

Xiaofa: Yes I have read those studies. They were used in bulk. I am worried about the following in food and applied to vegetables, polysorbate which is a 
PEG ester of sorbitan,peg-12,peg-8,both in toothpaste,PEG itself applied to vegetables. Once the polysorbate is digested it should free the PEG from the sorbitan, if so then the PEG is free to coat food and other micro particles,which can then penetrate the mucus. If the polysorbate reaches the colon intact then it will act as an emulsifier.

At anyrate the problem with both forms of IBD seems to be mucus.
Around 1920 when the incidence started to increase,we had pollution,chlorination,saccharin,canning,refrigeration,pasteurization,lecithin in foods,some industrial chemicals,no antibiotics,no pesticides,few surfactants,also industrial baking of bread using a yeast method as opposed to fermentation,start of nitrogen fertilizer,margarine.

Then after the second world war, many more chemicals and food additives,
antibiotics,pesticides.
We also have quite an increase in IBD.
So now we have more triggers,and triggers that vary with time.
For instance the type of pollution we have today,is much different than 100
years ago,both in chemical composition,and size of the particulate.
For this post my definition of trigger is a chemical or process in the body,caused by something in the enviorment which enables bacteria to breach the mucus.
Old Mike


----------



## AJC - Australia

simply - there must be something that is common place in England, America, Europe, South Africa and Australia - that is NOT happeneing in Russia, China, Japan, Africa.

I wonder what it is?

the way food is manufactured?
early childhood vaccines?
a type of food we eat that they dont?
something in the water?

some clever monkey must be able to connect the dots and work it out!??????????????


----------



## Xiaofa Qin

Old Mike: Apparently, you have a lot knowledge in chemistry. I learned a lot from your posts. Thank you very much.

Xiaofa


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## alfabeta

xiaofa, what's your opinion of parasites?


----------



## Xiaofa Qin

alfabeta said:


> xiaofa, what's your opinion of parasites?


Thank you alfabeta for the interest in my opinion on parasites. I think it would be no surprising that parasites in the gut may have some effect on the immune system, etc, of the intestine, thus the pathogenesis of IBD. Some studies suggest some beneficial effect by the worms treatment, while some patients experienced worsening of the symptoms. More studies and clinical trials would be needed for and will eventually provide more accurate and comprehensive evaluation. Even parasites indeed have some protective effect, the irregular changes of IBD even in the developed countries and also many other evidence of discrepancies would suggest IBD are unlikely just the result of the elimination of the parasites along with improved hygiene in modern society but rather increased exposure to some other risk factors in the environment. Clothes or sun lotion may have some protection for sunburn,  but sunburn will not occur without the exposure to the sun. There are big differences in IBD among the different countries. The differences in the sanitary condition and parasite infection would be much small among the big cities all over the world. This is just my personal opinion.


----------



## Xiaofa Qin

Just some updates. The paper that was rejected by the journal of Inflammatory Bowel Disease as I mentioned in my earlier post (#210) was readily accepted for publication by the Journal of Clinical Gastroenterology and now is available online (Qin X. When and How Was the New Round of Increase in Inflammatory Bowel Disease in the United States Started? J Clin Gastroenterol. 2013 Nov 13. [Epub ahead of print]). I strongly feel we should pay great attention to the peculiar epidemiological changes of IBD, as there may lie the most valuable information for the ultimate mystery of what caused IBD. Any theory and hypothesis would have to be rigorously checked against these evidences, both pros and cons, to make a comprehensive evaluation.

The previous post just discussed the hot topic regarding the parasites and IBD. I have not expected the result may come out so quickly. The negative result of Trichuris Suis Ova (TSO) (the whipworm parasite of pigs) clinical trial as discussed in this forum (see: Whip worm study and Worms Flop in Crohn's Disease) is not surprising to me. The fantasy has lasted for a decade and generated so much expectation. The lack of efficacy is disappointing but nevertheless it makes us a step forward toward the truth.


----------



## sir.clausin

I met with my GI today, sayin that I will start FMT any day now, he still say that it´s too early and that there are no evidence blablabla. 

So I told him, like I did before, that there ARE studies for FMT and crohns and that I would send him the links. Are they all in this thread?


----------



## kiny

Hey, Xiaofa.

Can you quickly look at this:

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0052132

I didn't know this, but Maltodextrin is used as a bulking agent for sucralose.

Splenda, the maker of sucralose produces tons of the stuff every year and holds the majority of the market in the West, they use maltodextrin to bulk it.

Would need to read the composition more, but you're getting in a lot of maltodextrin when you consume sucralose.

It ties sucralose together with invasive E Coli.

Here's my invasive E Coli thread btw:

http://www.crohnsforum.com/showthread.php?t=52198

Normal people sometimes harbour minute colonies of invasive E Coli too, but something pushes AIEC over the edge in people with crohn's disease, the exact amounts of AIEC in people with Crohn's disease is much higher.

Many normal people are already infected with AIEC but they don't have crohn's disease because for some reason AIEC does not colonise in those people, you need some kind of trigger...some thing that makes them grow....genetic predisposition and sucralose can do this...


----------



## rollinstone

What amazes me is that so many things have maltodextrin and sucrose in them, I.e modulen ibd...


----------



## kiny

It has to be something, crohn's disease didn't just appear from thin air, every country that industrialises get crohn's disease.

I looked up sucralose, it's produced with maltodextrin to bulk it.

edit: I mean saccharin, I already knew it of sucralose


----------



## kiny

Joshuaaa said:


> I.e modulen ibd...


It's really hard to know what EN actually has in it, I argued with Nutricia about this and said to them that their EN has maltodextrin in it, meant for IBD.

And they said that only some has it and their packets of 028 does not.

So I agreed at first, because those packets contain dried glucose syrup, but dried glucose syrup is not made through just one method, and the name dried glucose syrup has a lot of ambiguity to it, you can use maltodextrin to bulk almost any simple sugar apparently.


----------



## kiny

Also, regarding the reason they actually bulk with maltodextrin...is twofold as far as I understand:

1. Maltodextrin is cheap as hell, bulking anything with maltodextrin brings down the price

2. When you bulk with maltodextrin you can avoid regulations, since some countries don't see it as a normal simple sugar, and you can claim you have "0 calories" and lots of halftruths that allow you to sell your product under false pretences


----------



## rollinstone

Well when I had modulen ibd or fortisip for that matter it started to make me worse, so now I avoid it like the plague, it's weird though coz even some vitamin supplements have maltodextrin in them, I thought there were different types of maltodextrin though? And while we are on the subject of AIEC, can anti-map kill AIEC?


----------



## kiny

Splenda, the maker of sucralose that uses maltodextrin to make it, is from Johnson and Johnson, that also makes infliximab.

There has to be some irony in there.


----------



## kiny

Joshuaaa said:


> And while we are on the subject of AIEC, can anti-map kill AIEC?


It can.

Actually cipro is very effective against AIEC (until you run into resistance), cipro is very effective against any form of E Coli really.


----------



## kiny

The argument against anti-MAP use was the Australia trial.

(not borody, another group)

http://download.journals.elsevierhealth.com/pdfs/journals/0016-5085/PIIS0016508507008013.pdf

Anyway, this was the biggest trial that refuted anti-MAP therapy, not enough in remission, no sustained remission, etc.

People have argued against that trial, that some capsules didn't open, that the trial did cause remission but the paper itself was overly negative (and they were kind of overly negative to be honest).

ANYWAY,

At the end of the study, they say this:

_*"Despite its broad-spectrum activity, the antimycobacterial antibiotic
regimen used in the Australian study is not particularly effective against Gram-negative bacteria. New therapeutic trials should target members of the intestinal flora, such
as Bacteroides and adhesive Escherichia coli, which have now been associated with CD by different groups throughout the world."*_

And they are right, anti-MAP therapy, while somewhat effective against MAP, is not really effective against E-Coli.

It's not ineffective, but if you were targeting E Coli you would use a different cocktail.


----------



## kiny

Also, I have to add something to their "intestinal flora" in relationship to E Coli.

While AIEC is present in the intestine, it is present in the form of biofilms and it does not "stay in the lumen", it enters the gut wall, it can do this through the peyer's patches. AIEC is very much an intracellular pathogen, although I admit it is also present in the lumen.

That's the reason they have tried things like rifaximin, because rifaximin is effective against gram negative and has low bioavailability, it doesn't get absorbed through the gut wall really (well it does, but minute amounts).

Anyway, I can go on about this for a number of pages, but I don't want to spam this thread.


----------



## Xiaofa Qin

kiny said:


> Hey, Xiaofa.
> 
> Can you quickly look at this:
> 
> http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0052132
> 
> I didn't know this, but Maltodextrin is used as a bulking agent for sucralose.
> 
> Splenda, the maker of sucralose produces tons of the stuff every year and holds the majority of the market in the West, they use maltodextrin to bulk it.


Thanks kiny for referring me this article and interest in my opinion on Maltodextrin. I felt this is a pretty good study with quite a lot experiments and interesting results. However, as for the suggested causative role of maltodextrin added as food additives (such as those in splenda) in Crohn’s disease, I felt there is something we would have to consider. 

As described in the referred paper, maltodextrin is just the enzymatic and chemical degradation product of corn, potato or rice starch (http://www.plosone.org/article/info:doi/10.1371/journal.pone.0052132). As starch constitutes 92% of cornflour, 85.8% white rice, and 66.8% wheat flour (http://www.kickas.org/ubbthreads/ubbthreads.php?ubb=showflat&Number=143543), people with these grains as the main food for energy source would probably generate much more maltodextrin-like molecules during digestion before the final breaking down of these starches to glucose. Although maltodextrin constituents the bulk of splenda, it would be still tiny compared with those generated from the rice or bread that people have used far before the emergence of IBD in last century and also consumed now in many developing countries where IBD is low. According to Wikipedia (http://en.wikipedia.org/wiki/Maltodextrin), “Maltodextrin is easily digestible, being absorbed as rapidly as glucose”. If this statement is correct, we may wonder how much of the small amounts of maltodextrin taking as additives may really reach the lower intestine, especially multiple recent studies have revealed that damage limited to the colon (Crohn’s colitis) has become the main form of Crohn’s disease. 

Above is just my personal thought. I would like to hear how you think on this.


----------



## kiny

Ty, hm I don't know how similar maltodextrin broken down from a complex starch bond in the intestine would be compared to what splenda puts in their sucralose.

So why I'm interested is this study here that said:

http://www.ncbi.nlm.nih.gov/pubmed/11052483

"The number of patients with Crohn's disease has increased remarkably. The prevalence and the annual incidence of patients with Crohn's disease in Japan were estimated to be approximately 2.9 and 0.6 per 10(5) population in 1986, respectively, and 13.5 and 1.2 per 10(5) population in 1998."

And I also know that rates of MAP are much lower in Japan and actually went down, because unlike in the West, if a cow gets MAP in Japan, the farmer gets a reward for telling the government, basically they get the value of their cow back as if it was healthy. Compared to Europe and the US, the amount of MAP in cows in minuscule in Japan. But somehow the rates of crohn's disease went up dramatically.


There is another theory and it showed that an emulsifier called polysorbate 80 allows AIEC to translocate accross M-cells. M-cells are the caps on the peyer's patches in the small intestine that "sip" antigen content, usually bacteria, they're basically "mini lymph nodes" in the intestine.

http://gut.bmj.com/content/59/10/1331.full

There is another study about this, would have to find it again.

Crohn's disease is now most common (and afaik, has always been) around the teenage years, peyer's patches are most active around the teenage years, it is a very logic explanation why crohn's disease would be in the ileum (only place where peyer's patches really are), and why it would manifest itself around the teenage years.

Anyway, I really find it strange what happened in Japan over such a short period, because they have low MAP, their way of life didn't change really, only what they eat has changed dramatically, there are fast food joints everywhere in Japan now, I remember that 20 years ago, there were almost none in those same areas, oh well.


----------



## mf15

MAP is also found in ground beef, in the usa ground meat is usually made from culled cows,at least the bulk kind.
Anyway Japan imports a lot of meat for hamburger from Australia and
New Zealand, could this be the reason crohns increased while domestic
herds in Japan had low MAP.
MAP was a new disease first found in cows 1895,timelines with IBD fit well.
Being exposed to just the antigen or DNA may be enough to cause a problem,may
not even need to harbor live MAP,once antibodies are present.

Old Mike

LINK


----------



## Xiaofa Qin

Thanks kiny and Old Mike for sharing the thoughts and info. The increase in the incidence of Crohn’s disease in Japan from 0.6/100,000 in 1986 to 1.2 /100,000 in 1998 is still not that dramatic. Here is a Figure showing the number of IBD patients seen in a Saudi clinic during 1993 to 2009 in a study by Al-Mofarreh MA and Al-Mofleh IA published this year (Emerging inflammatory bowel disease in Saudi outpatients: a report of 693 cases. Saudi J Gastroenterol. 2013 Jan-Feb;19(1):16-22). We can see there was 0 or only 1 patient of Crohn's disease during 1993 to 2000; the number increased to 3 or 4 cases during 2001 to 2003, then jumped to 174 cases in 2009. Again this increase occurred shortly after the approval of sucralose in Saudi Arabia around 2000. Thus at least sucralose can be listed as a suspect. People would definitely need to put some effort to find out the cause behind this increase, no matter it turns out to be sucralose, emulsifier, MAP, or something else.


----------



## Xiaofa Qin

kiny said:


> Crohn's disease is now most common (and afaik, has always been) around the teenage years, peyer's patches are most active around the teenage years, it is a very logic explanation why crohn's disease would be in the ileum (only place where peyer's patches really are), and why it would manifest itself around the teenage years.


    Some studies demonstrated that damage limited to the colon (colonic Crohn’s disease) increased over time and has become the  main form of Crohn’s disease. For instance, in Stockholm County, Sweden colonic CD increased from 15% during 1959-1964 to 32% during 1980-1989, and further to 52% during 1990-2001, while the ileocaecal CD decreased from 58% during 1959-1964 to 41% during 1980-1989, and to 28% during 1990-2001 (see: http://www.ncbi.nlm.nih.gov/pubmed/9391246/ and http://www.ncbi.nlm.nih.gov/pubmed/16440421). This is one reason I suggest ulcerative colitis and Crohn’s disease are likely just two symptoms of the same morbidity rather than two different disease as stated in my paper discussed here (here is the link). What are your explanations for the damage in the colon and increase in colonic CD over time?



mf15 said:


> MAP is also found in ground beef, in the usa ground meat is usually made from culled cows,at least the bulk kind.
> Anyway Japan imports a lot of meat for hamburger from Australia and
> New Zealand, could this be the reason crohns increased while domestic
> herds in Japan had low MAP.
> MAP was a new disease first found in cows 1895,timelines with IBD fit well.


As discussed in the previous post, there is a remarkable increase in Crohn’s disease in Saudi since early 2000s, while the change for ulcerative colitis is much less, suggesting the increase in CD is unlikely just due to raised awareness to IBD in the society or increased referral to that clinic. Is there any evidence that there is dramatically increased consumption of MAP contaminated meat or milk in Saudi? As discussed some early post, IBD is pretty high in Sweden, but MAP infection is very low in the herds. Is there any evidence suggesting Sweden imported and consumed large amounts of meat or milk from countries with heavy MAP infection? Just curious. 



mf15 said:


> Being exposed to just the antigen or DNA may be enough to cause a problem,may not even need to harbor live MAP,once antibodies are present.


As for Johne’s disease in the herds or TB in human, the damage of the tissue seems indeed closely related to the amounts of bacteria existing. In the case of TB, antigen in the BCG vaccine would have helped generation of the protective immune response, and the antibody formed seems also beneficial rather than harmful to the body (See: Armando Acosta, et al. The Role of Antibodies in the Defense Against Tuberculosis). To my knowledge, nucleic acid (DNA and RNA) has been sold by some company as “superfood” with  rejuvenative powers  (here is an example). I knew this claim  has been challenged by some scientists. On the other hand, is there any evidence that DNA can cause a problem to the body?


----------



## mf15

Xiaofa,here is a quick look at some of the questions you brought up on 
beef imports and also MAP antigen,seems that timelines are suggestive.
Saudi beef imports chart,big increase since about 2000.
Old Mike

http://www.indexmundi.com/agriculture/?country=sa&commodity=beef-and-veal-meat&graph=imports

Australian beef is imported
http://halalfocus.net/saudi-arabia-at-saudi-food-importers-seek-brazilian-beef/

much from the EU prior to 2002 BSE scare now also a brazil BSE scare

http://www.fas.usda.gov/info/countrypages/sabfsit.pdf

Saudi milk imports increase dramatic around 2002.
https://knoema.com/atlas/Saudi-Arabia/topics/Food-Security/Food-Imports/Milk---Excluding-Butter

Sweden imports triple since 2000 beef from Ireland
http://www.bordbia.ie/industryservi...efimportscontinuestogrow.aspx?year=2012&wk=29

MAP antigen
http://www.ncbi.nlm.nih.gov/pubmed/23519342

http://www.crohns.org/articles/1999_08_115-9_cm.htm

CWD forms of MAP
http://www.paratuberculosis.info/images/stories/pdfs/14


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## sir.clausin

Just a little something I overheard today, when taking my kid to the pre-school to play with other kids. There was this chinese guy talking to a woman and he said something like "I know of this chinese family that moved from China to here (Sweden) and the children developed allergies. Then the oldest boy went to China for vacation to visit his grandparents and all the allergies  went away. Then when he came back to Sweden the allergies re-apeared. So the whole family moved back to China. 

Isn´t this a perfect example on how the microbiota works. I wonder what this boy was exposed to here in Sweden? I know that Swedes and Finnish people are the biggest milkconsumers in the world. Funny...that Sweden have the highest exalerating crohns incidents in the world!!! MAP? Did the boy retrieve the missing group of bacteria when he went back to China? And how fast did this shift occur.

Very interesting nevertheless.

Have a great weekend.


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## sir.clausin

My gut is telling me that there is certainly something in the food that causes this piece of shit disease. Milkproducts or beef (McDonalds etc.)


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## wildbill_52280

The current theory which allows us to treat IBD with some decent success has been to suppress inflammation, and it has worked to reduce symptoms and cause remission in most patients. we must acknowledge that this theory is somewhat successful, but we don't yet know all the underlying mechanisms as to why. Further studies will likely reveal more information that will allow us to create better theories and models.

Here are two recent observations that may help explain why suppressing inflammation can decrease symptoms in IBD. in a nutshell, the chronic state of inflammation may exist as a first event in IBD, then slowly, a byproduct of inflammation called nitrate and nitrite now can feed pathogens and allows us to accumulate bacteria that may be harmful either from our environment, or feed pathogens that naturally exists in low levels in the gut , but are now much higher then they used to be.


Host-derived nitrate boosts growth of E. coli in the inflamed gut. 2013
http://www.ncbi.nlm.nih.gov/pubmed/23393266
Streptomycin-Induced Inflammation Enhances Escherichia coli Gut Colonization Through Nitrate Respiration
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3705454/


So by inhibiting inflammation, nitrate and nitrate production is reduced, pathogens then reduce that cause diarhea and damage, and our symptoms reduce. This is still not a complete model or explanation as to how the disease works, but is more complete then before i believe. and that's why we still have issues controlling this disease as our knowledge is incomplete.  but it is the inflammation that may precede alot of these events, so to explain that, i believe damage to the microbiome is a very good explanation as now we have information that suggests these bacteria turn inflammation off. 


Commensal Clostridia: leading players in the maintenance of gut homeostasis
http://www.gutpathogens.com/content/5/1/23




> Clostridium spp. belonging to clusters XIV and IV have also been reported to be strong inducers of colonic T regulatory cell (Treg) accumulation [89]. CD4+Foxp3+ Tregs are the most prominent regulatory cells in the body and are most abundant in the colonic lamina propria [90,91]. Here, their frequency among CD4+ T cells is notably higher than in other organs [89], suggesting that the intestinal microbiota may be involved in the accumulation of colonic Tregs. Several reports have determined that intestinal Foxp3+ Tregs are markedly affected by the intestinal microbiota [92]. A fraction of intestinal Tregs express T cell receptors that recognize antigens derived from the gut microbiota [93]. It has been established that these colonic Tregs play critical roles in intestinal immune homeostasis, suppressing systemic and mucosal immune activation to control intestinal inflammation, and contributing to maintaining tolerance towards gut microbiota [94,95]. Atarashi et al. showed that colonization of germ free mice with a defined mixture of 46 Clostridium strains belonging to clusters XIVa and IV induced the accumulation and differentiation of colonic Tregs [89]. Clostridium spp. were also able to promote increased expression of IL-10 in Treg [89], expression of matrix metalloproteinases (MMPs), as well as activation of TGF-β [96] and indoleamine 2,3-dioxygenase (IDO) in colonic epithelial cells [89]. Intestinal epithelial cells are crucial for the maintenance of innate and adaptive immune homeostasis in the gut. Moreover, even the colonization with altered Schaedler flora (ASF), which includes Clostridium clostridioforme, leads to the accumulation of Tregs within the colon [97]. Consistent with these findings, F. prausnitzii, which belongs to Clostridium cluster IV, increases IL-10 production from peripheral blood mononuclear cells in vitro[98]. How Tregs induced by commensal Clostridia can contribute to immune homeostasis in the intestine is an important question to address. Foxp3+ cells with TCRs specific for CBir1, a flagellin related to those of Clostridium cluster XIVa, induce IgA+ B cells in the intestine in order to reduce the mucosal uptake of microbiota-derived antigens and prevent systemic T cell activation [99]. Therefore, Clostridium spp. can affect the number and function of colonic Tregs, inducing naive CD4+ T cells to differentiate into antigen-specific colonic Tregs that are able to enforce immune tolerance towards commensal bacteria. It is interesting to note that even conventional T cells express TCRs specific for commensal antigens, and are potentially colitogenic if not completely suppressed by intestinal Tregs [100]. Notably, elevated levels of Clostridium clusters XIVa and IV in mice leads to resistance to allergy and intestinal inflammation in experimental models [89]. Conversely, the microbiota of individuals with chronic inflammation show lower bacterial diversity and it has been determined that Clostridium clusters IV, particularly F. prausnitzii, and XIVa are significantly less abundant in IBD patients compared to healthy subjects [14,98,101]. It is still unknown whether the decrease in Clostridia is a cause or a consequence of chronic inflammation in IBD patients and in autoimmunity, but we can speculate that they are necessary for immune homeostasis, contributing to the suppression of autoimmunity and deleterious inflammation in humans.


these are only some of the reasons which support the use a fecal transplant to restore the missing bacteria in IBD to treat or possibly cure IBD. here is more info on fecal transplants- http://www.crohnsforum.com/showthread.php?t=52400


----------



## Xiaofa Qin

mf15 said:


> Xiaofa,here is a quick look at some of the questions you brought up on
> beef imports and also MAP antigen,seems that timelines are suggestive.
> Saudi beef imports chart,big increase since about 2000.
> Old Mike
> 
> http://www.indexmundi.com/agriculture/?country=sa&commodity=beef-and-veal-meat&graph=imports
> 
> Australian beef is imported
> http://halalfocus.net/saudi-arabia-at-saudi-food-importers-seek-brazilian-beef/
> 
> much from the EU prior to 2002 BSE scare now also a brazil BSE scare
> 
> http://www.fas.usda.gov/info/countrypages/sabfsit.pdf
> 
> Saudi milk imports increase dramatic around 2002.
> https://knoema.com/atlas/Saudi-Arabia/topics/Food-Security/Food-Imports/Milk---Excluding-Butter


Thanks Old Mike for quickly finding out the information. Indeed, both Crohn’s disease (CD) and the import of beef and milk in Saudi increased during 2000s. However, there seems still some discrepancy between them: beef and veal meat imports increased from 68,000 in 2000 to 119,000 MT CWE (1.75 fold), milk import increased from around 52 during 1997 – 2002 to 73 kg/person/year in 2007 (1.4 fold), while Crohn’s disease increased from 0 – 1 before 2000 to 174 in 2009.  Especially, the increased import of beef was largely from Brazil where CD is still relatively low. How to explain the extremely low CD before 2000 when the bulk of beef and meat imports being from Europe where the incidence of CD was pretty high?




mf15 said:


> Sweden imports triple since 2000 beef from Ireland
> http://www.bordbia.ie/industryservi...efimportscontinuestogrow.aspx?year=2012&wk=29


According to the article, beef imports in Sweden tripled over 2000 to 2011. Then we may expect a successive increase of CD over this period. Interestingly, a recent study on paediatric IBD in Northern Stockholm County revealed that ulcerative colitis increased from about 1/100000 during 2002-2004 to 4 during 2005-2007, while CD decreased from about 10/100000 during 2002-2004 to 7 during 2005-2007 (Malmborg P, et al. Increasing incidence of paediatric inflammatory bowel disease in northern Stockholm County, 2002-2007. J Pediatr Gastroenterol Nutr. 2013 Jul;57(1):29-34). I suspected that this may be caused by a change of regulation by European Union in 2004 that reduced the maximum permitted level for cyclamate in soft drinks from 400 to 250 mg/L(Qin X. How to explain the discordant change of ulcerative colitis and crohn disease in adjacent or even the same regions and time periods. J Pediatr Gastroenterol Nutr. 2013 Nov;57(5):e30. You can find the story as how I got to this at my early post #182). I would like to learn if there is any other explanation. 




mf15 said:


> MAP antigen
> http://www.ncbi.nlm.nih.gov/pubmed/23519342
> 
> http://www.crohns.org/articles/1999_08_115-9_cm.htm
> 
> CWD forms of MAP
> http://www.paratuberculosis.info/images/stories/pdfs/14


I felt the damage of gut described in the first link above is more like the local inflammatory reaction of the skin in a positive TB test. It may need the presence of large amounts of highly concentrated antigens to induce a reaction like this. We may wonder if the small amount of MAP components in the beef or milk may cause such damage as CD.


----------



## Xiaofa Qin

wildbill_52280 said:


> The current theory which allows us to treat IBD with some decent success has been to suppress inflammation, and it has worked to reduce symptoms and cause remission in most patients. we must acknowledge that this theory is somewhat successful, but we don't yet know all the underlying mechanisms as to why. Further studies will likely reveal more information that will allow us to create better theories and models.
> 
> Here are two recent observations that may help explain why suppressing inflammation can decrease symptoms in IBD. in a nutshell, the chronic state of inflammation may exist as a first event in IBD, then slowly, a byproduct of inflammation called nitrate and nitrite now can feed pathogens and allows us to accumulate bacteria that may be harmful either from our environment, or feed pathogens that naturally exists in low levels in the gut , but are now much higher then they used to be.
> 
> 
> Host-derived nitrate boosts growth of E. coli in the inflamed gut. 2013
> http://www.ncbi.nlm.nih.gov/pubmed/23393266
> Streptomycin-Induced Inflammation Enhances Escherichia coli Gut Colonization Through Nitrate Respiration
> http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3705454/
> 
> 
> So by inhibiting inflammation, nitrate and nitrate production is reduced, pathogens then reduce that cause diarhea and damage, and our symptoms reduce. This is still not a complete model or explanation as to how the disease works, but is more complete then before i believe. and that's why we still have issues controlling this disease as our knowledge is incomplete.  but it is the inflammation that may precede alot of these events, so to explain that, i believe damage to the microbiome is a very good explanation as now we have information that suggests these bacteria turn inflammation off.


Interesting explanation derived from fascinating theory published in prestigious journals. However, there would be still some questions that need to be answered:

1) At present, one of the most effective treatments for Crohn’s disease would be the anti-TNF therapy, which has also been very effective for the treatment of arthritis and psoriasis through a likely mechanism of direct inhibition on inflammation rather than growth of bacteria.

2) We know anti-TNF treatment increased the susceptibility of the infections by bacteria, fungus, virus, or parasites (here is a list). Can it really reduce the infection in the gut tissue where there are always large amounts of so many kinds of microbes in the lumen? 

3) Some antibiotics would be able to exert more potent inhibition on bacteria like E. coli than just a reduced generation of nitrate/nitrite by the host. Why antibiotics are not so effective as anti-TNF therapy?


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## rollinstone

Some anti-biotics are indeed effective until the bacteria or pathogen builds resistance. Xia, have you heard of the SSI vaccine by qu biologics? I think their hypothesis/model is very promising. They use deactivated bacteria to stimulate new macrophage production, as they believe that persons with crohns are malfunctioning at this step and as a result not clearing the bacteria/pathogen


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## kiny

The mouse model that looks most like crohn's disease is currently this one from this study in Nature. I asked the researchers about this, and I don't believe any mouse models is closer to crohn's disease than this one. It has the transmural inflammation, it has a similar immune response, it has fibrosis. It's a mouse model with AIEC (E Coli) infection:

http://www.nature.com/ncomms/2013/130610/ncomms2957/full/ncomms2957.html

What doesn't really look like crohn's disease is the previous mouse model, which is still used for most tests, and that's the dextran sodium sulfate model.


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## kiny

What's interesting about E Coli I feel when people talk about it, is that you don't really need the "infection" part to make the model work with AIEC. You can carry AIEC in your intestine just like you can carry H Pylori, in very low numbers it doesn't affect you.

There was a dutch study that could predict crohn's disease in family members by checking anti-OmpC, in English that means antibodies against the outer membrane protein of E Coli bacteria.


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## kiny

Another interesting part about AIEC is the zoonotic risk.

"_Finally, the presence of AIEC in the intestine of several animal species suggests a putative *zoonotic risk*._"

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165260/

It would be interesting to see if countries where crohn's disease goes up, not just westernise.....but have more pets.


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## rollinstone

Do you think colonic cd could still be due to AEIC?


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## kiny

Joshuaaa said:


> Do you think colonic cd could still be due to AEIC?


Kind of, since it's often close to the ileocecal valve. I don't know really, they have found the bacteria in the colon too, it's just more rare, but it's not impossible.

AIEC is a pretty mobile bacteria too, it has no issue moving around in tissue like commensals have, a commensal stays deep within the lumen, the mucosa constantly moves around, it "glides around" so the bacteria can't adhere to it, it's not a static layer like most people think. AIEC is special in that it is excellent in adhering and penetrating the mucosa, most bacteria are incapable of doing that.


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## Xiaofa Qin

Thanks Joshuaaa and kiny for sharing the thoughts and info. Yes, antibiotic indeed worked at some situations, but seems just not as effective as anti-TNF. As discussed in my early post (see #74), I have actually expected that antibiotics should be more effective than they currently appeared to be, and factors like the impaired inactivation of digestive proteases may have confounded its real efficacy (Qin X. Impaired inactivation of digestive proteases: a factor that may have confounded the efficacy of antibiotics aimed at reducing the exposure to luminal bacteria and their components. Am J Gastroenterol. 2008 Nov;103(11):2955-6). As discussed in my earlier posts (see: post #157 and post #74) as well as in my paper published recently (Qin X. Does the association with NOD2, autophagy and some pathogens really mean Crohn's disease is caused by uncontrolled infection? J Crohns Colitis. 2013 Aug 13 [Epub ahead of print]) I personally felt Crohn’s disease is more likely accompanied by excessive rather than deficient immune response, which nevertheless is still elicited to the increased infiltration of gut bacteria or their debris, E. coli or other bacteria, along with compromised gut barrier function. As for a new drug, its efficacy would be ultimately determined by the clinical trials. Hope the trial on SSI may come out with good results.


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## mf15

Here is a new comprehensive review on protease and IBD.
Seemed slow to load.
Old Mike
http://www.wjgnet.com/1007-9327/pdf/v19/i43/7531.pdf


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## Xiaofa Qin

mf15 said:


> Here is a new comprehensive review on protease and IBD.
> Seemed slow to load.
> Old Mike
> http://www.wjgnet.com/1007-9327/pdf/v19/i43/7531.pdf


Thank you Old Mike for sharing the paper. It reads excellent, with more than 100 references from scientific journals. However, it omitted a discussion of a fundamental question: why antibiotics increased the risk of IBD, despite that it reduced gut bacteria and bacterial proteases as mentioned several times in the paper. This paper is of great interest to me, as I also suspected that proteases, not from the bacteria, but rather originated from the pancreas that failed to be inactivated in the lower gut due to a reduction in gut bacteria has played a critical role in the pathogenesis of IBD, which was first published more than a decade ago (Qin XF. Impaired inactivation of digestive proteases by deconjugated bilirubin: the possible mechanism for inflammatory bowel disease. Med Hypotheses. 2002 Aug;59(2):159-63) and discussed again in more detail in the paper discuss in this thread (Qin X. Etiology of inflammatory bowel disease: a unified hypothesis. World J Gastroenterol. 2012 Apr 21;18(15):1708-22). 

According to the paper cited by this review (Macfarlane et al. Contribution of the microflora to proteolysis in the human large intestine. J Appl Bacteriol. 1988 Jan;64(1):37-46), protease activities in human ileal effluent were approximately 20-fold greater than in normal faeces. Another cited paper (Gibson SA, et al. Significance of microflora in proteolysis in the colon. Appl Environ Microbiol. 1989 Mar;55(3):679-83) showed even big differences between the protease actitivy of the ileal effluent (would be mainly digestive proteases originated from the pancreas) versus feces (may be mainly from bacteria under conventional condition), being 1214 versus 20 when casein used as the substrate and 319 versus 11 when azocasine used as the substrate, respectively. Thus impaired inactivation of digestive proteases would be capable of causing a more detrimental impact on the lower gut. The dramatic increase of digestive protease activity in the lower intestine and increase risk of IBD with antibiotics and improved hygiene would be more supportive of the notion that impaired inactivation of the digestive proteases from the host seems likely played a more significant role in the development of IBD. This is my personal opinion and open for discussion.


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## mf15

Macfarlane also indicates that.
 Comparative studies with faeces from a person who did not have a pancreas suggested that a substantial proportion of the proteolytic activity in normal faeces was of bacterial origin.

If we have dysbiotic bacteria which produce excess protease then perhaps
a problem.

It might also be possible that those with UC have a defect in host anti-protease
activity.

So perhaps there might be at least two other reasons that proteolytic activity
might be increased besides impaired inactivation of pancreatic protease.

I tend to believe there is a problem with excess protease the question is
what might be the real reason.


Old Mike


----------



## Xiaofa Qin

mf15 said:


> Macfarlane also indicates that.
> Comparative studies with faeces from a person who did not have a pancreas suggested that a substantial proportion of the proteolytic activity in normal faeces was of bacterial origin.


Yes, at normal condition almost all the proteases activity in the feces would be from bacteria, as the large amounts of digestive proteases secreted from the pancreas and reached the lower gut would be effectively inactivated. However, even all the fecal protease activity is from bacteria, according to the paper, it would still be just 20 casine units. However, a failure of inactivation of even a small fraction of the 1214 casine unit pancreatic proteases transited into the lower intestine could be much higher than 20.



mf15 said:


> If we have dysbiotic bacteria which produce excess protease then perhaps a problem.


I wonder is there any papers on this.



mf15 said:


> It might also be possible that those with UC have a defect in host anti-protease activity.


It is possible. Here is a study (Stone H, Pye A, Stockley RA. Disease associations in alpha-1-antitrypsin deficiency. Respir Med. 2013 Oct 14. pii: S0954-6111(13)00416-2). However, this would the problem originated from the host not gut bacteria. 


I do not say bacterial proteases are completely innocent in IBD. However, the reduced gut bacteria and bacterial proteases but increased risk of IBD by antibiotics seems against a critical role of bacterial proteases in IBD. Is there any good explanation for this?


----------



## mf15

Thank you Xiaofa: The first paper I posted talks about increased bacterial
protease from dysbiotic bacteria even in the abstract.

http://www.wjgnet.com/1007-9327/pdf/v19/i43/7531.pdf

Xiaofa said:
"I do not say bacterial proteases are completely innocent in IBD. However, the reduced gut bacteria and bacterial proteases but increased risk of IBD by antibiotics seems against a critical role of bacterial proteases in IBD. Is there any good explanation for this"

I suggest that antibiotics also produce dysbiosis as a possible trigger for IBD.
But I also see your point.

Do you happen to know if when eating a low protein/no protein meal that the
pancreas outputs less protease.  If so then one way to mitigate colitis might be to eat low protein, of course some are helped on a high meat paleo or SCD diet.  Then also of course we can get diversion colitis,but that is perhaps not the same as UC.
Another theory is that our gut bacteria are actually being starved and becoming more virulent due to lack of proper food entering the colon, such as resistant starch.

Anyway there is no question that excess protease is a factor in UC.
I believe I have some papers posted in this thread on Camostat and BBI
protease inhibitors which showed good improvement in human UC small studies.  So with something as simple as protease inhibitors we can see
improvement. 
My personal trial with BBI constipated me for a week and a half, I became quite nervous so had to end it.
http://www.ncbi.nlm.nih.gov/pubmed/8358131
http://www.ncbi.nlm.nih.gov/pubmed/17551835

Mike


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## kiny

If you divert the fecal stream in people with crohn's disease who have surgery, they improve drastically, the same happens in people on TPN.

Stool consists of undigested macronutrients and lots of antigen in the form of bacteria. Stool by itself is very infectious. Either the intestine is reacting to the bacteria, or the stool friction causes loss of mucus membrane, which does happen, but since so many people have liquit stools when they're sick, I don't think that is what is going on. In fact I'm pretty sure I read somewhere that chronic diarrhea actually stimulates mucus production.

Also, stool is liquid when it's still in the ileum, it's only deeper in the colon that stool starts to lose it's liquid content.

Most intestinal infections can be seen in stool, even mycobacterial and intracellular infections, there is usually antigen within the stool.



.

If it was that simple that antibiotics cause crohn's disease through dysbiosis, the biggest abusers of antibiotics, China and Africa, would have the highest indices of crohn's diseasse. They have the lowest. Yes, China has crohn's disease cases, but compared to the West, they are still low, and China is a major abuser of antibiotics. China is probably the number one abuser of antibiotics.

The gut flora helps you protect from intestinal infections, and that would explain the correlation between crohn's disease and prior antibiotics use. But in Europe and the US, antibiotics use has gone down considerably, there are warning signs in every office in Europe that antibiotics should not be used for viral infections and should not be abused for microbial infections. And yet...crohn's disease keeps rising in the West.


----------



## kiny

If you look at the recent genetic discoveries related to crohn's disease, every single one is related to handling of bacteria. Maybe instead of suggesting the issue is dysbiosis or lack of "good bacteria" and trying to treat people with probiotics, they should look at what happens when a crohn's disease patient gets an infection.

There is a good study from the 90s that showed that crohn's disease patients can not handle E Coli when it is infected in tiny slits in their forearm by causing small wounds (some type of sandpaper was used), they react very slow and bad to it because of macrophage deficiencies. This is their forearm, not their intestine. Controls had no issues clearing the E Coli, crohn's disese patients had lots of issue, macrophage deficiencies, decreased blood flow to the wound, cytokine deficiencies.

Maybe the question should be....can crohn's disease patients handle bacteria of any kind. pathogenic or not, can they even handle dead bacteria or would it be treated an as antigen.

.

Crohn's disease *doesn't* look like UC,* at all*, it actually looks like chronic granulomatous disease and intestinal TB.

Even mortality rates between these diseases show similarities, that latest study of increased mortality rates of crohn's disease patients versus UC, had to do with increased infections.

People and animals with immunodficiencies tend to be prone to intestinal infections, AIDS patients are not very prone to crohn's disease, interestingly, they tend to be protected from crohn's disease, it does happen, but rarely, but they are very susceptible to things like MAC infections.


----------



## Xiaofa Qin

mf15 said:


> Thank you Xiaofa: The first paper I posted talks about increased bacterial protease from dysbiotic bacteria even in the abstract.
> 
> http://www.wjgnet.com/1007-9327/pdf/v19/i43/7531.pdf



Yes, it is stated in the abstract that “Reports of increased protease activity in stools from IBD patients support a possible mechanism for a dysbiotic enteric microbiota in IBD”. Indeed multiple studies showed increased protease activity and dysbiosis of the microbiota in IBD. However, I found most studies are related to the increased activity of digestive proteases like trypsin and chymotrypsin originated from  the pancreas, a phenomenon that is also seen in people or animals treated with antibiotics or animals raised in germ-free condition, in which the amount of bacteria and bacterial proteases would be reduced or absent rather than increase. Despite that, it might be still possible that there exists some sort of dysbiosis in which the protease-producing bacteria become overgrowth amid a general reduction of gut bacteria. So I wonder if there was any study and paper having really demonstrated this. 




mf15 said:


> Do you happen to know if when eating a low protein/no protein meal that the pancreas outputs less protease.  If so then one way to mitigate colitis might be to eat low protein


Yes, here is a paper: HOWARD F, YUDKIN J. EFFECT OF DIETARY CHANGE UPON THE AMYLASE AND TRYPSIN ACTIVITIES OF THE RAT PANCREAS. Br J Nutr. 1963;17:281-94. It stated that “The control diet contained 47% starch, 18 % casein and 18 % fat. When the starch was increased to 67 % of the diet, there was a 40 % increase in the amylase activity of the pancreas and a 50 % fall in the trypsin activity. When the casein was increased to 67% of the diet, there was a 20% fall in amylase activity and a threefold increase in trypsin activity” and “The change in tryptic activity occurred in less Than 24 h”. Multiple studies also showed that meat and protein increased while vegetable and fruits decreased the risk of IBD. I have written some comments on this several years ago. Here is the paper: Qin X. Can meat and protein really increase, while vegetables and fruits decrease the risk of inflammatory bowel disease? How? J Crohns Colitis. 2009 Jun;3(2):136. I also suspected that some of the beneficial effect of enteral and parenteral nutrition may attributed to the reduced production of digestive proteases (Qin X. Reduced production of digestive proteases and the efficacy of enteral and parenteral nutrition on inflammatory bowel disease. Inflamm Bowel Dis. 2008 Jun;14(6):871), an area that awaits further study.


----------



## Xiaofa Qin

kiny said:


> If you divert the fecal stream in people with crohn's disease who have surgery, they improve drastically, the same happens in people on TPN.


This prompt improvements seems against the notion that the damage of Crohn's disease is caused by the persistent uncontrolled infection of bacteria like MAP in the mucosa. 



kiny said:


> Stool consists of undigested macronutrients and lots of antigen in the form of bacteria. Stool by itself is very infectious. Either the intestine is reacting to the bacteria, or the stool friction causes loss of mucus membrane, which does happen, but since so many people have liquit stools when they're sick, I don't think that is what is going on. In fact I'm pretty sure I read somewhere that chronic diarrhea actually stimulates mucus production.


The continuous loss of mucus layer from gut surface is not only caused by the friction, but also some other factors like the reduced viscosity after more and more water coming in, the degradation by proteases and glycosides from the host and bacteria, etc.




kiny said:


> If it was that simple that antibiotics cause crohn's disease through dysbiosis, the biggest abusers of antibiotics, China and Africa, would have the highest indices of crohn's diseasse. They have the lowest. Yes, China has crohn's disease cases, but compared to the West, they are still low, and China is a major abuser of antibiotics. China is probably the number one abuser of antibiotics.
> 
> The gut flora helps you protect from intestinal infections, and that would explain the correlation between crohn's disease and prior antibiotics use. But in Europe and the US, antibiotics use has gone down considerably, there are warning signs in every office in Europe that antibiotics should not be used for viral infections and should not be abused for microbial infections. And yet...crohn's disease keeps rising in the West.


As discussed early (see post # 66), the multiple large-scale epidemiological studies may suggest the positive link between antibiotics and IBD may probably be true. One alternative explanation for the low IBD in China and high in Western countries could be the exposure of some other factors in the west that make the effect of even such heavily used agents like antibiotics becomes trivial.


----------



## Xiaofa Qin

kiny said:


> Crohn's disease *doesn't* look like UC,* at all*, it actually looks like chronic granulomatous disease and intestinal TB.


So, how you explain the close relationship between the epidemiological distribution of UC and CD in the world, and how you explain the increased risk of infection of TB, but improved healing of CD by anti-TNF-alpha and other immune suppression agents?



kiny said:


> People and animals with immunodficiencies tend to be prone to intestinal infections, AIDS patients are not very prone to crohn's disease, interestingly, they tend to be protected from crohn's disease, it does happen, but rarely, but they are very susceptible to things like MAC infections.


This can be easily explained by the notion that CD is caused by an over-reaction rather than a deficiency of the immune system. What is your explanation for this?


----------



## kiny

Xiaofa Qin said:


> So, how you explain the close relationship between the epidemiological distribution of UC and CD in the world, and how you explain the increased risk of infection of TB, but improved healing of CD by anti-TNF-alpha and other immune suppression agents?
> 
> 
> 
> This can be easily explained by the notion that CD is caused by an over-reaction rather than a deficiency of the immune system. What is your explanation for this?


That crohn's disease has macrophage and autophagy deficiencies is extremely well establised by hundreds of studies. I don't think that is something you can argue about.

The innate immune system is severely compromised in people with macrophage deficiencies.

Autophagy and the innate immune system were considered secondary to the adapative immune system in the past, most focus was on the adaptive response. Many recent studies have shown autophgay is directly involved in control of intracellular pathogens, and the innate immune is a lot more important than first assumed. 

Immunosupressants used for crohn's disease, like imuran are actually used during certain infections to stop the destructive inflammation, in the inflammation affects organs and nerves, if you don't treat them with immunosupressants, they suffer from nerve damage or organ failure, regarless if you treat them with antibiotics or not. Some cases of TB are actually treated with immunosupressants.

If you treated some infections purely with antibiotics, you would cause nerve damage.

Why infliximab works, actually no one knows, all other anti-TNF alpha blockers like etanercept and the others that work for UC, don't work for CD.

.

Anyone who has looked at histology tissue, as I have from my own tissue, and compared it to tissue from UC, will tell you it looks nothing like UC. There are no granuloma in UC. Crohn's disease is transmural, it invovles things like fistula, granuloma, patchy inflammation.

It has didly squat to do with UC. The term "IBD" is really unfortunate.


----------



## kiny

Xiaofa Qin said:


> over-reaction of the immune system


there is 0 evidence that crohn's disease is caused by an over-reaction of the immune system

people with crohn's disease are immunodeficient

I have crohn's disease and I actually have severe lymphopenia of CD4+, so do others with crohn's diseasse.

My crohn's disease is not "gone".

An overreactive immune system would be really nice for me, I have to use antibiotics for my lungs sometimes as a countermeasure so I don't get a lung infection.

The only world where crohn's disease is an overreactive immune system is fantasy world.

*Crohn's disease: an immune deficiency state.*
http://www.ncbi.nlm.nih.gov/pubmed/19437144

_"A number of hypotheses have been proposed, most of which postulate a primary over-activation of the immune response, based on the pathological appearances of active Crohn's lesions. Interestingly, *none of these theories have been mechanistically proven*."_

I have looked everywhere, not a single study has shown that crohn's disease or the patients have an overreactive immune system.

There is 0 evidence for that, nothing.

On the other hand, there are literally hundreds of studies that show macrophage, cytokine and autophagy deficiencies in crohn's disease. Immunodeficiencies. There is so much evidence for immunodeficiency in crohn's disease that you can't argue against it with a straight face.


*Revisiting Crohn's disease as a primary immunodeficiency of macrophages*
http://jem.rupress.org/content/206/9/1839.full

*Mycobacteria in Crohn's disease: How innate immune deficiency may result in chronic inflammation*
http://informahealthcare.com/doi/abs/10.1586/eci.10.29

*Crohn抯 disease: Innate immunodeficiency*
http://www.wjgnet.com/1007-9327/12/6751.asp[/URL

*Vitamin D enhances macrophage function and improves killing of Crohn's associated E. coli*
[URL="http://www.crohnsforum.com/showthread.php?t=47789"]http://www.crohnsforum.com/showthread.php?t=47789

*Defective macrophage function in crohn's diseas*
http://gut.bmj.com/content/60/Suppl_1/A143.2.abstract


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## kiny

infliximab is actually deterimental to MAP survival btw

http://www.ncbi.nlm.nih.gov/pubmed/22398081

so is imuran and 6MP:

http://www.johnes.org/handouts/files/Shin_6MP.pdf

the world isn't as black and white as you think. immunosupressants are used extensively during infections, in fact the idea and basic need for immusupressants originated from infections, because the inflammation is in large part responsible for the tissue / organ and nerve damage in those people

the reason why some infections actually don't worsen on inflximab is because not every bacteria is the same, some cause very rapid cell division, others do not, some are intracellular, some are not, some can't handle an inflammatory environment, some exploit it

TB cause far more rapid cell divsion than something like MAP, which divides extremely slowly (that's why it takes months to culture it), even though they're both mycobacteria, they are very different bacteria, as a result, they also respond very differently to infliximab


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## Xiaofa Qin

kiny said:


> there is 0 evidence that crohn's disease is caused by an over-reaction of the immune system
> 
> people with crohn's disease are immunodeficient


Among the dozens of thousands of studies on Crohn’s disease, all effective treatments, from the different small molecules to biologics, are related to immune suppression, which would be a straight indication that CD is associated with an enhanced immune reaction.



kiny said:


> infliximab is actually deterimental to MAP survival btw
> 
> http://www.ncbi.nlm.nih.gov/pubmed/22398081
> 
> so is imuran and 6MP:
> 
> http://www.johnes.org/handouts/files/Shin_6MP.pdf


We already have a detailed discussion on this early (see post #164). I would like to repost some of that post here. 

"I also felt the notion that the high efficacy of the immune suppression agents like inflixmab and 6-MP is largely due to their bactericidal activity on MAP a fascinating idea, but I just wonder how this miracle occurred. A study (Greenstein RJ, et al. On the action of methotrexate and 6-mercaptopurine on M. avium subspecies paratuberculosis. PLoS One. 2007 Jan 24;2(1):e161) showed that although 6-MP have some inhibition on the growth of MAP, its activity is still much lower than some antibiotics like clarithromycin (4 ug/ml 6-MP versus 0.5 ug/ml clarithromycin to cause 80% growth inhibition of the bacteria). For the treatment of IBD, 6-MP is usually used in a dose below 100 mg/day and lasted for several weeks. However, in the study by Selby W, et al. (Antibiotics in Crohn's Disease Study Group. Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn's disease. Gastroenterology. 2007 Jun;132(7):2313-9), even clarithromycin used at 750 mg/day, along with 450 mg/day rifabutin and 50 mg/day clofazimine to treat the patients with Crohn’s disease for up to two years failed to show evidence of sustained benefit. I just cannot image how 6-MP, with much less bactericidal capability and used at a much lower dose and in such a short period can achieve the effective treatment for Crohn’s disease through the claimed killing of MAP".



kiny said:


> It has didly squat to do with UC. The term "IBD" is really unfortunate.


Again, what is your explanation for the close relationship between the epidemiological distribution of UC and CD in the world?


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## kiny

Xiaofa Qin said:


> Again, what is your explanation for the close relationship between the epidemiological distribution of UC and CD in the world?


It's not very close at all, crohn's disese and UC rates can differ greatly, double digit percentages, per country.

In some regions in canada diabetes rates are the same as crohn's disease rates.

Are we going to say diabetes is the same as crohn's disease...

that's not an argument, look at the clinical differences, UC and crohn's disease couldn't be farther apart

I remember we were talking about an article of V Kruiningen once, go ask him if crohn's disesase and UC are alike. He has shown multiple times through histology that they are completely different diseases.


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## kiny

Xiaofa Qin said:


> I just cannot image how 6-MP, with much less bactericidal capability and used at a much lower dose and in such a short period can achieve the effective treatment for Crohn’s disease through the claimed killing of MAP".


Why either 6mp or infliximab works for crohn's disease is unknown at this point.

And no...it's not as simple as saying it lowers the immune response. Very strong TNF-alpha blockers like etanercept do nothing for crohn's disease.

My counterargument to you is that you are trying to prove that cohrn's disease can't be related to an infectious organism because you use immunosupressants.

As I have said before, immunosupression does not always worsen infections. In fact immunosupressants were made to treat infections.

Where do you think T cells in crohn's disease come from if it isn't from an APC. They don't magically appear from a diet or the gut flora. You need a pathogen.

You're jumping to conclusions and assumptions based on fact that aren't even true, just because you can't accept that crohn's disease, like almost any intestinal disorder involving inflammation, could be from pathogenic origin.


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## kiny

read this, tell me how you can interpret this as anything else than immunodeficiency

there is no question that this is immunodeficiency

I can show you hundreds of studies that show innate immunodeficiency in crohn's disease, but if you're not willing to accept it, I'm just wasting my time

the conclusion actually asks the same question you are asking......supressing the immune system when you are dealing with immunosupressed patients is probably not the best of ideas

and it probably isn't....but until there is better treatment, this is what patients have to use often....it stops the destructive inflammation and the ROS damage in the intestine


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## kiny

this is the evidence for AIEC:

http://www.crohnsforum.com/showthread.php?t=52198

You don't get to argue if it's there or not.......there are 60 something studies that show it's there........it's there...there's no argument

the argument that  pathogens aren't causing inflammation in crohn's disease is over....the evidence is in, the only way to ignore the mountain of evidence is living on a secluded island in a bubble of denial

there's no argument anymore, you don't get to cherry pick articles


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## kiny

Xiaofa Qin said:


> (Antibiotics in Crohn's Disease Study Group. Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn's disease. Gastroenterology. 2007


Not sure what you're trying to say here. That study recommended the use of antibiotics effective against gram- iin their conclusion nstead of broad spectrum against MAP because AIEC is more consistently found in crohn's diseasse patients.

AIEC is gram-
MAP is gram+

I never said MAP is a causative agent, I said that it is highly unlikely to me that a pathogen would not be involved. Granuloma, adaptive immune response, peyer's patches, NOD2, ATG16L1, skip lesions, onset fevers. All the telltale signs of an infectious agent.

It is also unlikely that an immunocompromised person would only be susceptible to a single "holy grail" bacteria, HIV patients are susceptible to a whole host of infections. Crohn's disease patients would be susceptible to intracellular bacteria that can exploit the *macrophage deficiencies*, macrophages that line the whole digestive tract coincidentally.

And the granuloma look like 2 drops of water like intestinal TB. Differentiating UC from crohn's disease is not hard, differentiating it from TB without staining biopsies and histology, is extremely hard.

Unlike something like UC, which again, is a very different disease.


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## kiny

Your thought process is sometimes nonsensical I feel. You can't just disprove a pathogen is involved by cherry picking a single study that used antibiotics. Go try that with people with resistant TB infections, go tell them they don't have TB just because your amoxicillin doesn't get rid of their TB. These arguments are beyond ridiculous and you're hurting people with crohn's disease by using them.

Mycobacteria and AIEC are extremely resistant type of bacteria, they create resistance in-vitro within hours.

The nature of crohn's disease, the constant relapses and inability to cure crohn's disease with over the counter braod spectrum, requires it to be resistant bacteria, otherwise a few weeks of flagyl would have us all cured.

Most people have moved on from the idea that there is one single holy grail bacteria causing crohn's disease, any immunodeficiency  leaves you susceptible to multiple organisms.

Klebsiella and food borne bacteria like listeria and yersinia have also been associated with crohn's disease.


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## durwardian

It is a matter of sensitivity to any of the foods, additives, preservatives, sweeteners. I can't do any of them when I'm sick. When I get my immune system boosted, I can eat all of them and they don't bother me. So don't trust that what you ate yesterday is fine, it depends on how sick you are at the moment, and which direction it pushes you. If it is an irritant, it will get you the second, third, maybe fourth time. Also, look at what might be fed by these items, like candida. If you feed the bacteria what it wants to eat, it will thrive. Put back good bacteria as often as you can, in particular when you are doing antibiotics.


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## rollinstone

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3031217/

interesting article for you both to read, but to chime in, kiny is spot on, crohn's is definitely caused by an infection of some sort, all Koch's postulates have been fulfilled bar one which is unethically possible, whether it causes all cases - probably not, but like kiny said if you can't clear certain pathogens you're gonna end up with and inflammatory response. this being said out of the longest standing histological remissions that have been attained in CD they were achieved by either anti-map therapy and now most recently SSI vaccine - which left a patient in 100% histological - 4 years med free, the mechanism was to fix macrophage function so the innate immune system can do its job properly and clear out pathogenic bacteria. fecal transplant has also lead to sustained remissions, I don't know if it was restoring intestinal balance or through some sort of stimulation of peyers patches... there is soooo much still unknown, but just because immune suppressants work it doesn't mean its an auto immune disease, that shouldn't even be argued anymore its just creating false miss understanding, or making people bark up the wrong tree... absence of proof is not proof of absence


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## durwardian

I think what it proves is rather simple, these cases are not all Crohn's, and many of the other cases are not diagnosed correctly. Mine is a good example. I have a pseudo-Crohn's because my immune system is trashed. Boosting it fixes my issues. How many people out there might be in the same situation? Too many if you ask me. The doctors were very quiick to just give me Crohn's medicines and suppress my already messed up immune  system. Wrong thing to do, they almost killed me in the process. I had to be my own advocate and search for answers. I finally got to an immunologist and we figured it out before the doctors killed me with drugs I didn't need. Moral of the story is to be careful and not assume that doctors know everything or have it right. If you aren't reacting well to medications, and you get worse, make it  a point to find out what it really is before you just accept that the doctors are always right. Look at the bug they finally found for stomach ulcers. I feel soon they will discover more of these bugs are causing issues for many of you. And some of you have genetic issues that make your digestive tract have problems, and some of you will find out you are just allergic to certain foods or medicines, and others will find that they have other issues. Just don't roll over and accept that the doctor is right unless the treatment is working.


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## rollinstone

Dur thanks so much for posting, my crohns has never been 100% crohns on histology, can you please tell me what your immunologist looked for? How are you now, symptom wise etc and colonoscopies findings recently? If you don't mind sharing


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## Xiaofa Qin

Frankly, I am quite surprised that there were people even denying the close relationship between Crohn’s disease and ulcerative colitis, with the fact that quite a portion of IBD patients cannot be classified as either CD or UC and misdiagnosed among these two frequently occurred. Not only they shared a certain pattern of epidemiological distributions, a recent so-called “to-date largest microarray gene expression study on IBD” demonstrated lack of major differences between Crohn's disease and ulcerative colitis by whole genome gene expression meta-analysis of inflammatory bowel disease colon mucosa. Here is the study:


PLoS One. 2013;8(2):e56818. doi: 10.1371/journal.pone.0056818. Epub 2013 Feb 13.

Whole genome gene expression meta-analysis of inflammatory bowel disease colon mucosa demonstrates lack of major differences between Crohn's disease and ulcerative colitis.

Granlund Av, Flatberg A, Østvik AE, Drozdov I, Gustafsson BI, Kidd M, Beisvag V, Torp SH, Waldum HL, Martinsen TC, Damås JK, Espevik T, Sandvik AK.

Author information 

Abstract

BACKGROUND: 

In inflammatory bowel disease (IBD), genetic susceptibility together with environmental factors disturbs gut homeostasis producing chronic inflammation. The two main IBD subtypes are Ulcerative colitis (UC) and Crohn's disease (CD). We present the to-date largest microarray gene expression study on IBD encompassing both inflamed and un-inflamed colonic tissue. A meta-analysis including all available, comparable data was used to explore important aspects of IBD inflammation, thereby validating consistent gene expression patterns.

METHODS: 

Colon pinch biopsies from IBD patients were analysed using Illumina whole genome gene expression technology. Differential expression (DE) was identified using LIMMA linear model in the R statistical computing environment. Results were enriched for gene ontology (GO) categories. Sets of genes encoding antimicrobial proteins (AMP) and proteins involved in T helper (Th) cell differentiation were used in the interpretation of the results. All available data sets were analysed using the same methods, and results were compared on a global and focused level as t-scores.

RESULTS: 

Gene expression in inflamed mucosa from UC and CD are remarkably similar. The meta-analysis confirmed this. The patterns of AMP and Th cell-related gene expression were also very similar, except for IL23A which was consistently higher expressed in UC than in CD. Un-inflamed tissue from patients demonstrated minimal differences from healthy controls.

CONCLUSIONS: 

There is no difference in the Th subgroup involvement between UC and CD. Th1/Th17 related expression, with little Th2 differentiation, dominated both diseases. The different IL23A expression between UC and CD suggests an IBD subtype specific role. AMPs, previously little studied, are strongly overexpressed in IBD. The presented meta-analysis provides a sound background for further research on IBD pathobiology.


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## rollinstone

Very interesting, thanks for posting, did you happen to read the link I posted above? It is quite a long paper


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## Xiaofa Qin

Joshuaaa said:


> Very interesting, thanks for posting, did you happen to read the link I posted above? It is quite a long paper


Yes, I read this paper before. That paper (Pierce ES. Ulcerative colitis and Crohn's disease: is Mycobacterium avium subspecies paratuberculosis the common villain? Gut Pathog. 2010 Dec 17;2(1):21) proposed that not only Crohn's disease but also ulcerative colitis may be caused by MAP, a notion that further complicated the MAP controversy. 

People have suspected that Crohn's disease may be caused by MAP largely because it shared some clinical and histological similarities with Johne's disease, such as the existence of inflammatory granulomas, a characteristic feature for CD.  Compared to CD, similarities between UC and Johne's diseases are much less. Crypt abscesses, the characteristic changes in UC, are composed of large amounts of gut bacteria other than MAP and neutrophils, diminished a critical role of MAP in the inflammation of the tissue. The rate of MAP and its related parameters are also lower in UC. Even the discrepancies between CD and Johne's disease have caused so big  controversy. The notion that UC may be also caused by MAP would be even more controversial.


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## Xiaofa Qin

To my knowledge, the notion that Crohn’s disease may be caused by immune deficiency indeed draw quite attention years ago. People have even tried to develop the drug sargramostim, also known as granulocyte macrophage colony stimulating factor (GM-CSF) that stimulates stem cells to produce granulocytes and monocytes to boost the immune system. Unfortunately, the clinical trials failed to show much effect versus placebo. 

Here is a paper on this:

Cochrane Database Syst Rev. 2011 Nov 9;(11):CD008538. doi: 10.1002/14651858.CD008538.pub2.

Sargramostim (GM-CSF) for induction of remission in Crohn's disease.

Roth L, Macdonald JK, McDonald JW, Chande N.
Author information 
    London Health Sciences Centre - Victoria Hospital, London, Canada.


Abstract

BACKGROUND: 
Crohn's disease is an inflammatory condition of the gut, thought to involve an overactive immune response to gut flora. A novel theory postulates possible immunodeficiency as a cause, and aims to use sargramostim (granulocyte macrophage colony stimulating factor, GM-CSF) to boost the immune system in an effort to test this hypothesis.

OBJECTIVES: 
The primary objectives were to determine the efficacy and safety of sargramostim for induction of remission in patients with clinically active Crohn's disease.

SEARCH METHODS: 
A systematic search of MEDLINE, EMBASE, and CENTRAL was conducted from inception to April 2011. Reference lists of relevant review articles were also searched. Trial registries and abstract databases including Digestive Diseases Week (1980-2010) and United European Gastroenterology Week (2005-2009) were searched to identify studies published in abstract form.

SELECTION CRITERIA: 
Randomized controlled trials of sargramostim for the treatment of patients with active Crohn's disease were considered for inclusion.

DATA COLLECTION AND ANALYSIS: 
Data from selected articles were extracted and the Cochrane Risk of Bias tool applied independently by two authors. The primary outcome was induction of clinical remission as defined by a Crohn's Disease Activity Index (CDAI) of < 150 at the end of treatment. Secondary outcomes included clinical responses measures on the CDAI and safety outcomes. Pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated for dichotomous outcomes, in most cases using a random effects model due to high heterogeneity.

MAIN RESULTS: 
Three studies were identified, 2 published as full papers and one in abstract form (537 patients). The risk of bias was low for the 3 included studies. There was no statistically significant difference in the proportion of patients (GM-CSF 25.3% versus placebo 17.5%) who achieved clinical remission (RR 1.67; 95% CI 0.80 to 3.50; P = 0.17; 3 studies; 537 patients). There was no statistically significant difference in the proportion of patients (GM-CSF 38.3% versus placebo 24.8%) who achieved a 100-point clinical response (RR 1.71 95% CI 0.98 to 2.97; P = 0.06; 3 studies; 537 patients). There was no statistically significant difference in the proportion of patients (GM-CSF 54.3% versus placebo 44.2%) who achieved a 70 point clinical response (RR 1.23; 95% CI 0.83 to 1.82; P = 0.30; 1 study; 124 patients). There was no statistically significant difference in the proportion of patients (GM-CSF 95.8% versus placebo 89.3%) who experienced at least one adverse event (RR 1.07; 95% CI 0.99 to 1.16; P = 0.08; 2 studies; 251 patients), or serious adverse events (GM-CSF 12.0% versus placebo 4.8%; RR 2.21; 95% CI 0.84 to 5.81; P = 0.11; 2 studies; 251 patients). The incidence of bone pain, musculoskeletal chest pain, and dyspnea were higher in patients treated with sargramostim compared to placebo. Other adverse events commonly associated with sargramostim such as pulmonary capillary leak syndrome, pulmonary edema, heart failure, fever, and neurotoxicity were not reported in these studies.

AUTHORS' CONCLUSIONS: 
Sargramostim does not appear to be more effective than placebo for induction of clinical remission or clinical improvement in patients with active Crohn's disease. However, the GRADE analysis indicates that the overall quality of the evidence for the primary (clinical remission) and secondary outcomes (clinical response) was low indicating that further research is likely to have an impact on the effect estimates.


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## durwardian

Joshuaaa said:


> Dur thanks so much for posting, my crohns has never been 100% crohns on histology, can you please tell me what your immunologist looked for? How are you now, symptom wise etc and colonoscopies findings recently? If you don't mind sharing


My immunologist started me with tests for the immune system, out of the few they are aware of, they can't manipulate them all. Lucky me it was my iga system, treated by plasma infusion. My allergies also went from a positive reaction to no reaction after IgA treatment.


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## durwardian

Joshuaaa said:


> Dur thanks so much for posting, my crohns has never been 100% crohns on histology, can you please tell me what your immunologist looked for? How are you now, symptom wise etc and colonoscopies findings recently? If you don't mind sharing


The VA took my infusions away after reaching what they called a stable level. 2 years later I am back to suffering without it, and struggling with doctors to get treatment. It is very expensive. And now the fight to get treated has started again


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## kiny

Xiaofa Qin said:


> close relationship between Crohn’s disease and ulcerative colitis


there is no close relationship, go look at histology pictures and show me the close relationship

you need to stop cherry picking articles also, there's also studies that pointed out the ridiculousness of grouping these 2 diseases together, one compared it to comparing bronchitis it TB lung infections...they're very very different disease

not sure why you are even writing papers if you think they are similar, go actually look at histology slides, put them side by side and tell me the diseases are the same, I have done so for my own biopsies, they look nothing like UC, the crypts and granuloma are nothing like UC, if you don't believe me that they are very different, go ask a histologist, they'll tell you and show you


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## kiny

Xiaofa Qin said:


> Not only they shared a certain pattern of epidemiological distributions


great, you're choosing your words more carefully, "certain"..there is considerable differences between UC and crohn's disease rates in most countries


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## kiny

Xiaofa Qin said:


> To my knowledge, the notion that Crohn’s disease may be caused by immune deficiency indeed draw quite attention years ago.


years ago?

I have no idea why you come to a crohn's disease forum if you live in a bubble of denial, you're not helping.

If you want to blame both UC and crohn's disease on some diet and ignore the massive amount of data about immunodeficiency related to crohn's disease and bacterial involvement, studies from nature, the lancet, BMJ, immunodeficienies related to autophgay, NOD2, ATG16L1, macrophage deficiency, VDR, interleukin 23, be my guest, don't expect most people to take you serious, you're quickly losing any respect I had for you. You cherry pick articles and you ignore massive data that shows genetic differences between UC and crohn', fistula, skip lesions, granuloma, transmural inflammation, pathological differences between the 2, treatment differences, antibiotics use for crohn's disease, and immunodeficiencies in crohn's disease. The studies you made consist of guesswork and controversial titles, often ignoring established data, just so your hypothesis makes sense. A lot of your studies say "in my opinion", you never sway from that opinion, you never take data that speaks against that "opinon" into account. They're not studies, they're opinon pieces.


2011
*Defective innate immunity in inflammatory bowel disease*
http://www.ncbi.nlm.nih.gov/pubmed/21483259


"_Recent advances *continue to highlight defects in innate immunity in Crohn's patients*. Similar abnormalities may extend to other granulomatous disorders, *but not diseases such as ulcerative colitis.*_"


Believe it or not, UC does not look like crohn's disease. It can look a lot like chronic granulomatous disease and intestinal TB.



2013
*Crohn's as an immune deficiency: from apparent paradox to evolving paradigm.*
http://www.ncbi.nlm.nih.gov/pubmed/23256761


 2013
*Impaired autophagy leads to abnormal dendritic cell-epithelial cell interactions.
*
http://www.ncbi.nlm.nih.gov/pubmed/22981596

2012*
Evidence from genetics for a role of autophagy and innate immunity in IBD pathogenesis.*
http://www.ncbi.nlm.nih.gov/pubmed/22796792

 2012
*Defects in autophagy favour adherent-invasive Escherichia coli persistence within macrophages leading to increased pro-inflammatory response.*
http://www.ncbi.nlm.nih.gov/pubmed/22309232

2010
*
NOD2 polymorphisms in clinical phenotypes of common variable immunodeficiency disorders.*
http://www.ncbi.nlm.nih.gov/pubmed/20646002

2011
*Defective macrophage function in crohn's disease: role of alternatively activated macrophages in inflammation*
http://gut.bmj.com/content/60/Suppl_1/A143.2.abstract


----------



## Xiaofa Qin

kiny said:


> there is no close relationship, go look at histology pictures and show me the close relationship


Yes, the symptoms and histology of TB of the gut may quite similar as Crohn’s disease, but very different from TB in the lung, brain, kidney and bone. However, no matter in which organ, TB can be effective treated by anti-TB antibiotics, but anti-TNF alpha and other immune suppression agents effective for Crohn’s disease would execrated TB. Instead, CD and UC shared many similar treatments. SO CD and UC but not TB are more similar in nature.


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## kiny

Xiaofa Qin said:


> Instead, CD and UC shared many similar treatments. SO CD and UC but not TB are more similar in nature.


Plenty of diseases are treated with TNF-alpha blockers, that does not in any share or form mean they are similar.

I've said a few posts back that your thought process is very hard to argue with because you base all your theories on nonsensical evidence.


----------



## Xiaofa Qin

kiny said:


> great, you're choosing your words more carefully, "certain"..there is considerable differences between UC and crohn's disease rates in most countries


Do you know what the "certain pattern" here mean? It does not mean the difference of incidence between UC and CD, rather it means always UC starts to appears first followed by CD, but over time CD tends to catches up and even exceeds UC.


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## Xiaofa Qin

kiny said:


> If you want to blame both UC and crohn's disease on some diet and ignore the massive amount of data about immunodeficiency related to crohn's disease and bacterial involvement, studies from nature, the lancet, BMJ, immunodeficienies related to autophgay, NOD2, ATG16L1, macrophage deficiency, VDR, interleukin 23, be my guest, don't expect most people to take you serious, you're quickly losing any respect I had for you.


Looking back human history, when had people respected new theory? Are these important?



kiny said:


> A lot of your studies say "in my opinion", you never sway from that opinion, you never take data that speaks against that "opinon" into account. They're not studies, they're opinon pieces.


Yes, those are indeed just my opinions that I hope may bring people some new thinking. As I stated in my very early post, even Einstein made mistakes, and my opinion is always ready to adjust against new facts that emerge. On the other hand, the validity of my opinion and hypothesis would be also only   determined by the facts that are accumulating.


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## durwardian

I think what is way overdue, is breaking the broad approach to any of these diseases. I think we have similar symptoms and different causes, and the big mistake is clumping things together. My doctor was way too quick to base his findings on symptoms, not facts. The facts took 10 years to uncover because we trust that doctors are smart enough and concerned about our health. Generally they expect the medicines to work, if they do, great. If they don't more testing should be number one. Insist on it, the more data, the better it will get.


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## Xiaofa Qin

kiny said:


> Plenty of diseases are treated with TNF-alpha blockers, that does not in any share or form mean they are similar.


In addition to IBD, TNF-alpha blockers like Infliximab are also used for the treatment of psoriasis, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis. All these are regarded as autoimmune disease in nature.


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## kiny

Xiaofa Qin said:


> In addition to IBD, TNF-alpha blockers like Infliximab are also used for the treatment of psoriasis, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis. All these are regarded as autoimmune disease in nature.


That's right, many are, and to date, there is no real evidence crohn's disease is an autoimmune disease

An autoimmune disease requires a self-antigen.

Crohn's disease does not fulfill Witebsky's postulates.

In fact, just to point out once against how different UC and crohn's disease are, in UC there are self-antigen, colonic epithelial cells. In crohn's disease there are not, people who say there are tend to bend the definition of self-antigen quite a bit.

If the ileum epithelial cells or the gut flora was an antigen in crohn's disease, you would have inflammation everywhere, and you don't, there's skip lesions.........unlike....once again....UC. 

UC has lumen inflammation, extremely specific to the colon, they have no fistula, no transmural inflammation, it does not discriminate, there are no skip lesions, the whole organ is inflamed. Crohn's disese is *very* different, you have granuloma, crypt look different, you have transmural inflammation, fistula. Different disease.

UC actually has hallmarks of an autoimmune disease, it non-discriminately affects the whole organ, unlike in crohn's disease.


There might be a cross reaction, E coli and Klebsiella could be causing cross reactions, but if it was directed at tissue, the whole ileum would be inflamed, and once again, if you look at crohn's disease pathology, they're skip lesions, doesn't look like an autoimmune response in any shape or form.


*What’s in a name? The (mis)labelling of Crohn’s as an
autoimmune disease*
http://211.144.68.84:9998/91keshi/Public/File/36/376-9736/pdf/1-s2.0-S0140673610602826-main.pdf


----------



## kiny

If you believe all these diseases are "similar"...you're welcome to point out to us how etanercept that works for all these diseases does not work for crohn's disease.


----------



## mf15

Xiaofa: Thank you for the paper on trypsin output from the pancreas.
I may start to eat more starch and less meat.
Of course we have macrophage protease,and other proteases to worry about also.

Old Mike


----------



## Xiaofa Qin

mf15 said:


> Xiaofa: Thank you for the paper on trypsin output from the pancreas.
> I may start to eat more starch and less meat.
> Of course we have macrophage protease,and other proteases to worry about also.
> 
> Old Mike


I would like to thank you for sharing the thoughts and info. 

Be careful that the protease theory remains a hypothesis to be tested. 

Best wishes,

Xiaofa


----------



## Xiaofa Qin

kiny said:


> That's right, many are, and to date, there is no real evidence crohn's disease is an autoimmune disease
> 
> An autoimmune disease requires a self-antigen.


The inflammation of the gut may be caused by uncontrolled proliferation of bacteria infiltrated into the mucosa. At such a situation, we should see quite a number of bacteria in the cells like macropahges in the mucosa and lymph nodes under microscope, not just detected by PCR after billions of times of amplification of the signal. The scarcity of bacteria and effective treatment by agents like anti-TNF seems more fit into the pattern of autoimmune disease. We should realize that not like the joint and some other organs deep inside the body, there are always large amounts of luminal contents that contain many kinds of harmful agents in the gut. Thus, it may even not need the existence of a self-antigen, as the increased infiltration of lipopolysaccharides (LPS, or endotoxin) and other bacterial products or antigens from the diet might be enough to provoke an enhanced immune reaction. 

Again, this is just my personal opinion.


----------



## Xiaofa Qin

kiny said:


> If you believe all these diseases are "similar"...you're welcome to point out to us how etanercept that works for all these diseases does not work for crohn's disease.


There are actually some difference between etanercept and anti-TNF α antibodies like infliximab:  according the description, etanercept is a fusion protein produced by fusing the TNF receptor to the constant end of the IgG1 antibody, while infliximab is an antibody to TNF α. One explanation I think of regarding the difference of efficacy between these two would be that each infliximab molecule would be capable of binding and inactivated one TNF α, while the efficacy of etanercept to trap and inactivate TNF α would depand on the ratio of etanercept (the introduced exogenous TNF α receptors) to the amounts of endogenous TNF α receptor inside the body. If the exogenous and endogenous receptors are equal, only half of the administrated etanercept may bind a TNF α. If the endogenous receptors are 10 times in number of the injected etanercept, only about 1/10 of administrated etanercept may bind a TNF α. The gut has a large number of immune cells and the inflammation of gut may have caused a huge increase in endogenous TNF α receptor, thus a big variation and low efficacy of etanercept. This is just a speculation for a tentative explanation.


----------



## kiny

Xiaofa Qin said:


> The inflammation of the gut may be caused by uncontrolled proliferation of bacteria infiltrated into the mucosa. At such a situation, we should see quite a number of bacteria in the cells like macropahges in the mucosa and lymph nodes under microscope, not just detected by PCR after billions of times of amplification of the signal.


You can't aways accurately detect leprosy, can't culture it really without a host. If people are helped through antibiotics, and they are, you linked a single study, cherry picked. There are plenty of studies that have shown the benefit of cipro-flagyl, not just for fistula, as treatment, cipro happens to be very effective against E Coli. What does it matter if you can't find a holy grail bacteria if antibiotics helps, the patients don't care. AIEC is there, why not treat it. There's a lot of things that are far more dangerous than treating ppl with antibiotics, regardless of resistance.

Avoiding to treat people because you can't find a holy grail bacteria would have killed thousands of lepers.

If there's a primary macrophagy deficiency and autophagy deficiencies, you would get disseminated bacteria, you'd end up with lots of antigen that is really hard to detect. You'd have non-stop APC signaling lymphocytes and never be able to fully clear the antigen causing all the inflammation.

Microparticles so common in the West would make it far worse. It would be really hard to find one single culprit after a while.

It's also a fallacy that you "need lots of bacteria"...you don't need much to get an inflammatory reaction going. Immune cells can replicate by the thousands per second. You don't need  much to set off an adaptive immune response, the intestine is lined from top to bottom with macrophages, the small intestine is lined with peyer's patches. Look at what happens with other diseases of immunocompromised patients, a minor infection can quickly get out of control if they don't use preventive medication.


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## Xiaofa Qin

kiny said:


> You can't aways accurately detect leprosy, can't culture it really without a host.


Leprae is indeed difficult to culture. However, as I discussed with you about one year ago in a post in another thread,  Gerhard Henrik Armauer Hansen in Norway had announced back in 1873 the discovery of Mycobacterium leprae in the tissues of all sufferers, with just a "new and better" microscope, without the special stains developed by Albert Neisser and others later. Here, I would like to repost that post here.

“Thanks kiny for sharing the thoughts. I admired the great efforts you and many other patients in this forum took, trying so hard to understand the disease. The body is very complex. Apparently, it is not easy to read through the many research papers with the many jargons. 

Frankly, my intention is not to provoke sentimental arguments, although I have a lot of strong “scientific” evidences for both sides of the MAP controversy for an endless debate. Rather I think we should ponder thoroughly, deeply and carefully over the many conflicting “facts” to make a more accurate assessment and insightful judgments to figure out the likely true nature of the disease. 

I do not think finding MAP in the blood is a trivial thing. The long lasting MAP controversy would actually largely attribute to the scarce of MAP found in the patients, which is in fact in great contrast with the situations in the Johne’s disease, M Leprae and H Pylori. Yes, we still failed to find out the right condition for culturing M Leprae in vitro. However, Gerhard Henrik Armauer Hansen in Norway had announced back in 1873 the discovery of Mycobacterium leprae in the tissues of all sufferers, with just a "new and better" microscope, even without the special stains developed by Albert Neisser and others later (http://en.wikipedia.org/wiki/Gerhard_Armauer_Hansen). This had been also before the discovery of Mycobacterium tuberculosis by Robert Koch in 1882 (http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis) and the discovery of Johne’s disease by Heinrich A. Johne in 1905 (http://en.wikipedia.org/wiki/Paratuberculosis). The existence of H. Pylori (the spiral-shaped bacteria) in the lining of the human stomach had been found by German scientists back to 1875, a century before Barry Marshall and Robin Warren approved they are the key causative factors for peptic ulcers in 1980s (http://en.wikipedia.org/wiki/Helicobacter_pylori) . As we know, large amounts of MAP can easily be found in the feces and tissues of Cattle with Johne’s disease and cultured with the standard methods established long time ago. It is the scarce of MAP in the feces and tissue of Crohn’s disease made the report of successful culture of higher rates of viable MAP in the blood of Crohn’s patients become quite an important event. And only the consistent, reproducible differences between the patients and controls may suggest the existence of a possible link.     

I also do not agree with the notion that Crohn’s disease is more closely linked to diseases like leprosy rather than ulcerative colitis. There is no misdiagnosis between CD and leprosy at all. However, no matter how splendid the hospital, how good the doctor and how hard they try, there is always a portion of cases Non-Differentiable as either CD or UC. In addition, CD and UC but not leprosy also shared many similarities in epidemiological distribution, treatments, etc.”


----------



## Xiaofa Qin

kiny said:


> If people are helped through antibiotics, and they are, you linked a single study, cherry picked.


Are you referring “cherry picked” to the citation in my early post (#264) of the study by  Selby W, et al. (Antibiotics in Crohn's Disease Study Group. Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn's disease. Gastroenterology. 2007 Jun;132(7):2313-9) that failed to show sustained benefits by the antibiotics on MAP? You should realize that this is a prospective, parallel, placebo-controlled, double-blind, randomized trial with 2 years of treatment with a combination of clarithromycin, rifabutin, and clofazimine and a further year of follow-up, thus the most strictly controlled large-scale, long-term study in this regard. Yes, there were multiple open-labeled studies showing a wonderful effect with the same treatment for just a couple of months. However, which one would be more reliable? The same would be for the study on pig whipworms as discussed in this forum. Multiple open-label studies showed pretty good efficacy, but the company still terminated the trial after an interim analysis of the double-blinded study that failed to show the efficacy.  In your opinion, which study should we choose and which results should we believe?


----------



## kiny

Xiaofa Qin said:


> Are you referring “cherry picked” to the citation in my early post (#264) of the study by  Selby W, et al. (Antibiotics in Crohn's Disease Study Group. Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn's disease. Gastroenterology. 2007 Jun;132(7):2313-9) that failed to show sustained benefits by the antibiotics on MAP? You should realize that this is a prospective, parallel, placebo-controlled, double-blind, randomized trial with 2 years of treatment with a combination of clarithromycin, rifabutin, and clofazimine and a further year of follow-up, thus the most strictly controlled large-scale, long-term study in this regard. Yes, there were multiple open-labeled studies showing a wonderful effect with the same treatment for just a couple of months. However, which one would be more reliable? The same would be for the study on pig whipworms as discussed in this forum. Multiple open-label studies showed pretty good efficacy, but the company still terminated the trial after an interim analysis of the double-blinded study that failed to show the efficacy.  In your opinion, which study should we choose and which results should we believe?


Yes I am, you cherry picked it. I can't discuss stuff with you because you cherry pick studies.

Same trial, completely different conclusion.
http://www.ncbi.nlm.nih.gov/pubmed/17369114

You could have easily picked that study...but you didn't. 

A lot of things also went wrong in that cherry picked study...anyway.


Regardless, AIEC is very common in ileal crohn's disease. The conclusion in the cherry picked study was that antibiotics effective against gram- AIEC would be preferrable, and they probably are for people with ileal disease with granuloma.

Many trials done with cipro show success, cipro is quite effective against gram-, since many gram- live in biofilms, they are hard to eradicate, many many bacteria are extremely resistant to current day antibiotics. You are welcome to ignore those studies, I expect nothing less, you ignored half the data I present you, so why not add some more.

Part of the reason studies are so inconclusive, is because, like many people have said before, crohn's disease, crohn's collitis, collitis, are probably not the same diseases. And it is very unlikely that someone with colon involvement has the same disesase as someone with ileal disease, there are no peyer's patches in the colon, one of the first signs of crohn's disease in ileal patients, is inflammation of peyer's patches, my guess is because antigens are translocating and inflitrating M cells. The fact most crohn's disease ileal cases happen around the ages when peyer's patches are most active, is probably not an accident. There is a reason why crohn's disease manifsts itself at a certain age, it's clearly happening around 11-18 in most people. I don't have the numbers in front of me, around puberty.

Again........different diseases. Within crohn's disease there are probably different diseases, my guess is someone with crohn's colitis without granuloma does not have the same disease as someone with ileal involvement /inflammation of peyer's patches and granuloma. My guess is they are not the same disease. And UC is a very very different disease form crohn's disease.

If you bunch all these people up in the same studies, like some have done, yes you'll get studies that show great benefit and some that are not. Some people are extremely good candidates for antibiotics, ileal involvement, response to infliximab, granuloma, someone with crohn's collitis for example would not be a good candidate for those same studies.

But since some............."experts"..........like to bunch all the disesases together, uner the unfortunate IBD term, ppl are not getting individualised treatment. I am hardly the first person who has said that crohn's disesase should be divided into categories based on endoscopic and histological findings.


----------



## kiny

I don't know why you focus on MAP all the time either. No one has said that MAP is causative in crohn's disease. What people who believe in an infectious agent often argue is that we have very specific genetic deficiencies that leave us vulnerable to intracellular pathogens, in patients all around the globe, it's no longer the case that asian patients are exempt from crohn's disease predisposition, studies have found predisposition to autophagy genes in asian patients also.

Autophagy is essential to clearing intracellular pathogens. That we would be prone to intestinal infections would be extremely normal considering many of us have NOD2 / ATG16L1 / IRGM  / IL23 anomalies.

You can not ignore autophagy and macrophage disregulation in crohn's disease, it is a major part of the disease and one of it's major functions is clearing intracellular pathogens.

If you want to argue against bacterial involvment, then argue not just against MAP, argue against the studies that have shown AIEC, klebsiella, Listeria, Yersinia DNA in crohn's disease patients.....people with immunodeficiences are not vulnerable to one single bacteria.


----------



## Xiaofa Qin

kiny said:


> Yes I am, you cherry picked it. I can't discuss stuff with you because you cherry pick studies.
> 
> Same trial, completely different conclusion.
> http://www.ncbi.nlm.nih.gov/pubmed/17369114
> 
> You could have easily picked that study...but you didn't.


So in your eye, a retrospective study of 39 patients is superior to a 3 year prospective, parallel, placebo-controlled, double-blind, randomized trial of 230 patients. I have nothing to say.


----------



## kiny

Xiaofa Qin said:


> So in your eye, a retrospective study of 39 patients is superior to a 3 year prospective, parallel, placebo-controlled, double-blind, randomized trial of 230 patients. I have nothing to say.


I don't care what is "superior". I don't base my conclusions on one single study.

The idea that there is bacterial involvment is crohn's disease is not based on a single study. It's based on genetic findings that are all related to bacterial clearance, it's based on PCR tests, it's based on the presence of granuloma, it's based on limited success with antiboitics, disease clustering, history of other diseases, etc.

No one has said that the causative agent is, with 100% certainty, bacteria. But it should damn well be considered considering the mountain of evidence regarding autophagy, macrophage deficiencies, in vivo tests that show lack of bacterial clearance, in vitro tests, enhanced macrophage function with vitamin D, the benefit of vitamin D on both remission rates and stimulation of NOD2 to ATG genes.

How much evidence do you need to admit......or at the very least consider....that bacterial involvement is present. You can't be this stubborn.


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## kiny

The idea that bacteria are behind the inflammation is not a new idea etiher. Dalziel in 1913 in the BMJ considered bacteria as an agent behind the inflammation in crohn's disease, he called it chronic enteritis. Since they could check for TB back then, they ruled out TB, but they never ruled out bacterial involvement, in fact he suggested bacterial involvement, at that time they had no DNA tests like we have now.


----------



## kiny

Xiaofa Qin said:


> Looking back human history, when had people respected new theory? Are these important?


How do you explain people with diabetes who consume lots of saccharin, having low crohn's disease rates.

The American Diabetic Association has recommended saccharin for years, and yet these people have low rates of crohn's disease.


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## Xiaofa Qin

kiny said:


> How do you explain people with diabetes who consume lots of saccharin, having low crohn's disease rates.
> 
> The American Diabetic Association has recommended saccharin for years, and yet these people have low rates of crohn's disease.


As discussed in my early post (#148), to my knowledge, multiple studies back to 1980s found increased intake of refined sugar in patients with Crohn’s disease (here are some of the studies). However, the enthusiasm receded when some controlled trials failed to show a benefic with the restricted use of sugar (Ritchie JK, et al. Controlled multicentre therapeutic trial of an unrefined carbohydrate, fibre rich diet in Crohn's disease. Br Med J (Clin Res Ed). 1987 Aug 29;295(6597):517-20), especially the poor correlation between the Crohn’s disease and refined sugar consumption (Sonnenberg A. Geographic and temporal variations of sugar and margarine consumption in relation to Crohn's disease. Digestion. 1988;41(3):161-71 ). I suspected that this increased risk in IBD may relate to increased intake of artificial sweeteners rather than refined sugar. As patients with diabetes may have increased intake of sweeteners, I have tried to find if there is a link between diabetes and IBD. I indeed found some studies such as those showing an increased prevalence of diabetes in patients with ulcerative colitis (Kappelman MD, et al. Association of paediatric inflammatory bowel disease with other immune-mediated diseases. Arch Dis Child. 2011 Nov;96(11):1042-6) and a positive association between type 1 diabetes and Crohn’s disease in families (Sipetić S, et al. Family history and risk of type 1 diabetes mellitus. Acta Diabetol. 2002 Sep;39(3):111-5). I have not seen a study showing a reverse relationship between diabetes and CD, and would be happy to see the data you have.


----------



## durwardian

Look instead at what the bugs feed off of, and each individuals intestinal flora balance


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## durwardian

The more out of balance, and flattened, the harder it is to even absorb medicine or nuutrients


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## durwardian

So each case becomes a measure of poisons, toxins, diet, ability to absorb, actual bugs or bacteria present, state of the intestines, allergies, immune system, etc


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## durwardian

The causes are obviously, genetic, environmental, diet, and bugs, all different, but with similar results


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## mf15

Can anyone get the full paper on this so we can figure out exactly what they are saying here,this one is a few days old.
Old Mike






Curr Opin Gastroenterol. 2014 Jan 16. [Epub ahead of print]

Proteases and small intestinal barrier function in health and disease.

Giuffrida P, Biancheri P, Macdonald TT.



Author information 



Abstract

PURPOSE OF REVIEW: 

To summarize the recent knowledge regarding intestinal proteases and the gut barrier.

RECENT FINDINGS: 

It is now well established that intestinal proteases, such as matrix metalloproteinase (MMP)-1, MMP-3, MMP-10 and MMP-12, are key players in the development of ulcers in inflammatory bowel disease, have direct effects on epithelial barrier function and are involved in epithelial restitution. However, more recent work has suggested that the membrane-anchored epithelial cell serine protease matriptase is critical in maintaining the gut barrier, and roles have also been described for elastase, MMP-13, gelatinases, mast cell proteases and proteases derived from parasites and gut bacteria. Interestingly, epithelial proteases often co-localize with epithelial adherens junctions, and nonepithelial-derived proteases have junctional proteins as targets.

SUMMARY: 

The role of proteases in controlling normal barrier function in the gut is now becoming very clear, to go alongside their role in intestinal inflammation.


----------



## wildbill_52280

Xiaofa Qin said:


> As discussed in my early post (#148), to my knowledge, multiple studies back to 1980s found increased intake of refined sugar in patients with Crohn’s disease (here are some of the studies). However, the enthusiasm receded when some controlled trials failed to show a benefic with the restricted use of sugar (Ritchie JK, et al. Controlled multicentre therapeutic trial of an unrefined carbohydrate, fibre rich diet in Crohn's disease. Br Med J (Clin Res Ed). 1987 Aug 29;295(6597):517-20), especially the poor correlation between the Crohn’s disease and refined sugar consumption (Sonnenberg A. Geographic and temporal variations of sugar and margarine consumption in relation to Crohn's disease. Digestion. 1988;41(3):161-71 ). I suspected that this increased risk in IBD may relate to increased intake of artificial sweeteners rather than refined sugar. As patients with diabetes may have increased intake of sweeteners, I have tried to find if there is a link between diabetes and IBD. I indeed found some studies such as those showing an increased prevalence of diabetes in patients with ulcerative colitis (Kappelman MD, et al. Association of paediatric inflammatory bowel disease with other immune-mediated diseases. Arch Dis Child. 2011 Nov;96(11):1042-6) and a positive association between type 1 diabetes and Crohn’s disease in families (Sipetić S, et al. Family history and risk of type 1 diabetes mellitus. Acta Diabetol. 2002 Sep;39(3):111-5). I have not seen a study showing a reverse relationship between diabetes and CD, and would be happy to see the data you have.


Xiaofa Qin, i mentioned this study earlier but perhaps you never got around to looking at it, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1247426/

 but it did find a difference between sugar intake and fiber intake and benefits to crohns disease while following patients over the course of 4 years, contrary to the other study. i find that reducing my sugar intake to almost nothing has been one of the main principles that has eliminated diarhea symptoms, but not inflammation. i reduced not only refined sugar, but sugar that is naturally present in foods as well. and whenever i increase the sugar, diarhea can be brought right back, so the connection is irrefutable, many enterobacteria have what is called the lac operon, which enables them to utilize lactose as a food or to create metabolic by products.  i have also followed a high fibre diet and have never been to the hospital in 4.5 years since being diagnosed.


----------



## Xiaofa Qin

mf15 said:


> Can anyone get the full paper on this so we can figure out exactly what they are saying here,this one is a few days old.
> Old Mike
> 
> 
> Curr Opin Gastroenterol. 2014 Jan 16. [Epub ahead of print]
> 
> Proteases and small intestinal barrier function in health and disease.
> 
> Giuffrida P, Biancheri P, Macdonald TT.


I would like to help. However, my support as a researcher in the medical school was ended by the end of last year. Now I am staying at home and also cannot get the full text. 

This may not be a bad thing. I also lost my job in 2001 that had given me the chance and time to learn more and get involved in IBD. As a spare time IBD researcher during the last decade, I believe I may made more progress toward a better understanding and final solution of IBD than the many studies supported by hundreds of millions or even billions of funding.

Staying at home, I have a vivid feeling of the real world, not just bubble and fantasy. 

I can generate hypothesis and express my opinions through the literature. However, test of these hypotheses would need the field work. Before I have to find another job with IBD remaining a spare time hobby, if possible, I would like to use this opportunity to make a transition to become a full time IBD warrior – finding out the principle culprits in IBD that I believe could be just a few factors in the environment, and a cure for IBD that I believe the effective protection and fortification of gut barrier would be essential. Hope I may have the chance to do so. If anybody interested, please join the fight.


----------



## Xiaofa Qin

wildbill_52280 said:


> Xiaofa Qin, i mentioned this study earlier but perhaps you never got around to looking at it, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1247426/
> 
> but it did find a difference between sugar intake and fiber intake and benefits to crohns disease while following patients over the course of 4 years, contrary to the other study.


The paper you cited above seems just the one I was cited in my post (#305)(Ritchie JK, et al. Controlled multicentre therapeutic trial of an unrefined carbohydrate, fibre rich diet in Crohn's disease. Br Med J (Clin Res Ed). 1987 Aug 29;295(6597):517-20), with the conclusion that "No clear difference in clinical course was detected among patients who accepted the two different types of dietary advice". Do you mean you have another paper?


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## wildbill_52280

Xiaofa Qin said:


> The paper you cited above seems just the one I was cited in my post (#305)(Ritchie JK, et al. Controlled multicentre therapeutic trial of an unrefined carbohydrate, fibre rich diet in Crohn's disease. Br Med J (Clin Res Ed). 1987 Aug 29;295(6597):517-20), with the conclusion that "No clear difference in clinical course was detected among patients who accepted the two different types of dietary advice". Do you mean you have another paper?


wow, so sorry, i put the wrong link in there. here is the other study i was talking about.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1596427/

There was 32 patients in the control group and 34 in the diet treated group, so its small, but found good results. i wonder if, or why wouldnt their have been larger studies confirming the role of this diet to manage crohns disease in addition to meds. its amazing what information there is out there when you actually look for it, thank god for the internet and free information. to reduce the amount of time spent in the hospital by 75%, that would save alot of money treating this disease, or to the contrary, profiteers from making money off this disease.




*Treatment of Crohn's disease with an unrefined-carbohydrate, fibre-rich diet.*

Br Med J. 1979 September 29; 2(6193): 764–766.
PMCID: PMC1596427
K W Heaton, J R Thornton, and P M Emmett

*Abstract*

Thirty-two patients with Crohn's disease were treated with a fibre-rich, unrefined-carbohydrate diet in addition to conventional management and followed for a mean of four years and four months. Their clinical course was compared retrospectively with that of 32 matched patients who had received no dietary instruction. Hospital admissions were significantly fewer and shorter in the diet-treated patients, who spent a total of 111 days in hospital compared with 533 days in the non-diet-treated control group. Whereas five of the controls required intestinal operation, only one diet-treated patient needed surgery. This is in strong contrast to general experience with this disease. Treatment with a fibre-rich, unrefined-carbohydrate diet appears to have a favourable effect on the course of Crohn's disease and does not lead to intestinal obstruction.


----------



## Xiaofa Qin

wildbill_52280 said:


> wow, so sorry, i put the wrong link in there. here is the other study i was talking about.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1596427/
> 
> There was 32 patients in the control group and 34 in the diet treated group, so its small, but found good results. i wonder if, or why wouldnt their have been larger studies confirming the role of this diet to manage crohns disease in addition to meds. its amazing what information there is out there when you actually look for it, thank god for the internet and free information. to reduce the amount of time spent in the hospital by 75%, that would save alot of money treating this disease, or to the contrary, profiteers from making money off this disease.


Thanks for sharing the paper. Here again we can see the conflict results among the different studies.

Reading through the full text of these papers, we can found that the paper I cited (Ritchie JK, et al. Controlled multicentre therapeutic trial of an unrefined carbohydrate, fibre rich diet in Crohn's disease. Br Med J (Clin Res Ed). 1987 Aug 29;295(6597):517-20) was in fact just the larger study aimed at confirming the findings in the retrospective study you referred to, through a larger-scale, randomised prospective single blind trial. Unfortunately, it failed to repeat the beneficial effect of the unrefined-carbohydrate diet. Here is the link to the full text.


----------



## wildbill_52280

Xiaofa Qin said:


> Thanks for sharing the paper. Here again we can see the conflict results among the different studies.
> 
> Reading through the full text of these papers, we can found that the paper I cited (Ritchie JK, et al. Controlled multicentre therapeutic trial of an unrefined carbohydrate, fibre rich diet in Crohn's disease. Br Med J (Clin Res Ed). 1987 Aug 29;295(6597):517-20) was in fact just the larger study aimed at confirming the findings in the retrospective study you referred to, through a larger-scale, randomised prospective single blind trial. Unfortunately, it failed to repeat the beneficial effect of the unrefined-carbohydrate diet. Here is the link to the full text.



very interesting indeed. the second study was 2 years and the first was 4 years? didnt seem like the exact replication then, but im not really refuting their findings too much here though. I'll stick with the specificity of how my disease works, rather then enumerative induction(if 20 crohn's patients react the same way, then all must react this way), WHICH is unfortunatly how science is done. its possible some patients are more sensitive to these dietary factors then others which might explain the differences in findings.


----------



## wildbill_52280

Xiaofa Qin said:


> I would like to help. However, my support as a researcher in the medical school was ended by the end of last year. Now I am staying at home and also cannot get the full text.
> 
> This may not be a bad thing. I also lost my job in 2001 that had given me the chance and time to learn more and get involved in IBD. As a spare time IBD researcher during the last decade, I believe I may made more progress toward a better understanding and final solution of IBD than the many studies supported by hundreds of millions or even billions of funding.
> 
> Staying at home, I have a vivid feeling of the real world, not just bubble and fantasy.
> 
> I can generate hypothesis and express my opinions through the literature. However, test of these hypotheses would need the field work. Before I have to find another job with IBD remaining a spare time hobby, if possible, I would like to use this opportunity to make a transition to become a full time IBD warrior – finding out the principle culprits in IBD that I believe could be just a few factors in the environment, and a cure for IBD that I believe the effective protection and fortification of gut barrier would be essential. Hope I may have the chance to do so. If anybody interested, please join the fight.


of course my opinoin isnt very well developed yet, but take another look at soy products. i have some interesting studies ill send your way. this is based on using myself, my own testimony/experiance of having IBD a as source of clues. in 2006-7 i stopped drinking milk and switched entirely to drinking silk soy milk which has carageenen and trypsin inhibitors, i learned weeks ago of the possibility that trypsin is a requirement for the production of defensins, which vitamin d is also a requirement to make defensins, possibly bringing the information we have on north south gradient of ibd incidence and how low vitamin d may protect from dysbiosis, soy products may have a similar damaging effect increasing risk of ibd. The main variable i believe caused crohn's was amoxicillin, but the soy milk may have put me at greater risk. i believe i developed it in feb 2008 after antibiotics, diagnosed april 2009.

the presence of active trypsin is needed for maximum production of defensins in the lining of the gut, or at least maybe. it may take alot of soy mlik to depress enough defensins to create ibd though, some things to look into.


----------



## Xiaofa Qin

wildbill_52280 said:


> of course my opinoin isnt very well developed yet, but take another look at soy products. i have some interesting studies ill send your way. this is based on using myself, my own testimony/experiance of having IBD a as source of clues. in 2006-7 i stopped drinking milk and switched entirely to drinking silk soy milk which has carageenen and trypsin inhibitors, i learned weeks ago of the possibility that trypsin is a requirement for the production of defensins, which vitamin d is also a requirement to make defensins, possibly bringing the information we have on north south gradient of ibd incidence and how low vitamin d may protect from dysbiosis, soy products may have a similar damaging effect increasing risk of ibd. The main variable i believe caused crohn's was amoxicillin, but the soy milk may have put me at greater risk. i believe i developed it in feb 2008 after antibiotics, diagnosed april 2009.
> 
> the presence of active trypsin is needed for maximum production of defensins in the lining of the gut, or at least maybe. it may take alot of soy mlik to depress enough defensins to create ibd though, some things to look into.


The body is complex. The world is complex.  Trypsin may indeed stimulate the production of defensins that are regarded as important protective molecules for the gut. However, it has been well documented that treatment with antibiotics will result in a dramatic increase of digestive proteases like trypsin in the lower gut due to impaired inactivation, thus, according to your info, this may lead to great increase in the production of defensins. However, antibiotics increased but not decreased the risk of IBD. So, is increased trypsin really beneficial or actually detrimental? Is the inhibition of trypsin by some components in the soy milk more likely increased or decreased the risk of IBD? We may have to make a comprehensive analysis of the different evidences, most times being conflicting, rather than a piece of evidence, to get a likely right judgment.


----------



## wildbill_52280

Xiaofa Qin said:


> The body is complex. The world is complex.  Trypsin may indeed stimulate the production of defensins that are regarded as important protective molecules for the gut. However, it has been well documented that treatment with antibiotics will result in a dramatic increase of digestive proteases like trypsin in the lower gut due to impaired inactivation, thus, according to your info, this may lead to great increase in the production of defensins. However, antibiotics increased but not decreased the risk of IBD. So, is increased trypsin really beneficial or actually detrimental? Is the inhibition of trypsin by some components in the soy milk more likely increased or decreased the risk of IBD? We may have to make a comprehensive analysis of the different evidences, most times being conflicting, rather than a piece of evidence, to get a likely right judgment.


good points, i agree, the impact of trypsin inhibitors from soy milk, may be so miniscule. ill send some links anyway, its interesting stuff either way.


*Trypsin Mediates Growth Phase-Dependent Transcriptional Regulation of Genes Involved in Biosynthesis of Ruminococcin A, a Lantibiotic Produced by a Ruminococcus gnavus Strain from a Human Intestinal Microbiota*

ABSTRACT
Ruminococcin A (RumA) is a trypsin-dependent l antibiotic produced byRuminococcus gnavus E1, a gram-positive strict anaerobic strain isolated from a human intestinal microbiota. A 12.8-kb region from R. gnavus E1 chromosome, containing the biosynthetic gene cluster of RumA, has been cloned and sequenced. It consisted of 13 open reading frames, organized in three operons with predicted functions in lantibiotic biosynthesis, signal transduction regulation, and immunity. One unusual feature of the locus is the presence of three almost identical structural genes, all of them encoding the RumA precursor. In order to determine the role of trypsin in RumA production, the transcription of the rum genes has been investigated under inducing and noninducing conditions. Trypsin activity is needed for the growth phase-dependent transcriptional activation of RumA operons. Our results suggest that bacteriocin production by R. gnavus E1 is controlled through a complex signaling mechanism involving the proteolytic processing of a putative extracellular inducer-peptide by trypsin, a specific environmental cue of the digestive ecosystem.

link: http://jb.asm.org/content/184/1/18.full






> Biologically-active defensins are released upon the proteolytic processing of their proforms by certain enzymes[4], including trypsin for DEFA5 and DEFA6 in humans[5] and matrilysin for cryptdins in mice[6]. This suggests that appropriate control of homeostatic quantities of both defensins and defensin-activating proteases may ultimately dictate the outcome of the gut immunological response to intruding pathogens and to commensal microorganisms that are permanently present.


source: http://www.wjgnet.com/1007-9327/full/v17/i5/567.htm


----------



## Xiaofa Qin

Thank you wildbill for sharing the paper. Here is a study showing that trypsin in fecal extracts may increase 100 times after the treatment by antibiotics.

-----------------

Digestion. 1983;27(1):8-15.

Determination of immunoreactive trypsin, pancreatic elastase and chymotrypsin in extracts of human feces and ileostomy drainage.

Bohe M, Borgström A, Genell S, Ohlsson K.

Abstract

The total daily amount of extractable cationic trypsin, chymotrypsin, and pancreatic elastase 2 in feces and ileostomy fluids has been studied in normal individuals and healthy colectomized subjects. Quantitation was performed using immunological assays with polyethylene glycol as a fecal marker. The extractable amount of each of these enzymes in the feces of normal individuals was less than 1 mg/24 h. However, in fecal extracts from antibiotic-treated normal individuals a 100-fold increase in immunoreactive cationic trypsin was observed, while chymotrypsin and elastase 2 were only 2- to 3-fold higher. In extracts from ileostomy fluids cationic trypsin, elastase, and chymotrypsin all showed mean values in the order of 50-200 mg/24 h. The characterization of the immunoreactivity of pancreatic proteases showed no qualitative differences when measured in duodenal juice or fecal and ileostomy extracts.


PMID: 6554206  [PubMed - indexed for MEDLINE]


----------



## wildbill_52280

Xiaofa Qin said:


> Thank you wildbill for sharing the paper. Here is a study showing that trypsin in fecal extracts may increase 100 times after the treatment by antibiotics.
> 
> -----------------
> 
> Digestion. 1983;27(1):8-15.
> 
> Determination of immunoreactive trypsin, pancreatic elastase and chymotrypsin in extracts of human feces and ileostomy drainage.
> 
> Bohe M, Borgström A, Genell S, Ohlsson K.
> 
> Abstract
> 
> The total daily amount of extractable cationic trypsin, chymotrypsin, and pancreatic elastase 2 in feces and ileostomy fluids has been studied in normal individuals and healthy colectomized subjects. Quantitation was performed using immunological assays with polyethylene glycol as a fecal marker. The extractable amount of each of these enzymes in the feces of normal individuals was less than 1 mg/24 h. However, in fecal extracts from antibiotic-treated normal individuals a 100-fold increase in immunoreactive cationic trypsin was observed, while chymotrypsin and elastase 2 were only 2- to 3-fold higher. In extracts from ileostomy fluids cationic trypsin, elastase, and chymotrypsin all showed mean values in the order of 50-200 mg/24 h. The characterization of the immunoreactivity of pancreatic proteases showed no qualitative differences when measured in duodenal juice or fecal and ileostomy extracts.
> 
> 
> PMID: 6554206  [PubMed - indexed for MEDLINE]



thanks. maybe this slightly suggests trypsin inhibition would not be enough to deplete defensins and affect dysbiosis leading to IBD. but it could also suggest increases in trypsin production are a compensatory defense mechanism to also increase defensin to counteract the dysbiosis induced by antibiotics.

i'm still not sure that is enough to prove that trypsin inhibitors do not affect defensin production.

 the question remains:
 do trypsin inhibitors from soy products specifically in soy milk, in any quantity, affect defensin production. i suppose then that is my question.


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## wildbill_52280

here is some info on the production of soy milk and trypsin inhibitor content:

J Agric Food Chem. 2008 Sep 10;56(17):7957-63. doi: 10.1021/jf801039h. Epub 2008 Aug 9.

*Elimination of trypsin inhibitor activity and beany flavor in soy milk by consecutive blanching and ultrahigh-temperature (UHT) processing.*


Abstract

Soy foods contain significant health-promoting components but also may contain beany flavor and trypsin inhibitor activity (TIA), which can cause pancreatic disease if present at a high level. Thermal processing can inactivate TIA and lipoxygenase. Ultrahigh-temperature (UHT) processing is relatively new for manufacturing soy milk. Simultaneous elimination of TIA and soy odor by UHT processing for enhancing soy milk quality has not been reported. The objective was to determine TIA in soy milk processed by traditional, steam injection, blanching, and UHT methods and to compare the products with commercial soy milk products. Soybean was soaked and blanched at 70-85 degrees C for 30 s-7.5 min. The blanched beans were made into base soy milk. The hexanal content of the base soy milk was determined by gas chromatography to determine the best conditions for further thermal processing by indirect and direct UHT methods at 135-150 degrees C for 10-50 s using the Microthermics processor. Soy milk was also made from soaked soybeans by traditional batch cooking and steaming methods. Eighteen commercial products were selected from the supermarket. Residual TIA in soy milk processed by the traditional and steam injection to 100 degrees C for 20 min was approximately 13%. Blanching could inactivate 25-50% of TIAs of the raw soy milk. The blanch conditions of 80 degrees C and 2 min were selected for UHT processing because these conditions produced blanched soy milk without hexanal, indicating a complete heat inactivation of lipoxygenases. The TIA decreased with increased temperature and time of UHT heating. The maximal trypsin inhibitor inactivation was achieved by UHT direct and indirect methods with residual activities of approximately 10%. Some commercial soy milk products contained high TIAs (trypsin inhibitor activity). The results are important to the food industry and consumers. Kinetic analysis showed that heat inactivation (denaturation) of TIA, under the continuous processing conditions of the Microthermics processor, followed first-order reaction kinetics, and the activation energy of the inactivation was 34 kJ/mol.


----------



## durwardian

What about these trials? What does this tell us about what is going on in the gut?
http://www.medicalnewstoday.com/articles/249497.php


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## durwardian

Could it be that these parasites are killing off the competition before they perish? Not that the immune system is "BOOSTED" or "CORRECTED"


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## durwardian

The boost comes when the body is no longer fighting? And that the lack of ability to produce proper pancreatic balance is the root cause?


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## rollinstone

the pig parasite trials unfortunately came back as ineffective


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## durwardian

I am willing to bet they work in a certain type of bowel disease, hopefully they aren't tossing the soup for lack of salt?


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## durwardian

Which would prove my point that Crohn's isn't always the same disease, it is a bunch of different ones with similar symptoms


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## rollinstone

that seems to be the problem with most trials, they need to look at ALL the variables, I.e did the people that showed response have certain characteristics, i.e granuloma formation, or no granuloma, disease location etc, atm I think everything is too broadly looked at. I don't have the link to the results of the trials but they're somewhere on here, I remember it not being any higher than the placebo control though...


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## durwardian

And if an immune response showed promise, what other ways can that be triggered?


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## durwardian

The goal would be a cure, which could end up being genetic reprogramming. I have also heard of healthy family members donating healthy intestinal flora for an infusion into the afflicted's bowels.


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## durwardian

Like the body needs a reminder, it appears to work to restore balance?


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## wildbill_52280

durwardian said:


> The goal would be a cure, which could end up being genetic reprogramming. I have also heard of healthy family members donating healthy intestinal flora for an infusion into the afflicted's bowels.


thats called a fecal microbiota transplant.

- http://www.crohnsforum.com/showthread.php?t=52400


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## Xiaofa Qin

durwardian said:


> The goal would be a cure, which could end up being genetic reprogramming.


IBD only started to emerge and became epidemic in last century, which would be caused by changes of the environment but not the gene. There would be more easy solutions than genetic reprogramming.


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## durwardian

I am of the opinion that we started paying attention in the last century. And that dietary issues like preservatives and chemicals have increased the number of afflicted.


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## durwardian

Perhaps eating "dirtier" food was a better human condition? Perhaps we are degrading as human beings because we have the technology to keep pregnancies going and keep sick people alive longer?


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## durwardian

Fistula treatment can be seen in Ancient Egypt, using camel hair to seton the fistula. So that is proof enough for me that issues have always been here


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## durwardian

So, i think there are agitators, and genetics, and bugs


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## durwardian

Always have been, but in the past none of us would have survived the first onslaught of infection or sepsis


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## durwardian

Nothing would be left to study, or reproduce offspring


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## Xiaofa Qin

durwardian said:


> Fistula treatment can be seen in Ancient Egypt, using camel hair to seton the fistula. So that is proof enough for me that issues have always been here


We may never have the chance to check out if those ancient reports were indeed cases of IBD. However, as discussed early  (see post #236), the recent dramatic increase of IBD such as the increase of Crohn's patients in a Saudi clinic from 0 or 1 during 1993 to 2000, to 3 or 4 cases during 2001 to 2003, then jumping to 174 cases in 2009, should indeed raise some big concern (here is the figure). This would definitely not caused by the failure of evolutionary selection.


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## durwardian

Probably directly in relation to processed foods, or letting another population in, or it could be that a doctor finally just started documenting it? Without proper controls, it's not an epidemic


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## durwardian

I would love as much as anyone to figure this out. But the common tendency at the GI is to throw drugs first, check for actual cause after that doesn't work or if the symptoms expand.


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## durwardian

The problem I think, is that it then gets registered as Crohn's or IBD, when it isn't. Then the facts never get adjusted to what the real culprit was. So, like my case, you get treated with medicine that makes you sicker. Only after running to the RIGHT doctor do you get tests that prove they are trying to kill you by using the wrong medicine.


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## durwardian

In my case I simply have a genetic immune problem. Boosting my immune system fixes the problem. So I was on a Crohn's diagnosis. How many others are falsely being mistreated by GI doctors?


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## durwardian

I bet nobody went back and said, hey.. case number 16790 was not Crohn's, let's fix the data before we kill another few by suppressing an already damaged immune system


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## durwardian

Diagnostics is very, very important, and the signs for Crohn's does not make it Crohn's, this is a huge problem. The results are an end product, not the cause.


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## Xiaofa Qin

durwardian said:


> Probably directly in relation to processed foods, or letting another population in, or it could be that a doctor finally just started documenting it? Without proper controls, it's not an epidemic


From the figure in the paper published in the Saudi Journal of Gastroenterology, we can see a much more dramatic increase of Crohn’s disease (from 0 -1 during 1993 to 2000 to 174 in 2009) than ulcerative colitis (from 7-14 during 1993 to 2000 to 21 in 2009). This seems unlikely to be explained by increased awareness or referral, or a better diagnose and documentation, or a change in population. 

This dramatic increase in CD since early 2000s not only occurred in Saudi, but also reported in Singapore (Chu HP, Logarajah V, Tan N, Phua KB. Paediatric inflammatory bowel disease in a multiracial Asian country. Singapore Med J. 2013 Apr;54(4):201-5) and Ireland (Hope B, et al. Rapid rise in incidence of Irish paediatric inflammatory bowel disease. Arch Dis Child. 2012 Jul;97(7):590-4). 

Interestingly, these increases occurred shortly after the approval of sucralose in these countries, which were also showed in studies from other countries like Canada, Australia, United States, Norway, etc, as demonstrated in Figure 4 of my paper discussed here. Therefore, I have written to these journals advocating checking out this possibility. The papers have been published regarding the increase of IBD in Singapore (Qin X. Comment on: Paediatric inflammatory bowel disease in a multiracial Asian country. Singapore Med J. 2013 Dec;54(12):716) and Ireland (Qin X. The possible cause for the rapid rise in incidence of Irish paediatric inflammatory bowel disease).  The paper regarding Saudi has also been accepted for publication by The Saudi Journal of Gastroenterology, and hopefully people may see it soon. 

The paper published in Singapore Medical Journal has free access. For the convenience of the reader, I post it here.

******************************************

Comment on:  Paediatric inflammatory bowel disease in a multiracial Asian Country

Singapore Med J 2013; 54(12): 716   doi:10.11622/smedj.2013256

I read with great interest the study by Chu et al regarding the remarkable increase of paediatric inflammatory bowel disease (IBD) in Singapore since the beginning of the new millennium (1).

In the last decade, a series of findings have made me suspect that dietary chemicals like saccharin and sucralose may play an important causative role in IBD, through their inhibition on gut bacteria, and the resultant damage of the mucus layer and underlying gut tissue by poorly inactivated digestive protease. This eventually led me to publish a paper last year with a unified hypothesis on the aetiology of IBD.  In this paper, I included some evidence  ollected at that time, such as the remarkable increase of IBD in Alberta, Canada since the early 1990s, in Brisbane, Australia since the middle of the 1990s, in northern California, United States of America since the end of the 1990s, and in south-eastern Norway since the middle of the 2000s. These aforementioned increases in IBD occurred shortly after the approval of sucralose in Canada in 1991, in Australia in 1993, in the United States in 1998, and by the European Union in 2004. After the publication of my paper, another study was released, showing a remarkable increase in paediatric IBD in Ireland since the middle of the 2000s, which, again, occurred shortly after the approval of sucralose in Ireland in 2003 (2).  Similarly, this remarkable increase in paediatric IBD in Singapore since the beginning of the new millennium, as pointed out by Chu et al (3) happened shortly after the approval of sucralose in Singapore in 1998. Therefore, I recommend further investigation of the possible link between sucrolose and IBD.

Xiaofa Qin

References:

1. Chu HP, Logarajah V, Tan N, Phua KB. Paediatric inflammatory bowel disease in a multiracial Asian country. Singapore Med J 2013; 54:201-5.
2. Qin X. Etiology of inflammatory bowel disease: a unified hypothesis. World J Gastroenterol 2012; 18:1708-22.
3. Qin X. The possible cause for the rapid rise in incidence of Irish paediatric inflammatory bowel disease. Response to: Hope B, Shahdadpuri R,  Dunne C, et al. Rapid rise in incidence of Irish paediatric inflammatory bowel disease. Arch Dis Child. 2012; 97:590- 4.


----------



## kiny

There is a book called 

*Origins and Directions of Inflammatory Bowel Disease: Early Studies of the "Nonspecific" Inflammatory Bowel Diseases* that has the history of first cases of non-TB inflammation of the intestines.


----------



## kiny

durwardian said:


> Diagnostics is very, very important, and the signs for Crohn's does not make it Crohn's, this is a huge problem. The results are an end product, not the cause.


Crohn's disease is probably not one disease. People classify it all nicely in papers, they mention granuloma, how crypts look, ASCA tests, CRP, yada yada yada.

Often times they can't even see if there is granuloma or not because the tissue is for lack of a better word...a mess...half the time doctors have no idea what they're looking at.

Crohn's disease is a nice umbrella term for something that can be clinically very different from person to person.


----------



## durwardian

Speaking of sweeteners... what about the benzoates? Those are just as bad, different issues.


----------



## Xiaofa Qin

durwardian said:


> Speaking of sweeteners... what about the benzoates? Those are just as bad, different issues.


Here is a study (Cong D, Fong AK, Lee R, Pang KS. Absorption of benzoic acid in segmental regions of the vascularly perfused rat small intestine preparation. Drug Metab Dispos. 2001 Dec;29(12):1539-47) showing that benzoic acid injected into closed segments of shorter lengths (12 or 20 cm) can be effectively absorbed (92-96% dose). This would suggest benzoates people take along the food may probably be effective absorbed by the upper small intestine, without the chance to exert a big impact on the bacteria in the lower gut. Do not know if any body can find more studies on this.


----------



## rollinstone

Xiaofa in your opinion, how would one overcome this protease problem? Do you believe there is there a way to restore normal function?


----------



## Xiaofa Qin

Joshuaaa said:


> Xiaofa in your opinion, how would one overcome this protease problem?


I think one of the easy ways could be a targeted delivery of protease inhibitors to the lower intestine.




Joshuaaa said:


> Do you believe there is there a way to restore normal function?


I think if the damage of the gut is not too severe that make the crypt stem cells still capable of differentiating into different epithelial cells (absorptive cells, goblet cells, etc) and reconstruct a relative normal structure on the remaining tissue, a normal function probably can be gradually restored  after the inflammation was stopped.


----------



## Xiaofa Qin

kiny said:


> If you believe all these diseases are "similar"...you're welcome to point out to us how etanercept that works for all these diseases does not work for crohn's disease.





Xiaofa Qin said:


> There are actually some difference between etanercept and anti-TNF α antibodies like infliximab:  according the description, etanercept is a fusion protein produced by fusing the TNF receptor to the constant end of the IgG1 antibody, while infliximab is an antibody to TNF α. One explanation I think of regarding the difference of efficacy between these two would be that each infliximab molecule would be capable of binding and inactivated one TNF α, while the efficacy of etanercept to trap and inactivate TNF α would depand on the ratio of etanercept (the introduced exogenous TNF α receptors) to the amounts of endogenous TNF α receptor inside the body. If the exogenous and endogenous receptors are equal, only half of the administrated etanercept may bind a TNF α. If the endogenous receptors are 10 times in number of the injected etanercept, only about 1/10 of administrated etanercept may bind a TNF α. The gut has a large number of immune cells and the inflammation of gut may have caused a huge increase in endogenous TNF α receptor, thus a big variation and low efficacy of etanercept. This is just a speculation for a tentative explanation.


kiny, do you think the explanation above reasonable or nonsensical. Yes, both etanercept and anti TNF α antibodies bind TNF α. What is your explanation for the different efficacy of these two on Crohn's disease?


----------



## rollinstone

Xiaofa Qin said:


> I think one of the easy ways could be a targeted delivery of protease inhibitors to the lower intestine.
> 
> 
> 
> 
> I think if the damage of the gut is not too severe that make the crypt stem cells still capable of differentiating into different epithelial cells (absorptive cells, goblet cells, etc) and reconstruct a relative normal structure on the remaining tissue, a normal function probably can be gradually restored  after the inflammation was stopped.


Sorry I'm not very educated with this, do protease inhibitors exist? Whats an example of one and how would one get it to the colon?


----------



## kiny

Xiaofa Qin said:


> kiny, do you think the explanation above reasonable or nonsensical. Yes, both etanercept and anti TNF α antibodies bind TNF α. What is your explanation for the different efficacy of these two on Crohn's disease?


Infliximab binds to lamina propria and submucosa immune cells, etanercept doesn't. 

My point is that all these diseases are different.

Vedoluzimab for example works for UC and is completely ineffective for crohn's disease.

Infliximab doesn't even work for all crohn's disease, it works for like 50%, my guess is that within crohn's disease there are multiple separate diseases.

"IBD" is a really unfortunate term. I never use it because it perpetuates the idea that these diseases are similar or that treatment is similar. It's really bad for the progress for both patients to be put under an umbrella term.

If something works for UC does not in any shape or form mean it works for crohn's disease, and most of the time it doesn't. Because the diseases are very different.


----------



## Xiaofa Qin

Joshuaaa said:


> Sorry I'm not very educated with this, do protease inhibitors exist?


Yes, there are many kinds, such as Bowman-Birk inhibitor (BBI) (see post #128) and Camostat Mesilate (see post #133) discussed early in this thread.





Joshuaaa said:


> Whats an example of one and how would one get it to the colon?


Below are some reviews with discussions on targeted drug delivery to the colon:

Jain SK, Jain A. Target-specific drug release to the colon. Expert Opin Drug Deliv. 2008 May;5(5):483-98

Chourasia MK, Jain SK. Pharmaceutical approaches to colon targeted drug delivery systems. J Pharm Pharm Sci. 2003 Jan-Apr;6(1):33-66

Kumar P, Mishra B. Colon targeted drug delivery systems--an overview. Curr Drug Deliv. 2008 Jul;5(3):186-98


----------



## Xiaofa Qin

kiny said:


> Infliximab binds to lamina propria and submucosa immune cells, etanercept doesn't.


You are trying to solve a small puzzle with a bigger puzzle, trying to clean something with a thing even dirtier. 

Infliximab is effective not only for Crohn's disease in the gut, but also   arthritis of the joint, and psoriasis of the skin, suggesting the similar action of TNF-α over the body for inflammation. Do you have evidence that immune cells and, more specifically, TNF-α in lamina propria and submucosa are different from the other parts of the body? How?






kiny said:


> Infliximab doesn't even work for all crohn's disease, it works for like 50%, my guess is that within crohn's disease there are multiple separate diseases.


As mentioned above infliximab is also effective for autoimmune diseases like psoriasis and rheumatoid arthritis, but may be less effective for ulcerative colitis. However, according to your early post, you believe ulcerative colitis but not Crohn's disease being autoimmune disease. How do you explain this discrepancy?


----------



## kiny

Not going to restart the same argument, I explained for 4 pages why UC and crohn's disease are vastly different. 

Autophagy deficiencies, macrophage deficiencies, slow recruitment of immune cells, transmural disease, skip lesions, bacterial involvement, antibiotics use, differences in indices, lymphopenia in CD, granuloma, fistula, disease clustering.

None of the above is seen in UC. None of these things are seen in any autoimmune disease either.  Crohn's disease is a very complex disease.

You think UC and crohn's disease are similar, well fine, I disagree, I don't pretend the genetics data and pathology differences aren't there just to fit them in the same bracket like you do. It's the only way your study would make any sense.

UC and crohn's disease are vastly different diseases, they actually have very little in common. 

I can't even think of anything they have in common right now. Inflammation or dysbiosis of the intestine? Well there's many diseases that cause that, it doesn't mean they are similar, and we don't group those diseases either, the word "IBD" actually hurts both people with UC and CD.


----------



## Xiaofa Qin

kiny said:


> It's the only way your study would make any sense.


Ironically, only a clumsy theory from a spare time researcher without any funding explained and predicted what happened in the real world, from the emerging of clustered cases in 1888 to the recent worldwide increase of IBD, but it is utterly ridiculed by the patient. Yes, I just found there is no way to make sense out of everything, everybody.


----------



## durwardian

That makes little sense


----------



## wildbill_52280

Xiaofa Qin, 

you have had more then your fair share of great points to make, and contributions to the research. your track record is pretty good in my eyes.


----------



## wildbill_52280

Xiaofa Qin, were you aware of this study? it seems to support the theory that sucralose could be associated with ibd as it was supposedly approved in 1998.

http://www.sciencedaily.com/releases/2013/06/130625141208.htm
http://www.ncbi.nlm.nih.gov/pubmed/23797749


----------



## Xiaofa Qin

wildbill_52280 said:


> Xiaofa Qin,
> 
> you have had more then your fair share of great points to make, and contributions to the research. your track record is pretty good in my eyes.


Thanks for the warm words and inspiration. 





wildbill_52280 said:


> Xiaofa Qin, were you aware of this study? it seems to support the theory that sucralose could be associated with ibd as it was supposedly approved in 1998.
> 
> http://www.sciencedaily.com/releases/2013/06/130625141208.htm
> http://www.ncbi.nlm.nih.gov/pubmed/23797749


As I mentioned in an early post (#221), I wrote a paper regarding the possible link between the marketing of sucralose and the new round of increase of IBD in the United States, which was accepted and got published online recently by the Journal of Clinical Gastroenterology (Qin X. When and How Was the New Round of Increase in Inflammatory Bowel Disease in the United States Started? J Clin Gastroenterol. 2013 Nov 13. [Epub ahead of print]). I included several papers I found at that time such as:

Debruyn JC, Soon IS, Hubbard J, Wrobel I, Panaccione R, Kaplan GG. Nationwide Temporal Trends in Incidence of Hospitalization and Surgical Intestinal Resection in Pediatric Inflammatory Bowel Diseases in the United States from 1997 to 2009. Inflamm Bowel Dis 2013.

Nguyen GC, Tuskey A, Dassopoulos T, Harris ML, Brant SR. Rising hospitalization rates for inflammatory bowel disease in the United States between 1998 and 2004. Inflamm Bowel Dis 2007;13:1529-35.

Ananthakrishnan AN, McGinley EL, Binion DG, Saeian K. A nationwide analysis of changes in severity and outcomes of inflammatory bowel disease hospitalizations. J Gastrointest Surg 2011;15:267-76.

Bewtra M, Su C, Lewis JD. Trends in hospitalization rates for inflammatory bowel disease in the United States. Clin Gastroenterol Hepatol 2007;5:597-601

Sewell JL, Yee HF, Jr., Inadomi JM. Hospitalizations are increasing among minority patients with Crohn's disease and ulcerative colitis. Inflamm Bowel Dis 2010;16:204-7.

Ingle SB, Loftus EV, Tremaine WJ, Harmsen WS, Zinsmeister AR, Melton Lj, et al. Increasing Incidence and Prevalence of Inflammatory Bowel Disease in Olmsted  County, Minnesota, During 2001-2004 (Abstract). Gastroenterology 2007;132:A19-A20.



*However, the paper you listed here was out of my radar. Otherwise I would have included it as well. Any way, thanks for sharing the paper.*


----------



## wildbill_52280

Xiaofa Qin said:


> *However, the paper you listed here was out of my radar. Otherwise I would have included it as well. Any way, thanks for sharing the paper.*


I guess that's a good thing and a bad thing. Its good that you are now aware, and bad because it could have helped your paper a bit. 

just to be clear i'm not here to poke holes for the sake of making you look foolish, that's impossible because of your reputation, as it is firmly established. we are on the same side and hopefully none of us forget that. so it makes me happy to make my own contributions as well, such as, bringing something like this that escaped your awareness, for me that's a very cool moment. especially when we are so used to generating millions of hypothesis that seem to go nowhere, ha. until we get one that seems to fit, and thats such an awesome feeling.


----------



## kiny

Xiaofa Qin said:


> Ironically, only a clumsy theory from a spare time researcher without any funding explained and predicted what happened in the real world


sucralose use matches crohn's disease indices, and so do 1000 of other things

you're not the "only" person who has made up a theory and managed to match crohn's disease  up with something inherent to a Western lifestyle

it matches many things, ppl don't do it because you can keep generating hypothesis like that until you're blue in your face

I've learned quickly not to partake in that, because you can explain crohn's disease a million and one ways, I base myself on what is out there and can be verified, genetic predisposition and clinical symptoms



crohn's disease is a perfect inverse map of TB infections, in fact it is far more accurate a match than your sucralose, countries with high TB have low CD, countries with low TB have high CD, it matches perfectly, not only that, when TB goes down in countries, CD goes up

obviously you should drop your sucralose theory for the inverse TB relationship, it is more accurate, many people have noted this inverse relationship, no one has written a paper on it, you could be the first one

the reason people don't do it, is because you can do that with a million and one things, you end up nowhere







it matches helminths contact:







sunlight exposure:







industrialisation:







micronutrient deficiency:








internet usage:







and 1000 other things


----------



## wildbill_52280

kiny, you have made some worthy contributions yourself.


----------



## Xiaofa Qin

wildbill_52280 said:


> just to be clear i'm not here to poke holes for the sake of making you look foolish, that's impossible because of your reputation, as it is firmly established. we are on the same side and hopefully none of us forget that. so it makes me happy to make my own contributions as well, such as, bringing something like this that escaped your awareness, for me that's a very cool moment. especially when we are so used to generating millions of hypothesis that seem to go nowhere, ha. until we get one that seems to fit, and thats such an awesome feeling.


The theory I proposed is indeed just a hypothesis with holes. As stated in my early post (see # 126), without a more vigorous test, even myself do not know how much this hypothesis would be correct. I am just an ordinary person, and foolish – spend so much time and energy on something that will predictably bring in a lot of criticism and radicle. Yes, as you stated in your post, it still makes us happy when we make our own contribution to something meaningful, which may have helped us to overcome the hardship we encountered. I think this may also be the innate force that has driven human civilization forward.


----------



## Xiaofa Qin

kiny said:


> sucralose use matches crohn's disease indices, and so do 1000 of other things
> 
> you're not the "only" person who has made up a theory and managed to match crohn's disease  up with something inherent to a Western lifestyle
> 
> it matches many things, ppl don't do it because you can keep generating hypothesis like that until you're blue in your face
> 
> I've learned quickly not to partake in that, because you can explain crohn's disease a million and one ways, I base myself on what is out there and can be verified, genetic predisposition and clinical symptoms
> 
> 
> 
> crohn's disease is a perfect inverse map of TB infections, in fact it is far more accurate a match than your sucralose, countries with high TB have low CD, countries with low TB have high CD, it matches perfectly, not only that, when TB goes down in countries, CD goes up
> 
> obviously you should drop your sucralose theory for the inverse TB relationship, it is more accurate, many people have noted this inverse relationship, no one has written a paper on it, you could be the first one
> 
> the reason people don't do it, is because you can do that with a million and one things, you end up nowhere


You feel acting like an angel, but you accused it a sin for tips that may track down the devil, just because you perceived many are capable of doing this bad thing. I have made about half of dozen of comments last year on most, if not all, newly published epidemiological findings with incidence data on IBD that encompass not only the increases of IBD in Ireland, Singapore, Saudi Arabia, and United States, but also the decrease of CD and increase of UC in Sweden, and the even higher incidence of IBD in Guangzhou, China than the adjacent more developed Hong Kong and Macau (here are some of these publications). Yes, I am the only person doing this. Do you find any other person providing explanations on these? If you or anybody indeed have a better explanation than I do and really interested in solving the mystery of IBD, you should bring it up. These new findings may provide us a rare chance to find out the cause and thus the possible root mechanism of IBD.  Yes, there are many possibilities. Should we give up because, as you suggested, it will end up nowhere? Or try our best to find the cause? I had a post (see post # 109) about one year ago with some discussions on the same issue. I would like to re-post it here.


“Indeed, million things may be changed along with the modernization; each of them may be correlated somehow with the changes in IBD at certain time point and thus presented as a possible connection. So what should we do? Give up or continue? Can we still find those truly responsible? How? 

I felt the current situation of IBD is somehow like a long unsolved complicated case of crime. There are many tips and suspects; the crime remains unsolved usually not because there are too many but rather none of the suspects really match the evidence of the crime scene. The same would be true for IBD with the many suspected agents as described in the introduction section of the paper and vividly discussed in this forum. 

Luckily, the crime can still usually be solved, no mater it is committed by just an individual or groups of gangs, but this can usually only be achieved by finding out the specific match, like DNA rather than some general evidences like the type of blood. 

We are talking about the recent increase of IBD. In fact, the pattern of increases is quite different even among the development countries. As shown in Figure 4 in the paper discussed here, it showed a dramatic increase of IBD in Brisbane, Australia during middle 1990s but started decrease since early 2000s. However, in Oslo, Norway, a dramatic increase of IBD started since early 2000s. This would be the kind of specific evidence needed to track down the criminal. These increases seems quite unlikely to be explained by many currently suspected factors such as the genes, smoking, sunshine, nutrients, refrigeration, or even a further improvement in the sanitary condition, but I found many of these increases occurred shortly after the approval of sucralose in the different countries like Canada, Australia, New Zealand, Norway, and US. It also predicted the remarkable increase of IBD in the children in Ireland that were reported shortly after the publication of this paper (http://adc.bmj.com/content/97/7/590.abstract/reply#archdischild_el_15773). 

As for saccharin, I also had wondered if and to what extent it would be linked to IBD. This had driven me looking into the history of IBD and saccharin. It is a painstaking process that had taken me more than a decade so far. As shown in the paper, it covered from the earliest of reports of clustered cases of ulcerative colitis in London since 1888 and the earliest marketing and favorite use of the German made saccharin in UK since 1887, through the multiple reports of the leveling off or decrease of IBD during 1980s in many countries and the finding of carcinogenicity and attempted ban on saccharin in later 1970s, with included a brief description of wide spread use of saccharin along with World War I. The more evidence I found, there seems more to support rather against the possible link. Despite that, without a vigorous test, they are just the suspects like the many others. We can definitely bring in more suspects. However, I think we should remove dietary chemicals like saccharin and sucralose from the list of suspects for IBD only after we have found out those with a more perfect and specific match and pinned down as the real criminal.”


----------



## mf15

Xiaofa: I don't know whether you are right or wrong on the artificial sweeteners,I never
ate any,except in toothpaste. I have now eliminated saccharin from my toothpaste.

But we do know at least in UC there is excess protease in the colon,this does cause a problem.
We also know from very small trials of BBI,that UC is put into remission, also the
two people who were given Camostat went into remission.

So if nothing else I have learned that excess protease is part of the disease process,
whether casual,not sure.


Keep up the good work.
Old Mike


----------



## kiny

Xiaofa Qin said:


> Yes, *I am the only person doing this. *
> 
> Do you find any other person providing explanations on these? If you or anybody indeed have a better explanation than I do and really interested in solving the mystery of IBD, you should bring it up.


There have been many hypothesis.

-refrigeration of foods, which leads to an increase in psychotropic food borne bacteria, the rise of refrigeration accurately matches the rise in crohn's disease, it's the "cold chain hypothesis", and yes listeria and yersinia have both been found in people with crohn's disease, you can't dismisss  this hypothesis easily

-exposure to sunlight, or rather lack thereof, it "fairly" accurately matches crohn's disease indices, low vitamin D status is linked to higher incidence of crohn's disease, vitamin D helps restore macrophage function through autophagy stimulation

-increase in types of domesticated pets in industrialised nations, which can carry invasive E Coli

-hygiene hypothesis, Th expansion bias

-inverse relationship with TB, mycobacteria live in competitive environments

-western diet that promotes the expansion of invasive E Coli, I linked the study not too long ago

-MAP, pretty sure I don't need to explain that one, milk consumption is far more common in western society because of lactose tolerance

I disagree that you're the only person who suggested an explanation for the rise in crohn's disease.


----------



## Xiaofa Qin

kiny said:


> There have been many hypothesis.


Yes, I certainly know there are many hypotheses. Many have been discussed in my paper. 

However, my original post is as following:



Xiaofa Qin said:


> Ironically, only a clumsy theory from a spare time researcher without any funding explained and predicted what happened in the real world, from the emerging of clustered cases in 1888 to the recent worldwide increase of IBD, but it is utterly ridiculed by the patient. Yes, I just found there is no way to make sense out of everything, everybody.


Do you find anyone explained and predicted what happened in the real world, from the emerging of clustered cases in 1888 to the recent worldwide increase of IBD?


----------



## Xiaofa Qin

mf15 said:


> Xiaofa: I don't know where you are right or wrong on the artificial sweeteners,I never
> ate any,except in toothpaste. I have now eliminated saccharin from my toothpaste.
> 
> But we do know at least in UC there is excess protease in the colon,this does cause a problem.
> We also know from very small trials of BBI,that UC is put into remission, also the
> two people who were given Camostat went into remission.
> 
> So if nothing else I have learned that excess protease is part of the disease process,
> whether casual,not sure.
> 
> 
> Keep up the good work.
> Old Mike


Thanks Old Mike for sharing your thoughts. As I mentioned in my early post (see #132),  I think the small amount of saccharin in the toothpaste, if not swallowed, probably would not be enough to cause a big problem on gut bacteria. Without more rigorous study, nobody can be sure if and to what extent these artificial sweeteners may be linked to IBD.  Definitely, there would be some other agents, such as antibiotics, that may cause IBD. Hope the recent worldwide increase of IBD may bring people more interest and effort to find out the causative agent(s) in the environment.


----------



## kiny

Xiaofa Qin said:


> Do you find anyone explained and predicted what happened in the real world, from the emerging of clustered cases in 1888 to the recent worldwide increase of IBD?


I don't put UC and Crohn's disease in one group. Regarding crohn's disease, there's a paper from dalziel I linked once.

http://www.crohnsforum.com/showthread.php?t=39658







I've written down the name of a book a few pages ago that has the history of all intestinal diseases that could potentially have been crohn's disease. The earliest I am convinced of is the one from 1913...he tested for intestinal TB, he saw both inflammation of the small and large intestine, the ages of his patients match the ages most people tend to be diagnosed with crohn's disease today, often children and young adults. He named it chronic interstitial enteritis, my guess is, he's describing crohn's disease.

The Cold-chain hypothesis was described here:

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2803%2915024-6/abstract

It matches Dalziel's study, industrial large scale refrigeration started around the beginning of the 1900s. But so did many other things.

ATG16L1 and NOD2 variants are extremely common in the West, much more common than in Asia, a study showed considerable underreporting of CD cases in Asia too since it still to this day gets confused with intestinal TB, I don't think you can easily weigh in all those factors and claim one hypothesis is more likely than the next.


----------



## Xiaofa Qin

kiny said:


> There is a book called
> 
> *Origins and Directions of Inflammatory Bowel Disease: Early Studies of the "Nonspecific" Inflammatory Bowel Diseases* that has the history of first cases of non-TB inflammation of the intestines.


A very good book by Dr. Joseph B. Kirsner, a professor at University of Chicago Medical Center and one of the most renowned IBD researcher in the world. I read this book more than a decade ago and learn a lot from it. In fact, I emailed him a copy of the draft of the manuscript that was eventually published in Medical Hypotheses in 2002 (Qin XF. Impaired inactivation of digestive proteases by deconjugated bilirubin: the possible mechanism for inflammatory bowel disease. Med Hypotheses. 2002 Aug;59(2):159-63) to seek his opinion, but failed to get a response.


----------



## Xiaofa Qin

kiny said:


> I don't put UC and Crohn's disease in one group.


If you read through my paper discussed here, you will find I not only provided explanation for the connections between UC and CD, such as why UC emerged first, followed by CD, then CD tends to exceed UC, but also provided some explanation for their difference such as the characteristic feature of crypt abscess in UC and inflammatory granulomas in CD. People have to face the fact that UC and CD have both differences and similarities.


----------



## Xiaofa Qin

kiny said:


> ATG16L1 and NOD2 variants are extremely common in the West, much more common than in Asia.


I wrote a paper that gave a new explanation for the relationship among NOD2, autophagy and gut bacteria (Qin X. How NOD2 and autophagy may be related to Crohn's disease? A viewshifted from live microbes to luminal bacterial debris. J Crohns Colitis. 2014 Jan 1;8(1):88). You are welcome to read it, think over it, then bring in some analytic critiques, but not just arguments with some extreme words.


----------



## kiny

I don't agree that immunosupressant use that makes people with CD better in the short terms somehow then indicates that there is no infection present. Inflammation is in large part responsible for the tissue damage in infectious disease, and a large part of patients who die from an infection, die from that tissue damage. Sepsis is a good example how destructive the inflammation to antigen form bacterial origin can be.

But I don't completely disagree with what you write either, autophagy is involved in a lot more than bacterial clearance and is a general housekeeper, I don't agree that people keep recommending us probiotics like we're some sort of group of people you can sell your wares to, and we're supposed to just accept this unregulated industry is good for us. Million of those bacteria will die, they will release considerable amounts of toxins and cytokine.


----------



## wildbill_52280

All these different hypothesis are important, even if they do not lead one one solid answer just yet. variables like diet and vitamin d levels exposure to antibiotics, sucralose, low fiber are all things that seem to enhance the risk of developing crohn's disease, what we need is that one universal explanation that connects them all, because all are valid and explain parts of the puzzle. I do believe eradication of indigenous bacteria would at least for now, be the universal cause. i believe in the end, the slight differences in disease state will be a combination of genetic variation among patients, variations among specific indigenous flora that are extinct, and variations in pathogens that colonize the gut after healthy flora have been damaged. These different combinations will likely explain variations in symptoms between UC and Crohn's.


----------



## durwardian

I agree, and feel that pancreatic issues may be the cause of much of the problems.


----------



## JMC

Judith said:


> I think the reason environmental factors are not more well documented in the literature is the result of a couple of factors. First, I believe the genetic components predispose one to IBD but the environmental effects that push one over the edge are probably not due to a single exposure but are probably additive over time and in number. From an epidemeological standpoint, it is very difficult to pinpoint factors under these conditions. If there is an outbreak of say, Salmonella, it is far easier to pinpoint the source and exposure since it is restricted in time and number of persons involved.


So let's assume that Crohn's is a result of genetic predisposition, plus some external environmental factor.  If it was a single external environmental factor, then it would probably have been identified by now, which probably means there are multiple factors as you suggest above.

Now, historically, this makes it very hard to identify the key factors as the human brain has a very finite capacity for retaining and processing data. Essentially though, this is just a data mining problem and with the internet and computing power now available we have the capability to:
a) collect a huge amount of data from relevant patients from all over the world
b) search that data for patterns very quickly and easily

Capturing all of the environmental factors you have been exposed to is probably still not simple, but I see no reason why this problem cannot be tackled with a brute force, big data approach and as far as I know, no one is doing this.


----------



## mf15

I have been trying to do this for years,but lots of multiple factors that perhaps change with time.
Early on 1890's, early 1900's-1920 ish.
MAP new in 1895,new viruse,aluminum in baking powder,artifical lights,office work/indoor,cities,central heating,shift work,chlorination,lead pipes,lecitin,pollution water and air,mercury fillings,root canals,
new fruits and veggies in diet,industrial chemicals,saccharin,improved sanitation,refrigeration, canning, pasteurization,wesson oil 1899,crisco 1911,
cooking methods high heat,less fermented foods,nitrate fertilizers,toothpaste,
possible,some synthetic detergents.
All this before antibiotics,and many industrial chemicals.
Plus I guess a zillion other things.
I try to concentrate on these early timelines,since from the history of IBD
the increase started in this time frame. 
Lest I forget increased sugar and salt consumption.
The switch from whole grains,to industrial flour, the switch from
sourdough to industrial bakers yeast. They also have to look carefully at twins,
and clusters.
Old Mike


----------



## kiny

JMC said:


> Capturing all of the environmental factors you have been exposed to is probably still not simple, but I see no reason why this problem cannot be tackled with a brute force, big data approach and as far as I know, no one is doing this.


How does it matter.

Are people drinking less milk because milk contain MAP? No.

Are people going more in the sun because crohn's disease has been linked to low vitamin D status? No.

Do people stop getting pets because they can carry invasive E Coli? No.


I don't want money invested in that because, 
A..it probably doesn't matter...
B...many diseases are effectively cured long before causality is found.

Find out what is driving in the inflammatory process so we get better and safer treatment and hopefully a cure one day. YES

Find out how this whole process initially started. NO. They wasted enough money on things that got us nowhere.

It's really interesting to discuss, but it would be money wasted trying to find out why country A has 2% more crohn's disease than country B.

We have a disease that is severely lacking in safe treatment.


----------



## Xiaofa Qin

kiny said:


> I don't agree that immunosupressant use that makes people with CD better in the short terms somehow then indicates that there is no infection present. Inflammation is in large part responsible for the tissue damage in infectious disease, and a large part of patients who die from an infection, die from that tissue damage. Sepsis is a good example how destructive the inflammation to antigen form bacterial origin can be.


Yes, inflammation is in large part responsible for the tissue damage during infection. Have you thought over what inflammation is and how it cause tissue damage? Inflammation is largely just the  phenomenon of fighting between the immune system against the perceived enemy, and the damage of the tissue is largely caused by the bombing and firing mainly from the immune cells of the body. The enemy could be real, like pathogens invaded into the tissue, or false such as self-antigens in autoimmune diseases. Immune suppression is by nature an action to disarm the immune system. This would indeed lead to a radical solution for autoimmune disease, as the self-antigen they attacked is not the real enemy but itself. However, it would be a totally different scenario when there is existence of real enemy. Yes, the ceasefire order to the defending force fighting fiercely with the enemy also result in temporary peace. As you suggested, immunosupressant use that makes people with CD better in the short terms somehow cannot rule out that there is no infection present. However, a long term disarmament of defense would definitely result in losing but not winning of battle. This is why the long term use of immune suppression agents like TNF-alpha blocks result in the escape of TB prisoned by the immune system after a dormant infection and become flourishing inside the body. These immune suppression agents also result in invasion and rampage of some opportunistic pathogens that otherwise would never have the chance to do so with a normal immune system. However, largely by virtue of the great finding of some genes like NOD2 and autophagy that related to both Crohn’s disease and bacteria, it become a popular notion that immune suppression agents like TNF-alpha blocks exerted their effect by killing and clearance of the invincible bacteria that are unconquerable even by the most powerful antibiotics and the uncompromised immune system. Is there any explanation how this is possible? Frankly, that is beyond my ability of imagination and thus I brought in an alternative explanation: NOD2 is related to bacteria not through its binding to live bacteria but rather binding to the infiltrated luminal bacterial debris containing Muramyl dipeptide (MDP, the NOD2 binding motif in peptidoglycan that has a molecular weight of only 500) that penetrated the weakened gut barrier. Autophagy is associated with CD not through the killing and clearance of live bacteria but rather the degradation of NOD2/MDP complex, as described in the published paper (Qin X. How NOD2 and autophagy may be related to Crohn's disease? A view shifted from live microbes to luminal bacterial debris. J Crohns Colitis. 2014 Jan 1;8(1):88)


----------



## JMC

kiny said:


> How does it matter.


How can you solve a problem without information?  Guess work?  What happened to the scientific process?



kiny said:


> I don't want money invested in that because,
> A..it probably doesn't matter...


Why?



kiny said:


> B...many diseases are effectively cured long before causality is found.


How?  Give me examples. 



kiny said:


> Find out what is driving in the inflammatory process so we get better and safer treatment and hopefully a cure one day. YES


That is one way. Should it be the only approach. No. 

What you seem not to have grasped is that the world has changed _*significantly*_ over the last 20 years and our ability to collect and process data has grown exponentially. The cost of doing this has collapsed, yet medical research, from my exposure to it from having Crohns and constantly asking my doctor "tell me about progress with treating this disease" seems to be stuck in the dark ages. 

Curing Crohns is a data processing and pattern matching problem.  We have radically more ability to do that now than we did in the past, I think this deserves more focus.


----------



## kiny

Xiaofa Qin said:


> NOD2 is related to bacteria *not through its binding to live bacteria* but rather binding to the infiltrated luminal bacterial debris
> 
> *Autophagy *is associated with CD *not through the killing and clearance of live bacteria*


That is completely false, where are you getting these ideas from.

NOD2 and autophagy signaling of ATG16L1 is directly involved in control of live LF82, which is consistently being isolated from crohn's disease patients, has been shown in studies.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3743084/

NOD2 and autophagy is crucial for controlling intracellular infections. 

http://www.ncbi.nlm.nih.gov/pubmed/19802566

Our Forum Wiki explanation:

http://www.crohnsforum.com/wiki/Nod2-Card15-Gene

Subverting autophagy is actually how AIEC manages to survive in people with crohn's disease. If you stimulate autophagy, or optimise vitamin D status or deprive cells of nutrients, AIEC actually dies so do mycobacteria, because it stimulates autophagy.

NOD2 KO mice have a very hard time controlling bacterial infections. Autophagy is involved in neutrophil phagocytosis which is essential for control of intracellular bacteria.

Plenty of studies both in vivo and vitro that have shown this. That's something I'm not going to even discuss, people have linked plenty, there's a laundry list of studies on this forum about it.

You consistently manipulate data and twist facts around to further your own ideas, it's not objective. Don't write papers if you can not be objective. Not bothering anymore.


----------



## Xiaofa Qin

kiny said:


> That is completely false, where are you getting these ideas from.



Can you learn to get the true meaning and key points from the whole context, rather than just jump to conclusions with your extreme words? Of course, I know there are a lot of studies on NOD2 and autophagy. That is how I can make comments on this and get published. The big question we have to answer is, as discussed in my early post (#385), is really possible that immune suppression agents like TNF-alpha blockers exerted their effect by killing and clearance of invaded bacteria that have been regarded by some people as unconquerable even by the most powerful antibiotics and the uncompromised immune system, while this disarmament of the immune system has greatly increased the risk of infection by TB and many other weaker opportunistic pathogens. I proposed an alternative explanation for this. If you think you have a better, cohesive explanation on this, share it with us. That would be a more reasonable and constructive approach. 

Looking back human history, we may find that the truth usually hide behind small pieces of bizarre phenomenon, rather than the vast evidences people take for granted as true. For so long, people deeply believed the earth is the center of the universe, with the sun, the moon and all stars turning around it. A doubt on this started from the back-and-forth movements of some planets that were only observed at very rare occasions. We all feel time is absolute and the space is straight. But from the constancy of speed of light, Einstein postulated that the time is relative and the space is curved. People started to believe this because it predicted the bending of light observed during eclipse and many other things in the universe. These taught us that we need think it over and over before jumping to a conclusion from our intuition and it is not easy to find the piece of evidence that bares the clues of the truth.


----------



## wildbill_52280

kiny said:


> You consistently manipulate data and twist facts around to further your own ideas, it's not objective. Don't write papers if you can not be objective. Not bothering anymore.



since you are giving advice about getting papers published in scientific journals, i was wondering if you could provide some links to the papers you have written and successfully published, so we can see what experience you have?

thanks.


----------



## Xiaofa Qin

kiny said:


> You consistently manipulate data and twist facts around to further your own ideas, it's not objective. Don't write papers if you can not be objective. Not bothering anymore.


You should realize that many of epidemiological studies such as the increases of IBD in Ireland, Singapore, Saudi Arabia, and United States, the decrease of CD and increase of UC in Sweden, and the even higher incidence of IBD in Guangzhou, China than the adjacent more developed Hong Kong and Macau were published after I published this paper discussed here, but can be easily explained by the already published hypothesis. Are you suggesting I have the power to manipulate what will happen in the future. Is it a sin to provide evidence for the possible cause of IBD? As stated in my early post, if you indeed have better explanations than I do and really interested in solving the mystery of IBD, you should bring it up, as these new findings may provide us a rare chance to find out the cause and thus the possible root mechanism of IBD. 

You are the victim of the devil, but you denounce the efforts to track down the devil. Why?


----------



## mf15

Now this is interesting,in China they say tap water is protective for UC.
The first time I have ever seen that one.
Meaning it is untreated, as opposed to boiled,and that none pathogenic
bacteria in the tap water is having an immune modulating effect.
Chlorination in the USA started around 1908.

Would be interesting to see how much of the tap water in China is chlorinated,
or treated in some other manner.
Well well well.
http://www.travelchinaguide.com/essential/water.htm

http://www.nytimes.com/2013/11/08/opinion/if-you-think-chinas-air-is-bad.html

Also would be interesting to find out when chlorination started in England
to see in timelines match up with the increase in IBD, in the span from
say 1890 to 1920.
Ask and you shall receive,interesting 1890 for England.
While correlation is not causation,I have to now start to become
much more interested in what might be going on here.
This is why I spend a lot of time on historical timelines.
http://humboldt.edu/arcatamarsh/chlorination.html

Here is a good history of IBD,best I have ran across.
http://onlinelibrary.wiley.com/doi/10.1002/ibd.3780010103/pdf



This a link to the cached version,cant pull up the live version,where it
talks about tap water.
Wow chlorination has probably saved many millions of people from infection,yet it might be killing us.
Old Mike

http://webcache.googleusercontent.c...df/v19/i11/1827.pdf+&cd=9&hl=en&ct=clnk&gl=us


----------



## kiny

Xiaofa Qin said:


> You are the victim of the devil, but you denounce the efforts to track down the devil. Why?


I'm not insane. that's why.


----------



## Xiaofa Qin

mf15 said:


> Now this is interesting,in China they say tap water is protective for UC.
> The first time I have ever seen that one.
> Meaning it is untreated, as opposed to boiled,and that none pathogenic
> bacteria in the tap water is having an immune modulating effect.
> Chlorination in the USA started around 1908.
> 
> Would be interesting to see how much of the tap water in China is chlorinated,
> or treated in some other manner.
> Well well well.
> http://www.travelchinaguide.com/essential/water.htm
> 
> http://www.nytimes.com/2013/11/08/opinion/if-you-think-chinas-air-is-bad.html
> 
> Also would be interesting to find out when chlorination started in England
> to see in timelines match up with the increase in IBD, in the span from
> say 1890 to 1920.
> Ask and you shall receive,interesting 1890 for England.
> While correlation is not causation,I have to now start to become
> much more interested in what might be going on here.
> This is why I spend a lot of time on historical timelines.
> http://humboldt.edu/arcatamarsh/chlorination.html
> 
> Here is a good history of IBD,best I have ran across.
> http://onlinelibrary.wiley.com/doi/10.1002/ibd.3780010103/pdf
> 
> 
> 
> This a link to the cached version,cant pull up the live version,where it
> talks about tap water.
> Wow chlorination has probably saved many millions of people from infection,yet it might be killing us.
> Old Mike
> 
> http://webcache.googleusercontent.c...df/v19/i11/1827.pdf+&cd=9&hl=en&ct=clnk&gl=us


Thanks Old Mike for sharing the info. Below is the link to the live version of the paper above:

Wang YF, et al. Multicenter case-control study of the risk factors for ulcerative colitis in China. World J Gastroenterol. 2013 Mar 21;19(11):1827-33.

This is a paper out of my radar. It is interesting to find that sugar and spice food have been the main risk factors for UC.

In China, drinking hot water is a general habit. Here is a link with several pictures showing how the students line up to get hot water from the hot water facility of the school.. Regular tap waters are usually not that sterile and contain some bacteria, which may be the reason for its protective effect on UC.


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## mf15

Thanks Xiaofa:
We have known about the sugar connection for many years.
What I have never seen, or no one will admit is that untreated water is protective for UC.
Perhaps the connection is only possible in China or few other places.
In the USA and England the connection is buried in time.
We also know that at least in the West , UC is associated with urban living, which in the USA would imply water chlorination,also the hygiene hypothesis
perhaps a hidden not talked about consequence is mostly sterile water,which
improves the health of the general population,but is of course perhaps not good for our colons or small intestines.


Old Mike


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## Xiaofa Qin

I am surprised that the study did not find any difference between urban and rural areas, as there is usually a big difference regarding their sanitary condition. Probably, the poor hygiene condition in the rural area has led more people there drinking boiled water and avoided tap water. 

Another thing that interested me is sugar versus spicy food. In another recent study (Ng SC, et al. Asia–Pacific Crohn's and Colitis Epidemiologic Study (ACCESS) Study Group. Incidence and phenotype of inflammatory bowel disease based on results from the Asia-pacific Crohn's and colitis epidemiology study. Gastroenterology. 2013 Jul;145(1):158-165), it is showed that Guangzhou, the capital of Guangdong Province and a city near Hong Kong with sugar usually an important gradient in their dishes (see Guangdong, also known by foreigners as Cantonese cuisine) has the IBD incidence of 3.44 (CD 1.09, UC 2.05), while Chengdu, the capital of Sichuan Province with a fame for hot and spicy food (see Sichuan, also known by foreigners as Szechuan cuisine) has an IBD incidence of only 0.58 (CD 0.15, UC 0.42), (here is the table), suggesting sugar may probably have a more tight link than spicy food for IBD.


----------



## mf15

Xiaofa: I ran across that study on my searching on China.
I believe the research doc's are missing a big opportunity to solve the cause of IBD if 
they do not concentrate efforts on countries such as China with emerging/increasing IBD incidence.
Old Mike


----------



## Xiaofa Qin

Old Mike: I agree with you. 

This study found the increased sugar consumption as one of the most important risk factors for UC. In fact I have sent email years ago to quite a few of the top IBD researchers in China (some of them being in the author list in the published paper: Wang YF, et al. Multicenter case-control study of the risk factors for ulcerative colitis in China. World J Gastroenterol. 2013 Mar 21;19(11):1827-33) suggesting them checking out the possible link between artificial sweeteners and IBD. Apparently, it failed to raise any action. Thus, we still do not know if artificial sweetener may be  involved in the observed increased risk, as suggested in the paper discussed here. Anyway, I think people should put more effort to find out the cause of recent dramatic increase of IBD, but not just repeat again and again on factors we already know that are positive but not essential, rather we should check out the other suspected agents that may have played more significant causative role.


----------



## Xiaofa Qin

JMC said:


> Capturing all of the environmental factors you have been exposed to is probably still not simple, but I see no reason why this problem cannot be tackled with a brute force, big data approach and as far as I know, no one is doing this.


I personally feel IBD could be much simple than people currently perceived. The dramatic increase of Crohn's patients in the Saudi clinic from 0 or 1 case during 1993 to 2000 to 174 cases in 2009 (here is the figure) would be more likely due to a sudden introduction of one risk agent rather than a changed balance of complex interactions between numerous risk versus protective factors.


----------



## durwardian

Can't we work on getting a real study funded to figure out the real causes, differences in diseases, treatments and cures? Where is the help to be found? Who can write up the request among you? Design proper controls?


----------



## JMC

Xiaofa Qin said:


> I personally feel IBD could be much simple than people currently perceived. The dramatic increase of Crohn's patients in the Saudi clinic from 0 or 1 case during 1993 to 2000 to 174 cases in 2009 (here is the figure) would be more likely due to a sudden introduction of one risk agent rather than a changed balance of complex interactions between numerous risk versus protective factors.


I tend to agree.  I expect the cause to be something relatively simple as it was with peptic ulcers and Coeliac disease.  We just need the key insight to unlock the problem and I think we are in a much better position now than we were 20 years ago, simply because it is much easier to get in contact with ten of thousands of people with the disease and analyse the data.


----------



## Xiaofa Qin

JMC said:


> I tend to agree.  I expect the cause to be something relatively simple as it was with peptic ulcers and Coeliac disease.  We just need the key insight to unlock the problem and I think we are in a much better position now than we were 20 years ago, simply because it is much easier to get in contact with ten of thousands of people with the disease and analyse the data.


As mentioned in my early post (see #294), the existence of H. Pylori (the spiral-shaped bacteria) in the lining of the human stomach had been found by German scientists back to 1875. As early as 1899, Professor Walery Jaworski of the Jagiellonian University in Kraków had suggested that these spiral shape bacteria, which he called Vibrio rugula, may have played a possible role in the pathogenesis of gastric diseases (http://en.wikipedia.org/wiki/Helicobacter_pylori). However, time and again, these findings and suggestions were soon forgotten. It took nearly a century that Barry Marshall and Robin Warren rediscovered these bacteria in the stomach and proved they are actually even more detrimental to the mucosa than the strong acids and have been the primary cause of peptic ulcer. Probably one day when we look back we may find that the cause of IBD is also just this simple.


----------



## Xiaofa Qin

durwardian said:


> Can't we work on getting a real study funded to figure out the real causes, differences in diseases, treatments and cures? Where is the help to be found? Who can write up the request among you? Design proper controls?


Sorry for the delayed response. Frankly, I have hesitated but now I feel it would be necessary to share what I experienced during the more than a decade pursuit in IBD, so we may have a more clear vision of the situation and problems in current IBD research and where could be the likely simple solution for IBD.  

Regarding funding, as mentioned in the paper discussed here (Qin X. Etiology of inflammatory bowel disease: a unified hypothesis. World J Gastroenterol. 2012 Apr 21;18(15):1708-22) I have tried many times to apply grants from different agencies such as NIH, Crohn's and Colitis Foundation of America (CCFA), Broad Foundation, and Rainin Foundation, etc. However, all the submitted applications were triaged, meaning the applications were so bad that they were even not worthy to be brought up for  a formal discussion at the study sections, or the Letter of Interest was turned down, meaning the idea is so bad that there is no need to submit a formal application.  Right now the annual funding in IBD research by National Institute of Health (NIH) of the United States alone is about 120 million (Here is the link). It is not a lot, but still can do a lot of things. As discussed in multiple of my early posts (see posts on 08-19-2012,    on 01-12-2013,   on 03-29-2013,   on 03-31-2013, and   on 08-24-2013), I feel the big problem is not the resource but rather the attitude. As discussed in my early  post on 08-19-2012,  I found the possible link between saccharin and IBD in 2001, about the same time of finding the first IBD gene, NOD2/Card15, also called IBD1, associated with Crohn’s disease. During the last decade, people conducted genome wide analysis of 75,000 patients and controls with the cost of hundreds or even thousands of US dollars at early times for each and thus hundreds of millions for the whole study. However, nobody have interest to spend a little effort to check out if dietary chemicals like saccharin could be indeed a risk factor for IBD as I demonstrated in the paper published in 2002, by just collecting the urine or feces from some patients and controls and conducting an analysis with the well-established methods that are sensitive enough for an accurate assay for these chemicals even in the contaminated rivers and lakes (here is a recent paper from Canada: Spoelstra  J, Schiff SL, Brown SJ. Artificial sweeteners in a large Canadian river reflect human consumption in the watershed. PLoS One. 2013 Dec 11;8(12):e82706). As the result, although we still do not know how NOD2 related to IBD, we found about 200 more risk genes (Jostins L, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012 Nov 1;491(7422):119-24). It generated a lot hypotheses and theories, but they can hardly explain anything happened in the real world. NOD2, the gene with the strongest association with Crohn’s disease, not only failed to show an association with CD in Asian, but also failed to show a correlation with the incidence of CD in the western countries that encompass three continents: Europe (France, Germany, UK, Italy, Belgium, Finland), Northern America (US and Canada) and Australia (Hugot JP, et al. Prevalence of CARD15/NOD2 mutations in Caucasian healthy people. Am J Gastroenterol. 2007 Jun;102(6):1259-67). This would have simply reflected the fact that the dramatic increase of IBD since last century is caused by factors in the environment rather than the gene. Nobody can catch the moon appeared in the water, because the moon is not there, but it still can generate a lot of hypothesis such as the water is too deep, the rope is not long enough, etc. Similarly, as discussed in my early post on 01-12-2013, despite of the low explaining ability, these genetic studies were presented as great achievements and explained as extra complexity of IBD that can only be deciphered by finding out the much more risk genes and the interactions among these genes, the gut microbiota with genes being 100 times of human genome, and many other epigenetic and other factors. In contrast, I believe the hypothesis I proposed a decade ago without any funding provided much better explanation and prediction for what happened in the real world, as demonstrated by the multiple papers I wrote. In my opinion, a simple breakthrough more likely lays in finding out the principal causative factors in the environment and thus the root mechanism of IBD. Probably, several hundreds of thousands may make even bigger progress than the hundreds of millions or even billions spent in the last decades. But we need finding the people who would like to do so.   


Regarding the help, when I found the possible link between saccharin and IBD, I thought I may get some help from government or international agencies in charge of food safety, and foundations or professionals related to IBD research, but it turned out that none of these seemed really helped. Following is a list of some of my efforts: 

-	National Institute of Health (NIH) of US: I contacted in December 2001 the Director of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) responsive for studies in diseases of digestive system like IBD. The director responded through a person at the Office of Communications and Public Liaison, suggested me to apply grants from NIH or Crohn's and Colitis Foundation of America (CCFA). At that time, I had no way to do so, as I was ousted from my job since July 2001 largely due to my pursuit in the possible role of digestive proteases in diseases like IBD, then the immigration agency messed up my record and I had to stay at home for more than one year waiting for the correction and new process of hiring.  After I went back to research and became a faculty I indeed tried very hard to apply some grants from NIH and CCFA, but all these applications were triaged as stated above.  

-	Food and Drug Administration (FDA) of US: I contacted in December 2001 the Director of the FDA’s Center for Food Safety and Applied Nutrition (CFSAN), but failed to get any response. 

-	Crohn's and Colitis Foundation of America (CCFA): I contacted in December 2001 the Chair of CCFA's National Scientific Advisory Committee and I was suggested to apply grant. I did try multiple times, but all triaged. During the last decade, I have also contact quite a number of the annually rotating Chairs of CCFA's National Scientific Advisory Committee suggesting a discussion on the evidence I gathered regarding the possible link between dietary chemicals and IBD, but I got no positive response. 

-	Center of Disease Control (CDC) of US: In February 2008, I learnt from CDC web site that some scientists/epidemiologists there were conducting an epidemiological study on IBD. I contacted the people there. The medical officer of CDC participated in this study told me that they were working as collaborating scientists with CCFA. Then she introduced me to the top officer in CCFA in charge of research and this officer then introduced me to a well-known IBD researcher. The professor told me he would like discuss with me after reading the material I sent him, but I failed getting any response. 

-	Joint Food and Agriculture Organization(FAO)/World Health Organization (WHO) Expert Committee on Food Additives (JECFA):  I contacted in December 2001 the Secretary of JECFA and I was told in the response that they do not have sufficient resources to undertake work in this area.

-	The European Union: I contacted in January 2002 the office of Scientific Committee for Food of European Union, but failed to get any response. 

-	Health Canada: I contacted in January 2002 the top officer in Canadian Food Inspection Agency. I got a response by the end of April telling me that my email was forwarded to Chemical Health Hazard Assessment Division in Health Canada. Then I got the opinion that saccharin was unlikely an important causative factor as Canada restricted its use after finding its carcinogenicity in animals in 1977. I felt this opinion reasonable and started to believe that even there is a link between artificial sweeteners and IBD, the link may not be strong. However, this notion changed after I found a paper in 2011 that sucralose inhibited gut bacteria and further leant that this new artificial sweetener was first approved by Canada in 1991.  I immediately realized that sucralose may have played an important role in the high incidence of IBD observed in Canada in recent years. More evidences I collected seemed to support this notion. I wrote a paper on this that was published in Canadian Journal of Gastroenterology (Qin X. What made Canada become a country with the highest incidence of inflammatory bowel disease: could sucralose be the culprit? Can J Gastroenterol. 2011 Sep;25(9):511). Meanwhile, I contacted Health Canada again and tried to reach those I communicated about a decade ago, but failed to get any response. 

-	Food Standard Agency of UK: I contacted in March 2002 people in the Chemical Safety and Toxicology Branch of Food Standard Agency. They told me that they would be most interested to see new published data in my possession that casted doubt over the safety of saccharin. I sent them a draft of the manuscript that was eventually published in Medical Hypotheses (Qin XF. Impaired inactivation of digestive proteases by deconjugated bilirubin: the possible mechanism for inflammatory bowel disease. Med Hypotheses. 2002 Aug;59(2):159-63), but I never got any further response. 

-	IBD professional: As mentioned in my previous post on 01-30-2014, shortly after I found the possible link between saccharin and IBD, I contacted and would like to get an opinion from Dr. Joseph B. Kirsner, Professor at University of Chicago Medical Center and one of the most renowned IBD researcher in the world, but failed to get any response. During the 2003 Digestive Disease Week (DDW) conference, I also handed a copy of my paper published In Medical Hypotheses in 2002 as mentioned above to Dr. Stephen B. Hanauer, also a professor at University of Chicago Medical Center and one of the most renowned IBD researcher, and the multiple year co-Chairman for the yearly Advances in Inflammatory Bowel Diseases, Crohn’s & Colitis Foundation’s Clinical & Research Conference, asking for his opinion, but failed to get a response. As stated in my early post on 01-12-2013, I also started a discussion at several IBD-related LinkedIn groups including the European Crohn's and Colitis Organisation (ECCO), CCFA (Crohn's & Colitis Foundation of America), IBD - Crohn's disease & Ulcerative Colitis – CCF, and IBD Research Foundation, entitled “We should put a little bit more effort to find out the cause of inflammatory bowel disease”, in hoping to generate some in-depth discussion on the cause and etiology of IBD among the IBD professionals, but none of the IBD professionals responded. I had also submitted an abstract to the 2012 Advances in Inflammatory Bowel Diseases: Crohn's and Colitis Foundation's Clinical and Research Conference and the 8th European Crohn's and Colitis Organisation Congress of Inflammatory Bowel Diseases 2013, in hoping to have the chance exchanging information, evidences and views with IBD professions regarding the etiology of IBD, but the abstract was rejected by both of the conferences. As stated in my early post on 03-17-2013, shortly after the publication of this paper discussed here, I have emailed a copy of this paper to each member of the Epidemiology and Natural History Task Force of the International Organization of Inflammatory Bowel Disease (IOIBD)  advocating them checking out this possibility. Apparently it failed to raise any attention, which is reflected by the fact that this group later published a paper regarding the environmental risk factors in IBD (Ng SC, et al. Geographical variability and environmental risk factors in inflammatory bowel disease. Gut. 2013 Apr;62(4):630-49) without mentioning the existence of such a hypothesis. I submitted a manuscript as a letter to the editor entitled “Dietary chemicals like saccharin and sucralose should not be omitted by epidemiologists as the possible important causative factors for inflammatory bowel disease”, but was rejected (see the post on 03-17-2013 for the rejected paper). 

From my experience, and time and again demonstrated in human history, the only thing that can ultimately help to differentiate truth versus false is time, despite that the behavior of human may greatly affect how long it will take to achieve this. It took nearly 2000 years from someone proposed the earth turning around the sun to people really accepted it, and It took nearly a century from someone proposed the spiral-shaped bacteria may have played a role in the pathogenesis of gastric diseases to the finding of H. Pylori as the primary cause of peptic ulcer. We still do not know how long it will take for a final solution of IBD. However, as stated in my previous post on 08-24-2013, “I and the mainstream presented two totally different scenarios: I feel I, as a spare time IBD researcher and without any funding on IBD, may have virtually solved the mystery of IBD more than a decade ago, while the mainstream presented an extremely complex IBD that may need billions, if not trillions, and decades, if not centuries, to decipher it”. Which one is right? Some very easy tests can tell. As described above, I have tried so hard in the last decade to get this test down, either by myself through a grant or others capable of doing so. However, none would like to provide the tiny bit of resource or spent a little bit efforts. With time passing by, more and more evidences suggest my concern on the possible link between dietary chemicals and IBD is likely real rather than lunatic illusion, as demonstrated by the multiple recent epidemiological findings in IBD that I have commented on  (here included some of these papers I wrote). As an individual, I often feel so helpless in front of the mainstream. The mainstream is so powerful. They can get and spend billions and asking for trillions under the glories claim to seek a solution of the disease, but put any evidence of the possible easy solution into the abyss of shadow and make the suggestion for this easy solution as heresy and ridiculous. Luckily, time and nature is even more powerful and always teach us, little by little, what is true, although time and again we just take too long to comprehend it. Looking back into what happened during the last decade, now I feel more confident to say there seems simple cause and easy solution for IBD. However, to reach this goal, we may need not only the efforts of the whole society but also, more importantly, the right approach that leads towards to but not away from the solution.


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## mf15

Xiaofa: Part of the problem is the not invented here syndrome with American doctors.
What really baffles me is that since say around the 1930's some of the best medical minds
have been working on IBD,with no solution. There last chance perhaps for a cause is emerging countries like China,I believe they missed their chance in Japan.
As we see in one of the above papers, unsterilized tap water may be a key,at least for protection. An implication from this is chlorination/boiling possibly as a cause.
Resulting in loss/lack of renewal of protective bacteria,which perhaps are killed off by certain foodstuffs.

Old Mike


----------



## Xiaofa Qin

Old Mike: I agree. The dramatic increase in low IBD countries like China may provide a chance to find out its cause. Hope people may put more efforts.

It would be no surprising that the unsterilized water may protective. However, drinking chlorination/boiling sterilized water seems not enough to cause IBD. In fact, drinking boiled water is a very old tradition and common practice in China. The unboiled water is called "raw water" and generally regarded as not safe. As the result, many people in China drink boiled water the whole life, even in hot summer. The recent increase in IBD in China is more likely related to changes such as the westernized life style and foodstaffs.


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## durwardian

What about not looking at the clean water issue, but at the byproducts that these cause. Are they poisoning us slowly? Such as trihalomethanes, haloacetic acids, bromate, and chlorite?


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## durwardian

If you combine sodium benzoates with vitamin C, you get benzene. So this very popular and natural preservative is being replaced by the industry for our health. I would like to see the same thing happen with other known chemistry issues that are common place, like chlorination without better filtration, flouride addition, chemical sweetening, and anything else "questionable". Until studies prove they are harmless, I will continue to assume that the combination of substance A with B is killing us.


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## durwardian

I would be interested in matching particular products and distribution with health problems. Awareness would at least allow avoidance. I wonder if the grant to ask for isn't for bowel disease, but public health issues greater than just our symptoms, bowel issues becoming part of a bigger problem.


----------



## Xiaofa Qin

durwardian said:


> What about not looking at the clean water issue, but at the byproducts that these cause. Are they poisoning us slowly? Such as trihalomethanes, haloacetic acids, bromate, and chlorite?


Nothing seems simple. Talking about toxicity, anything we take would far less toxic than the endotoxin (also known as lipopolysaccharides, or LPS) possessed by the bacteria inside our body. A dose of 1 µg/kg can induce shock in humans, while 1 ml saliva or 1 g feces contains 1 mg endotoxin (here is a link), enough to cause many times of shock. However, multiple studies demonstrated use of antibiotics increased rather than decreased the risk of IBD. People are trying using fecal transplant or probiotics to treat IBD. Similar as antibiotics, dietary chemicals like saccharin and sucralose have very little effect on the body, as almost all of them are eliminated from the body without any metabolism. However, they may have a big impact on gut bacteria.  




durwardian said:


> I would be interested in matching particular products and distribution with health problems.


I also think we at least need to see a match, i.e., a correlation, before we may further determine if this is the causation. We can raise a lot of possibilities and suspects for IBD, but they would have to be checked against the peculiar temporal and geographical distributions of the disease. As demonstrated in Figure 2A in my paper, data collected over 60 years in Monroe County in New York showed a dramatic increase in both ulcerative colitis and Crohn's disease during early 1960s to middle 1970s, then a remarkable drop during later 1970s and early 1980s. Now it seems a new round of increase of IBD in US since early 2000s (Qin X. When and How Was the New Round of Increase in Inflammatory Bowel Disease in the United States Started? J Clin Gastroenterol. 2013 Nov 13. [Epub ahead of print]). I think we would have to take into consideration of these peculiar features when we seek an answer for the mystery.


----------



## kiny

JMC said:


> I tend to agree.  I expect the cause to be something relatively simple



there's this expression

"For every complex problem there is an answer that is clear, simple, and wrong."


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## JMC

kiny said:


> there's this expression
> 
> "For every complex problem there is an answer that is clear, simple, and wrong."


“Truth is ever to be found in the simplicity, and not in the multiplicity and confusion of things.” 
― Isaac Newton

In my experience, mediocre academics spend their careers obsessing over irrelevant complexity unable to see the simple patterns in what they studying...


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## Xiaofa Qin

Measured objectively, what a man can wrest from Truth by passionate striving is utterly infinitesimal. But the striving frees us from the bonds of the self and makes us comrades of those who are the best and the greatest. 

― Albert Einstein


----------



## wildbill_52280

JMC said:


> “Truth is ever to be found in the simplicity, and not in the multiplicity and confusion of things.”
> ― Isaac Newton
> 
> In my experience, mediocre academics spend their careers obsessing over irrelevant complexity unable to see the simple patterns in what they studying...


they are biased to do so, for it is their profession, but i will never belittle their work.

So this in some cases is true. But the process of abstraction and theorizing, is a the process of simplification, to find the underlying common concepts of causes that link a multitude of observations. the end goal is ultimately to simplify and give meaning to previously meaninglessness processes. 

one major issue that may be related to your point is with reductionism and current limitations of inductive reasoning. The simulation of natural environments from which we gather data, data to be taken with a grain of salt regarding if that is the true behavior of the cell within the organism, but it helps us build theoretical models to test them in vivo. For my own intellectual progress, i sought to take science back out into the real world and consider the most general rather then the smallest parts, for a different perspective. but there is no difference, an empirical observation is an empirical observation whether the parts are small or large, it all counts. For me this was a matter of empowerment, i thought science was only done somewhere in a lab, i thought, can i gather knowledge too? can i propose a hypothesis to? do my own observations count too? i used this as a starting point to direct all my research, then, to outline different theories with high tech experiments i found online. all that work brought me to............ fecal transplants!!!

http://www.crohnsforum.com/showthread.php?t=52400


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## mf15

Xiaofa:You might be interested in this old paper,if you have not seen it in
the past.
These findings indicate that inactivation of pancreas tryptic activity is mainly carried out by the intestinal microbial flora.
Old Mike
http://www.microbecolhealthdis.net/index.php/mehd/article/viewFile/7395/8728


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## Xiaofa Qin

mf15 said:


> Xiaofa:You might be interested in this old paper,if you have not seen it in
> the past.
> These findings indicate that inactivation of pancreas tryptic activity is mainly carried out by the intestinal microbial flora.
> Old Mike
> http://www.microbecolhealthdis.net/index.php/mehd/article/viewFile/7395/8728


Old Mike: Thank you very much for sharing the paper. Although I have collected quite a number of research papers from Drs. Norin and Midtvedt, the one you listed above is out of my radar. I usually use pubmed to check out references. It seems this one is out of their collection. Yes, I take a great interest in this paper. I always would like to have some new inputs and, as stated early, adjust my thoughts against the new facts. This paper, although published more than two decades ago, would still bring me some fresh new thoughts:

1) As large amounts of digestive proteases can be found in the large intestine of animals raised under germ-free but not conventional condition, I have thought most, if not all, antibiotics would be able to cause dramatic reduction in gut bacteria and thus severely impaired inactivation of digestive proteases. However, as demonstrated in Table 2 of this paper, this seems not the case – among the ten antibiotics tested only doxycycline showed an increase in faecal tryptic activity during the treatment period compared to the two samples before the treatment. Interestingly, doxycycline is also the best know antibiotics that increased the risk of inflammatory bowel disease, especially Crohn’s disease (see: Inflammatory bowel disease linked to antibiotic treatment for acne). 

2) Study showed that putting saccharin in the diet can cause more than 10 fold increase in trypsin activity in the feces and contents of large intestine (Naim M, Brand JG, Kare MR. Effect of unpalatable diets, food restriction and saccharin-adulterated diet on tryptic, chymotryptic, and amylolytic activity in pancreas, intestine and feces of rats. J Nutr. 1982 Nov;112(11):2104-15), suggesting dietary chemicals like saccharin may cause even big impairment than antibiotics on the inactivation of digestive proteases, which may be one of the reasons for the much higher use of antibiotics  but still lower incidence of IBD in China compared with the western countries as discussed in some early posts (on 11-17-2012, 07:52 PM,  on 11-17-2012, 10:52 PM,  and on 11-18-2012, 05:30 PM).

Here is a very recent paper showing the reduced alpha1-antitrypsin in serum and colon of ulcerative colitis patients (Wang JY, et al. Correlation between pulmonary function impairment and levels of alpha1-antitrypsin in serum and colon of ulcerative colitis patients: a clinical research]. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2014 Jan;34(1):20-6). The more severe of the disease is, the longer the disease lasts, the lower the alpha1-antitrypsin is in the body, suggesting the likely gradual exhaustion of the endogenous anti-trypsin capacity of the body.

Thanks again for sharing the info.


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## mf15

Xiaofa: Thank You.
As you can see pubmed/medline does not have everything we might be looking for,you must use google with some specific search terms.

Here is the path I went down yesterday,which I copy and paste from another
forum I frequent.  I went down the path of antibiotics and gut bacteria,
and then found the paper on tryptic activity. Then I came across the non
human protein in red meat and milk.


Influence of antibiotics on intestinal mucin in healthy subjects
www.ncbi.nlm.nih.gov/pubmed/3492375


more on antibiotics and gut bacteria.

It seems that after antibiotics the gut bacteria can be disturbed for a very long time.

Of course UC started to increase before antibiotic use.

But I also have to wonder with the advent of antibiotics in pill form as opposed to injection, like when I was a kid,

might have led to the explosion of IBD.

I might speculate that when taking a pill there might be more antibiotic in the gut than with an injection.



http://mic.sgmjournals.org/content/156/11/3216.full



Something on tryptic activity.

These findings indicate that inactivation of pancreas tryptic activity is mainly carried out by the intestinal microbial flora.
Old Mike
http://www.microbecolhealthdis.net/i...File/7395/8728



more,if it says page not found just google this

Breakdown of Mucin as Barrier to Digestive Enzymes in the Ischemic Rat Small Intestine 

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040087

Now this one is real interesting,quite a few people indicate their UC started after antibiotic use.

You can get a little more info by clicking on the read cube section.

Seems that sialic acid in the diet might not be good, at least after taking antibiotics, red meat and dairy.

Old Mike 



http://www.nature.com/nature/journal/vaop/ncurrent/full/nature12503.html



more

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2752721/



gets even more interesting,normal humans make antibodies to it,wonder if UC people make more.

Wonder if cooking denatures it.

Of course the Masai eat lots of meat,blood and milk, and don't have inflammatory disease.

http://www.pnas.org/content/100/21/12045.long



more stuff

http://www.pnas.org/content/early/2010/05/04/0914634107.full.pdf


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## durwardian

http://articles.mercola.com/sites/a...ows-link-between-mmr-vaccine-and-autism.aspx#!
So far 70 of 82 have tested positive for vaccine measles in the gut tissue. No cases of wild measles. This could point to batches of the vaccines being a cause of one form of bowel disease. I'm glad they are revisiting this. In order to come back to this point, we all know that the public, and researchers have to agree something warrants a study.
If vaccines or illness have lasting effects, it may at least lead to creating a different vaccine so future generations don't suffer. 
The studies are far too many to be ignored, but the connections are still fuzzy.


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## Xiaofa Qin

durwardian said:


> http://articles.mercola.com/sites/a...ows-link-between-mmr-vaccine-and-autism.aspx#!
> So far 70 of 82 have tested positive for vaccine measles in the gut tissue. No cases of wild measles. This could point to batches of the vaccines being a cause of one form of bowel disease. I'm glad they are revisiting this. In order to come back to this point, we all know that the public, and researchers have to agree something warrants a study.
> If vaccines or illness have lasting effects, it may at least lead to creating a different vaccine so future generations don't suffer.
> The studies are far too many to be ignored, but the connections are still fuzzy.


Here is an example how a controversy, no matter how many evidences highly suggestive one side likely wrong, can still last forever. From the link above, we can see it was mainly based on a Daily Mail report back to 28/05/2006 (here is the link: Scientists fear MMR link to autism)  regarding a study by Dr. Stephen Walker at Wake Forest University. According to a post on April 30, 2013 at the Autism Science, News and Opinions website entitled “A few points about Steve Walker’s measles/autism study”, this study was never published and actually failed to replicate and dismissed. In fact, shortly after the appearance of the article on Daily Mail, Wake Forest University Baptist Medical Center where Dr. Walker was working made a press release entitled “Wake Forest Researcher Warns Against Making Connection Between Presence of Measles Virus and Autism”, and quoted what Dr. Walker said as “That is not what our research is showing”. According to another post entitled “The Daily Mail (UK) continuing sorry contribution to fear, uncertainty, doubt, and vaccine fears”, Daily Mail also deeply regretted for what it did. 


According to a recent review that included five randomised controlled trials (RCTs), one controlled clinical trial (CCT), 27 cohort studies, 17 case-control studies, five time-series trials, one case cross-over trial, two ecological studies, six self controlled case series studies involving in all about 14,700,000 children, exposure to the MMR vaccine was unlikely to be associated with diseases like autism and Crohn's disease. (Demicheli V, Rivetti A, Debalini MG, Di Pietrantonj C. Vaccines for measles, mumps and rubella in children. Cochrane Database Syst Rev. 2012 Feb 15;2:CD004407). 

In facing these discrepancies, which one should we prefer to believe? As discussed in my early post on 07-10-2013, we live in the age of information explosion that made it a big challenge to find out those evidences that may help solving instead of adding the mystery. Hope the exchange of info and views may sharp our vision.


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## durwardian

I posted a reply and it got lost in the Internet.... LOL
What if, the kids were already sick, and the vaccines are the straw that breaks the camel's back?
Is there screening before vaccines? If so, they could see some kind of relative connection between those that got ill, and those that don't. In any case, the good outweighs the bad, sad to say, in the case of vaccines. And we know that any bugs seem to accumulate in the tissues when the immune system is shut off, or busy fighting. Or perpetually burned out.

It isn't really adding to the mystery. Look at the breed of dogs that seem to perpetually suffer with similar disease issues? What is that connection? It isn't just a human one.
It is most likely a hereditary issue, of which then a correction using stem cells might work. Just what are we correcting? Is it a pancreas enzyme balance issue? Is it a cellular component and function issue?
I think some of the clinics have good ideas, they see that the ability to fight C-Diff and MAP are dead, that infusion with stool from healthy people works at times, that worms from pigs work at times, that drugs work at times. But is anyone really healed? Or are they just setting the stage so we can go back to fighting constantly for our health?
The healthy system compared to the sick system should give us the difference to correct, and I know it is much more complicated than just turn number 2 off and number 9 on. But I do think that we should stop trying to find more symptomatic and related issues, and get to what is really malfunctioning, the correct cell and chemistry response to life as we live it. If that is hereditary, then it can probably be corrected soon. I'm putting my money on stem cell research.


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## Xiaofa Qin

Thanks for sharing the thoughts. 

Theoretically, if vaccine really increased the risk of autism or Crohn’s disease, no matter worked primarily or secondarily, it should be shown up in the many epidemiological studies.

Talking about the dog, I have actually suspected that IBD in human might be more like IBD in dogs and cats more than Johne’s  disease in cattle (Qin X. What is human inflammatory bowel disease (IBD) more like: Johne's disease in cattle or IBD in dogs and cats? Inflamm Bowel Dis. 2008 Jan;14(1):138)  

IBD just emerged and became more and more popular for about a century. In my opinion, environmental factors would have played the predominant role, although genetic and hereditary factors may also be involved in its display. I agree on the notion that we should stop trying to find more symptomatic and related issues, and get to what is really malfunctioning, the correct cell and chemistry response to life as we live it. However, without a clear understanding of the whole process especially the primary cause, we may even not be able to tell what we see is a malfunction or a normal reaction. I suspected that the inflammation in IBD might be just a natural reaction of the immune system to the infiltrated bacterial and dietary components from the lumen due to a weakening in gut barrier (Qin X. What caused the increase of autoimmune and allergic diseases: a decreased or an increased exposure to luminal microbial components? World J Gastroenterol. 2007 Feb 28;13(8):1306-7), just like an inflammation of the skin in response to an infection after the cut, as discussed in my early post on 11-25-2012. I am afraid if the original causative factor is not identified and got rid of, the “good” cells generated from the stem cells may just react the same way and became “bad” again. Any way, stem cell is a hot area of study, it would be sure people will pursue in this area. More studies and clinical trials will eventually tell.


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## mf15

Xiaofa: This just came out,about an hour ago.
Popular artificial sweetener not so sweet.
As you may have guessed before reading the article, sucralose.
Hopefully this is new work and not the older paper.
Old Mike


http://medicalxpress.com/news/2014-06-popular-artificial-sweetener-sweet.html


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## Xiaofa Qin

mf15 said:


> Xiaofa: This just came out,about an hour ago.
> Popular artificial sweetener not so sweet.
> As you may have guessed before reading the article, sucralose.
> Hopefully this is new work and not the older paper.
> Old Mike
> 
> http://medicalxpress.com/news/2014-06-popular-artificial-sweetener-sweet.html


Thanks Old Mike for sharing the info. I think we should take a more prudent attitude toward the safety of artificial sweeteners and other dietary chemicals. At least, their effect on gut bacteria has never been taken into account when assessing their toxicity. Based on early discussion on the possible link between spicy food and sugar and IBD in China (see post on 02-01-2014), I submitted a paper to Chinese Medical Journal entitled “May artificial sweeteners not sugar be the culprit of dramatic increase of inflammatory bowel disease in China?”, and it has been accepted for publication. 

As for the paper I communicated with you early, now it is published online (Qin X. May bacterial or pancreatic proteases play a critical role in IBD World Journal of Gastroenterology 2014 (in press)). The full article as well as Peer-review Report from the reviewers, etc, can be found there. As stated in the ACKNOWLEGEMENTS section of the paper (just before the references), thank you Old Mike for sharing the original paper with me on this forum. 

Xiaofa


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## mf15

Xiaofa: Thank you again.

This might be another interesting aspect of the western diet which has been overlooked, over eating.
Throughout history humans did not always eat 3 meals a day, really started
in England with industrialization. As you know from the history of IBD,the increase in incidence started also in England.
Fasting may in fact be a necessary control on the immune system,by getting
rid of damaged cells, or even erasing some memory cells that are defective.
Then again are we also over feeding the gut bacteria.

As a tie in with your theory,over eating/excessive amount of food too many times a day, might produce a constant load of pancreatic protease,which may overwhelm our colon anti-protease enzymes.
Perhaps an answer to many of our so called idiopathic diseases.
Old Mike
http://medicalxpress.com/news/2014-06-fasting-triggers-stem-cell-regeneration.html



full text

http://www.cell.com/cell-stem-cell/fulltext/S1934-5909(14)00151-9

Few more thoughts.
I have to imagine in paleo times, there were many years of intermittent fasting throughout a persons life.

Makes you wonder if over eating is perhaps a cause of autoimmune disease.

Then again do we want to generate new high powered immune cells,might not be good,dont know.

I quess will have to start to look at this more,perhaps fasting is normal for humans,and perhaps even necessary.

http://en.wikipedia.org/wiki/Hematopoietic_stem_cell



http://en.wikipedia.org/wiki/Stem_cell_theory_of_aging

Autophagy.
http://www.ncbi.nlm.nih.gov/pubmed/9003009

http://www.ncbi.nlm.nih.gov/pubmed/23295687



autophagy seems to be mostly involved with crohn's at least for a defect in infected cell clearance

but at this point who knows what other defects are in the immune system cells that might be cleared.

http://www.herbalzym.com/2013/02/ul...hagy-and-innate-immunity-in-ibd-pathogenesis/

Another case for fasting. Got to wonder if we eat too much to often. New info.

Also too much fortification/vitamins/antioxidants.



http://medicalxpress.com/news/2014-06-theory-diabetic-complications-therapeutic-approach.html

older paper might even be dangerous if old,unless of course you get new immune cells

http://ajcn.nutrition.org/content/74/5/670.full

some history of breakfast.
http://www.bbc.com/news/magazine-20243692



http://en.wikipedia.org/wiki/History_of_breakfast



animal overeating

http://www.aces.edu/pubs/docs/U/UNP-0089/UNP-0089.pdf



people,perhaps depending on genetics some get overweight some get IBD

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3650896/


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## Xiaofa Qin

Thanks Old Mike for sharing the thoughts and info.


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## Xiaofa Qin

JMC said:


> Being reported on the BBC website today.  I am not sure the connection with "junk food" is helpful or accurate, but good to see this problem getting the attention it deserves.


As described in the paper discussed here and multiple papers published afterwards (Here is the link), I have suspected that sucralose may be the important causative factor for the recent worldwide increase of IBD. I have found evidence for countries like Canada, the US, Australia, Norway, Ireland, Singapore, Saudi, etc. I have wondered for a long time why we did not see an increase in IBD in UK after its approval of sucralose in 2002. Well, here comes the evidence. Now we have another “coincidence”.


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## wildbill_52280

Xiaofa Qin said:


> As described in the paper discussed here and multiple papers published afterwards (Here is the link), I have suspected that sucralose may be the important causative factor for the recent worldwide increase of IBD. I have found evidence for countries like Canada, the US, Australia, Norway, Ireland, Singapore, Saudi, etc. I have wondered for a long time why we did not see an increase in IBD in UK after its approval of sucralose in 2002. Well, here comes the evidence. Now we have another “coincidence”.


check this out, maybe this is the data you need.

http://www.crohnsforum.com/showthread.php?t=64770


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## jjk308

I've never used saccharin or sucralose and have probably had Crohn's since 1970 - but wasn't diagnosed until 1987.   Some family members had it back before WWII, and they certainly didn't use any artificial sweeteners then.

I suspect this is just another dead end, caused mostly by the improved diagnosis and reporting of IBD that coincided with the introduction of artificial sweeteners.  

No doubt any "evidence" is caused by an inevitable biased treatment of the individual data points to support the hypothesis.  Even scientists and physicians are human and can't help but support their pet ideas that they have a lot invested in.


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## wildbill_52280

jjk308 said:


> I've never used saccharin or sucralose and have probably had Crohn's since 1970 - but wasn't diagnosed until 1987.   Some family members had it back before WWII, and they certainly didn't use any artificial sweeteners then.
> 
> I suspect this is just another dead end, caused mostly by the improved diagnosis and reporting of IBD that coincided with the introduction of artificial sweeteners.
> 
> No doubt any "evidence" is caused by an inevitable biased treatment of the individual data points to support the hypothesis.  Even scientists and physicians are human and can't help but support their pet ideas that they have a lot invested in.


Saccharin I think came out in late 1800's, i think i may have been popularized during world war 1, it was also used as a preservative for canning as it was very good at inhibiting the growth of bacteria.These properties make it a good candidate for disturbing the intestinal bacteria, which is now suspected to be the prime cause of IBD, recent success in fecal transplants seem to suggest this is all true. lack of bacterial diversity is likely the prime cause of IBD, regardless of the toxin that is secondary to its disturbance such as antibiotics, saccharin, sucralose, carrageenan etc.


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## Xiaofa Qin

jjk308 said:


> I've never used saccharin or sucralose and have probably had Crohn's since 1970 - but wasn't diagnosed until 1987.   Some family members had it back before WWII, and they certainly didn't use any artificial sweeteners then.


As explicitly described in the paper discussed here (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3332284/pdf/WJG-18-1708.pdf ), saccharin was introduced into the market in 1887, decades before even World War I (WWI). It had been used in thousands of kinds of foods, beverages and other things like tooth pastes. Learn to read more and think more, before claim an assumption as CERTAIN.


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## mf15

Xiaofa: Here you go new study,artifical sweeteners really messing with 
our gut bacteria,they even tested saccharin so you might be thrilled.
I cant get the whole paper but sure someone can.
Also tested with humans.
I don't eat any but still have UC,never the less quite interesting.
Old Mike
http://medicalxpress.com/news/2014-09-artificial-sweeteners-linked-abnormal-glucose.html


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## Xiaofa Qin

Thanks Old Mike for sharing the info. It is indeed a very interesting study. I do not think artificial sweeteners are the sole cause of IBD. However, as for the wide use, I believe they could be one of the major causative factors for the disease. In China, the highest incidence of IBD including both Crohn’s disease and ulcerative colitis occurred in Guangzhou, one of the most southern cities of China, which is totally opposite to the general North-South gradient of IBD. However, Guangzhou is well know for the sweet taste of the dishes. As discussed in the early posts, I suspected that artificial sweeteners might be the possible cause for the high incidence of IBD there. I submitted a paper to Chinese Medical Journal and it is just published (Qin X. May artificial sweeteners not sugar be the culprit of dramatic increase of inflammatory bowel disease in China? Chin Med J (Engl). 2014 Sep;127(17):3196-7).

Recently there was also a paper regarding nationwide study of IBD in Denmark (Nørgård BM, et al. The incidence of ulcerative colitis (1995-2011) and Crohn's disease (1995-2012) - Based on nationwide Danish registry data. J Crohns Colitis. 2014 Mar 24. pii:S1873-9946(14)00103-2. [Epub ahead of print]). Interestingly, if we check it against the studies on incidence of IBD in the same period in the adjacent countries, we can find that pediatric IBD in Sweden shared similar trend of change as the general population IBD in Denmark but not pediatric IBD in Norway (see the figure below): 







Again these peculiar phenomena fit into the pattern of consumption of some artificial sweeteners, but seems difficult to be explained by many current popular hypotheses such as hygiene condition, vitamin D and sunshine (Stockholm shared similar latitude with Oslo but not Denmark), smoking, Mycobacterium avium subspecies paratuberculosis (MAP, which is very low in Sweden but high in Denmark and Norway), worms, etc. I wrote a paper on this and it is just published (Qin X. Why pediatric inflammatory bowel disease (IBD) in Sweden shared similar trend of change as general population IBD in Denmark but not pediatric IBD in Norway? Scand J Gastroenterol. 2014 Oct;49(10):1268-1269). Right now, there are many theories regarding the cause of IBD. I believe each hypothesis would have to be checked constantly against what happened in the real world where lays the clues to differentiate real from tale.


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## mf15

Xiaofa:Just an aside.
I quite smoking 1977 UC 1980.
My wife quit smoking at the same time, no IBD.
She also drinks about a 12 pack of diet pepsi a week,no IBD.
There is of course something else going on as risk factors,such as genetics,MAP infections.

Also this was off my radar, MAP is in fruits and vegetables,which might
confound some of the thinking on MAP in herds and high IBD rates,
versus areas with low MAP in animal herds and high IBD rates.
here is a
LINK
Old Mike


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## Xiaofa Qin

mf15 said:


> Xiaofa:Just an aside.
> I quite smoking 1977 UC 1980.
> My wife quit smoking at the same time, no IBD.
> She also drinks about a 12 pack of diet pepsi a week,no IBD.
> There is of course something else going on as risk factors,such as genetics,MAP infections.
> 
> Also this was off my radar, MAP is in fruits and vegetables,which might
> confound some of the thinking on MAP in herds and high IBD rates,
> versus areas with low MAP in animal herds and high IBD rates.
> here is a
> LINK
> Old Mike


There is definitely reason for the striking increase of IBD since last century. I would be happy to see explanations better than mine.  

However, to my knowledge, large amounts of MAP are only generated by animals with Johne’s disease and shed into the environment through feces. Then MAP will eventually die (although that may take months) but WITHOUT the capability of replication/proliferation in the environment. If these would be the case, MAP on the vegetable or fruit would be more likely just the result of contamination from those animals, making the scenario of low MAP in animal herds (but high MAP in vegetables and fruits) in high IBD areas seems unlikely. Do you have any evidence other than this?


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## mf15

Xiaofa: There is no doubt in my mind that artificial sweeteners disrupt gut bacteria, so therefore they would seem to be a risk factor for IBD.  Yet multiple millions ingest sweeteners and do not have IBD. Of course there are multiple millions that have IBS which might be a mild form of gut disease that has not manifested into IBD. I know you are saying that sweeteners are not the only cause of IBD,and other risk factors must be involved.
At some point the risk factors add up and IBD manifests.

In the case of my wife,she has at least two risk factors for IBD, quitting smoking and ingesting a large amount of artificial sweetners,and she lives with me which may also be a risk factor, yet she has no IBD,or IBS.

I forgot to mention in my other post that we moved into my current house in 
1979,which is a 1/4 mile from a working dairy farm, I drank their milk she did not, my UC came on in 1980.

What I was trying to say in my other post is that importation of MAP contaminated vegetables may somehow confound IBD incidence patterns.
Also MAP has now been found in domestic shower water.

If I remember correctly in about 28% of non IBD people they find MAP in the colons,yet they do not have IBD,so again one possible risk factor is not sufficient to cause IBD.

How do we explain IBD clustering, of course it might be chance but unlikely.
Here is a quote from someone on this forum,from about 2 weeks ago.

"Up until about 2 years ago, I had never heard of Crohn's Disease. Since I've been diagnosed, off the top of my head I know now of 10 people within my workplace who also have it. For a relatively small staff pool, that ratio raises concern for me.

I work within the animal care industry which makes me believe that whilst predisposition to the disease may exist, a form of bacteria may "activate" the disease."


Here is an interesting cluster.
http://www.ncbi.nlm.nih.gov/pubmed/21703899

As we can see here MAP was first discovered in South Korea in 1967.
http://www.ncbi.nlm.nih.gov/pubmed/22749233
By the way I spent the year 1971 in Korea.

From this we learn an low but increasing incidence.
Now I have to suspect there is also increasing consumption of sweeteners.
Have to look for data on this.
http://www.ncbi.nlm.nih.gov/pubmed/17941073

All that being said. MAP may also just be a bystander bacteria,and that
is why it is so difficult to determine what is really going on.

Old Mike


----------



## Xiaofa Qin

Thanks Old Mike for sharing the thought and info. I share the same notion with you that IBS might be just a mild form of gut disease that has not manifested into IBD. As discussed in my early posts, I think even some artificial sweeteners or something else indeed the main culprit of IBD, the relationship between these agents and IBD would be more like those between smoking and lung cancer. Although more than 90% lung cancer attribute to smoking, most smokers did not develop the disease and lung cancer definitely can also be caused by other factors like radon. Yes, there are many factors that may have participated in the eventual manifestation of the disease in a certain individual. However, there may be still some primary cause(s) and shared root mechanism we may need to find out for the effective treatment and prevention of the disease. For instance, although I also believe gut bacteria played a critical for the sustained inflammation of gut in IBD patients. However, in my opinion, the increased infiltration of gut bacteria and their debris may be just the consequence secondary to the impaired inactivation of digestive proteases and the resultant damage of gut barrier due to reduction of some kinds of gut bacteria. Therefore, I believe giving back certain kinds of bacteria capable of doing so (probably one or two strains might be enough, which would be much better than the poorly defined cumbersome FMT from randomly selected donors) such as same strains of probiotics would be a simple and potentially highly effective approach. This is in contrast to the notion that this disease is caused primarily by uncontrolled infection by some pathogens and thus a cure can only be achieved by eliminating the bacteria via agents like high doses of combined antibiotics, which may result in further reduction in gut bacteria and, if my notion would be true, exacerbate the disease. So, finding the cause of IBD would be an important issue. However, it seems still a long way to go. 


As for MAP, I deeply respected the great endeavor of some researchers in this area and the high enthusiasm of the patients. However, I personally feel there are still many questions we may have to face for the asserted causal relationship. For instance, you mentioned the finding of MAP in domestic shower water in recent reports, which had caused panic in some people. That study is done by quantitative PCR (http://www.mdpi.com/2076-0817/3/3/577) that detects a tiny piece of DNA, not the living bacteria. Even what they found is indeed livable MAP, the treatment of the open water by filtration and chlorination at water plants would have greatly reduced the amount of MAP.  However, multiple studies had well documented long time ago that people with tap water had increased risk of IBD than those drinking raw water where the amount of MAP would be likely even much higher, indicating there seems actually a negative correlation between the amount of MAP in drinking water and the risk of IBD. It was also claimed that MAP may get into the aerosols that may be associated with the clustered cases of CD along the river adjacent to some farms or increased incidence of CD at the downwind side of the river. However, on the other hand, it is also documented that Johne’s disease in a farm can be even eliminated by just designating the newly born MAP-negative and positive calves into separated pens (http://www.johnes.org/dairy/control.html), indicating not only the aerosols but even the potentially heavily contaminated dusts, grass, leaves, etc, floating over the farm are not enough to cause the real infection of MAP to the healthy but highly susceptible calves in the adjacent pen. How come people can so easily catch the disease, even by the trace amount of MAP in the aerosol generated from the water of river far away from the farm? Usually increased susceptibility is accompanied with augmented proliferation of the pathogen. However, MAP in patients is barely detectable, not because the method is not available, rather because the amount is too little. We have no problem to detect many kinds of virus that are much smaller than bacteria. Now we can see atoms through a microscope. How come it turns out to be so difficult to detect the bacteria that caused such massive damage of the gut as seen in CD patients? There are multiple well-established methods to identify MAP infected animal in herds. Large amounts of MAP can be found in the tissue or feces of animal with Johne’s disease and the disease can be easily transmitted from one animal to another and from the mother to the calve. However, CD is still regarded as noncontagious among people or mother to the babe. Apparently, there are actually some fundamental differences between Johne’s disease and CD we may have to face. It has also been claimed that more than 90% of Crohn’s disease may attribute to MAP. As we know, places such as Sweden and Western Australia have very low MAP contamination but high rates of CD. As shown in the figure in the early post above, Sweden has pediatric IBD even higher than the adjacent Norway, indicating also a negative correlation between the incidence of IBD and prevalence of MAP that seems difficult to be explained by importation of vegetables, fruits, etc, from the adjacent MAP contaminated areas. In facing these conflicting “facts”, we may have to take into account all the evidences to make a sagacious judgment. Hopefully, those ongoing clinical trials would provide us with more valuable information. The possible link between some artificial sweeteners and IBD is also just a hypothesis. As constantly advocated during the more than a decade, I hope those capable checking out this possibility. Despite the long effort, it still failed to raise any action. This made me strongly feel that IBD remains a mystery not because the disease and the cause is too complicated, rather too little efforts was spent on the right approach. Therefore, it may still take some time to determine the cause of IBD, but we will eventually reach the goal.


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## Xiaofa Qin

Here is a new study showing that little effect of vitamin D on colitis in IL-10 deficient mice (Glenn AJ, et al. Long-Term Vitamin D3 Supplementation Does Not Prevent Colonic Inflammation or Modulate Bone Health in IL-10 Knockout Mice at Young Adulthood. Nutrients. 2014 Sep 22;6(9):3847-3862), suggesting minimal role of vitamin D/sunshine in IBD. This is in striking contrast with the recently envisioned critical role of vitamin D in the disease. Evidence for both sides would be definitely accumulating and it just served as another example of controversy that may again last incessantly.  So, many of the current medical research is not bring a solution to the problem rather generating a lot of conflicting “facts”.


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## Lady Organic

thx, I ve never really believed vitamine D played a role in triggering IBD. I dont think southern USA states (very sunny and hot) have lower prevalence of IBD, and mostly the prevalence of IBD in developping countries such as India, China and arabic countries is dramatically increasing since a decade; countries where sweets, transformed and processed food sold in groceries are gainning popularity over home cooked meals with all natural ingredients. Countries and cities where access to groceries is limited have lower prevalence of IBD.


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## Xiaofa Qin

Yes, the recent striking increase of IBD in many countries over the world seems unlikely to be explained by sunshine/vitamin D.  Interestingly, there are multiple recent reports on decrease in the incidence of IBD including both Crohn’s disease and ulcerative colitis in Canada (Leddin D, et al. Decreasing incidence of inflammatory bowel disease in Eastern Canada: a population database study. BMC Gastroenterol. 2014 Aug 9;14:140   AND   Bitton A, et al. Epidemiology of inflammatory bowel disease in Québec: recent trends. Inflamm Bowel Dis. 2014 Oct;20(10):1770-6), suggesting this disease would be indeed preventable once we find out what caused it.


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## xeridea

Xiaofa Qin, your mention the reduced incidence of CD/UC is preventable once we know what caused it, which goes without saying. And you point to this study as evidence. Yet I cannot believe that the Canadians have figured out how to reduce the incidence rate and are holding out on the rest of the world. Will you please expand on your reasoning regarding this?


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## Lady Organic

Thanks a lot Xiaofa.

thats quite interesting... these two research go really against what I had thought! One fact that has not been mentionned in the discussions of both papers, and that couls also account for this decrease is that the waiting list to see a GI is extremly long here in Québec. Not sure about Nova Scotia, but Im guessing it would be the same. A patient with mild to moderate symptoms of possible CD can wait for longer than 6 months to meet a GI. Gi's have been super loaded having to screen and scope colo-rectal cancer which had been largely pushed and advertized in general 50+ population for prevention in the last decade. THe trend has just shut down now, and since a year, its litteraly impossible for a healthy patient without risk factors to be screened at public hospital endoscopy. I put my father on a waiting list 2 years ago upon recommendation of my GI and finally, the hospital cancelled his demand, telling him, the rules have changed. I guess they realized GIs were overwhelmed and needed more time for the really sick people and no more for general prevention...

So do these patients on long waiting lists seek alternative treatments? with naturopaths, natural remedies, diets, etc? have they been lost? The system is overwhelmed here, its a possibility. Im wondering. it will be interesting to see additional epidemiologic research after this recent stop in universal coloscopy colorectal-cancer screening. Maybe Im off target and wrong, but thats what crossed my mind when I tried to explain why there would be a decrease in incidence of reported IBD. Yet, Im truly hoping Im wrong, and that there is a real decrease in population. future will tell. thanks again for your participation in the forum.


----------



## Xiaofa Qin

xeridea said:


> Xiaofa Qin, your mention the reduced incidence of CD/UC is preventable once we know what caused it, which goes without saying. And you point to this study as evidence. Yet I cannot believe that the Canadians have figured out how to reduce the incidence rate and are holding out on the rest of the world. Will you please expand on your reasoning regarding this?


I am not implying some people have figured out the cause of the disease and held it out. Rather I am suggesting the need to put more efforts to find out the cause of the disease. 



Lady Organic said:


> Thanks a lot Xiaofa.
> 
> thats quite interesting... these two research go really against what I had thought! One fact that has not been mentionned in the discussions of both papers, and that couls also account for this decrease is that the waiting list to see a GI is extremly long here in Québec. Not sure about Nova Scotia, but Im guessing it would be the same. A patient with mild to moderate symptoms of possible CD can wait for longer than 6 months to meet a GI. Gi's have been super loaded having to screen and scope colo-rectal cancer which had been largely pushed and advertized in general 50+ population for prevention in the last decade. THe trend has just shut down now, and since a year, its litteraly impossible for a healthy patient without risk factors to be screened at public hospital endoscopy. I put my father on a waiting list 2 years ago upon recommendation of my GI and finally, the hospital cancelled his demand, telling him, the rules have changed. I guess they realized GIs were overwhelmed and needed more time for the really sick people and no more for general prevention...
> 
> So do these patients on long waiting lists seek alternative treatments? with naturopaths, natural remedies, diets, etc? have they been lost? The system is overwhelmed here, its a possibility. Im wondering. it will be interesting to see additional epidemiologic research after this recent stop in universal coloscopy colorectal-cancer screening. Maybe Im off target and wrong, but thats what crossed my mind when I tried to explain why there would be a decrease in incidence of reported IBD. Yet, Im truly hoping Im wrong, and that there is a real decrease in population. future will tell. thanks again for your participation in the forum.


Thanks for sharing the thoughts. As a chronic disease without a cure, I do not think workload of GI may result in missed diagnose of IBD over a decade that attributed to the reported decline of IBD in Canada. As shown in the Figure in the paper discussed here, a decline or plateau in incidence of IBD had also been observed during later 1970s and early 1980s in multiple studies from many countries such as Canada, the United States, Demark, Germany, Japan, Israel, Sweden, and United Kingdom, but those declines were followed by striking increase again in IBD in these countries and all over the world afterwards. These multiple ups and downs of IBD seems more likely caused by dynamically changed exposure to some agents in the environment. Therefore, I advocate sparing more efforts to find out these environmental causative factors that may be critical not only for the cure but also effective prevention of the disease.


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## Xiaofa Qin

A large scale multi-countries prospective epidemiological study just comes out (Chan SS, et al. Carbohydrate Intake in the Etiology of Crohn's Disease and Ulcerative Colitis. Inflamm Bowel Dis. 2014 Sep 26. [Epub ahead of print] ), showing no association between the intakes of carbohydrates, sugar, starch, and inflammatory bowel disease (IBD) including both Crohn's disease (CD) or ulcerative colitis (UC). Again, this would be another strong controversy with the claimed critical role of carbohydrate (sugar, starch, etc) in IBD and the asserted miracle efficacy of some special carbohydrate diet (SCD) on the disease. 

**************************************************

*Inflamm Bowel Dis.* 2014 Sep 26. [Epub ahead of print]

*Carbohydrate Intake in the Etiology of Crohn's Disease and Ulcerative Colitis.*

Chan SS1, Luben R, van Schaik F, Oldenburg B, Bueno-de-Mesquita HB, Hallmans G, Karling P, Lindgren S, Grip O, Key T, Crowe FL, Bergmann MM, Overvad K, Palli D, Masala G, Khaw KT, Racine A, Carbonnel F, Boutron-Ruault MC, Olsen A, Tjonneland A, Kaaks R, Tumino R, Trichopoulou A, Hart AR.

Author information 
1Norwich Medical School, Department of Medicine, University of East Anglia, Norwich, United Kingdom; 2Department of Gastroenterology, Norfolk and Norwich University Hospital NHS Trust, Norwich, United Kingdom; 3Strangeways Research Laboratory, Institute of Public Health, University of Cambridge, United Kingdom; 4University Medical Center Utrecht, Department of Gastroenterology and Hepatology, Utrecht, the Netherlands; 5National Institute of Public Health and the Environment (RIVM), Bilthoven, the Netherlands; 6Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, United Kingdom; 7Department of Public Health and Clinical Medicine, Nutritional Research, Umeå University, Umeå, Sweden; 8Department of Public Health and Clinical Medicine, GI Unit, Umeå University, Umeå, Sweden; 9Department of Clinical Sciences, University Hospital, Malmö, Sweden; 10Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom; 11Department of Epidemiology, German Institute of Human Nutrition, Potsdam, Germany; 12Department of Clinical Epidemiology, University of Aarhus, Denmark; 13Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Centre, Florence, Italy; 14INSERM, Centre for Research in Epidemiology and Population Health, Institut Gustave Roussy, Paris, France; 15Université Paris Sud, UMRS 1018, Paris, France; 16Department of Gastroenterology, Bicêtre University Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France; 17Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark; 18Division of Clinical Epidemiology, DKFZ-German Cancer Research Centre, Heidelberg, Germany; 19Cancer Registry and Histopathology Unit, "Civic - M.P.Arezzo" Hospital, Ragusa, Italy; 20WHO Collaborating Center for Food and Nutrition Policies, Athens, Greece.

*Abstract*

*BACKGROUND:*
Diet may have a role in the etiology of inflammatory bowel disease. In previous studies, the associations between increased intakes of carbohydrates, sugar, starch, and inflammatory bowel disease are inconsistent. However, few prospective studies have investigated the associations between these macronutrients and incident Crohn's disease (CD) or ulcerative colitis (UC).

*METHODS:*
A total of 401,326 men and women were recruited between 1991 and 1998. At recruitment, dietary intakes of carbohydrate, sugar, and starch were measured using validated food frequency questionnaires. The cohort was monitored identifying participants who developed incident CD or UC. Cases were matched with 4 controls, and odds ratios were calculated for quintiles of total carbohydrate, sugar, and starch intakes adjusted for total energy intake, body mass index, and smoking.

*RESULTS:*
One hundred ten participants developed CD, and 244 participants developed UC during follow-up. The adjusted odds ratio for the highest versus the lowest quintiles of total carbohydrate intake for CD was 0.87, 95% CI = 0.24 to 3.12 and for UC 1.46, 95% CI = 0.62 to 3.46, with no significant trends across quintiles for either (CD, Ptrend = 0.70; UC, Ptrend = 0.41). Similarly, no associations were observed with intakes of total sugar (CD, Ptrend = 0.50; UC, Ptrend = 0.71) or starch (CD, Ptrend = 0.69; UC, Ptrend = 0.17).

*CONCLUSIONS:*
The lack of associations with these nutrients is in agreement with many case-control studies that have not identified associations with CD or UC. As there is biological plausibility for how specific carbohydrates could have an etiological role in inflammatory bowel disease, future epidemiological work should assess individual carbohydrates, although there does not seem to be a macronutrient effect.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.


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## mf15

Read these two again.

http://www.ncbi.nlm.nih.gov/pubmed/8358131
http://www.ncbi.nlm.nih.gov/pubmed/17551835



It now occurs to me that if UC people can be put into remission just with the camostat or BBI,there are implications.

Excess protease can come from digestive enzymes that are not deactivated, bacteria, and immune cells.

The proteases are dissolving the mucus and I guess any part of the colon they can contact,UC people also have excess

proteases in stools.



Implications:

By inhibiting protease/keeping the mucus intact you can go into remission, regardless if UC is autoimmune,or biofilms or bacteria are driving the inflammation.




We have an, alpha 1-proteinase inhibitor system which can become overwhelmed and allow protease to attack the mucus and tissue.


This is a way to perhaps accomplish the same thing without taking protease inhibitors.

http://www.ncbi.nlm.nih.gov/pubmed/2833080


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## Xiaofa Qin

Microb Cell Fact. 2015 Feb 26;14(1):26. doi: 10.1186/s12934-015-0198-4.

*Serine protease inhibitors protect better than IL-10 and TGF-β anti-inflammatory cytokines against mouse colitis when delivered by recombinant lactococci.*

Bermúdez-Humarán LG1,2, Motta JP3,4,5,6, Aubry C7,8, Kharrat P9,10, Rous-Martin L11,12,13, Sallenave JM14,15,16, Deraison C17,18,19, Vergnolle N20,21,22,23, Langella P24,25.

Abstract

BACKGROUND: Different studies have described the successful use of recombinant lactic acid bacteria (recLAB) to deliver anti-inflammatory molecules at the mucosal level to treat Inflammatory Bowel Disease (IBD).

METHODS: In order to identify the best strategy to treat IBD using recLAB, we compared the efficacy of different recombinant strains of Lactococcus lactis (the model LAB) secreting two types of anti-inflammatory molecules: cytokines (IL-10 and TGF-β1) and serine protease inhibitors (Elafin and Secretory Leukocyte Protease Inhibitor: SLPI), using a dextran sulfate sodium (DSS)-induced mouse model of colitis.

RESULTS: Our results show that oral administration of recombinant L. lactis strains expressing either IL-10 or TGF-β1 display moderate anti-inflammatory effects in inflamed mice and only for some clinical parameters. In contrast, delivery of either serine protease inhibitors Elafin or SLPI by recLAB led to a significant reduction of intestinal inflammation for all clinical parameters tested. Since the best results were obtained with Elafin-producing L. lactis strain, we then tried to enhance Elafin expression and hence its delivery rate by producing it in a L. lactis mutant strain inactivated in its major housekeeping protease, HtrA. Strikingly, a higher reduction of intestinal inflammation in DSS-treated mice was observed with the Elafin-overproducing htrA strain suggesting a dose-dependent Elafin effect.

CONCLUSIONS: Altogether, these results strongly suggest that serine protease inhibitors are the most efficient anti-inflammatory molecules to be delivered by recLAB at the mucosal level for IBD treatment.


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## wildbill_52280

This might be related I'm not sure.

PLoS One. 2012;7(11):e49547. doi: 10.1371/journal.pone.0049547. Epub 2012 Nov 14.
*A low dose of fermented soy germ alleviates gut barrier injury, hyperalgesia and faecal protease activity in a rat model of inflammatory bowel disease.*


Abstract
Pro-inflammatory cytokines like macrophage migration inhibitory factor (MIF), IL-1β and TNF-α predominate in inflammatory bowel diseases (IBD) and TNBS colitis. Increased levels of serine proteases activating protease-activated receptor 2 (PAR-2) are found in the lumen and colonic tissue of IBD patients. PAR-2 activity and pro-inflammatory cytokines impair epithelial barrier, facilitating the uptake of luminal aggressors that perpetuate inflammation and visceral pain. Soy extracts contain phytoestrogens (isoflavones) and serine protease inhibitors namely Bowman-Birk Inhibitors (BBI). Since estrogens exhibit anti-inflammatory and epithelial barrier enhancing properties, and that a BBI concentrate improves ulcerative colitis, we aimed to evaluate if a fermented soy germ extract (FSG) with standardized isoflavone profile and stable BBI content exert cumulative or synergistic protection based on protease inhibition and estrogen receptor (ER)-ligand activity in colitic rats. Female rats received orally for 15 d either vehicle or FSG with or without an ER antagonist ICI 182.780 before TNBS intracolonic instillation. Macroscopic and microscopic damages, myeloperoxidase activity, cytokine levels, intestinal paracellular permeability, visceral sensitivity, faecal proteolytic activity and PAR-2 expression were assessed 24 h, 3 d and 5 d post-TNBS. FSG treatment improved the severity of colitis, by decreasing the TNBS-induced rise in gut permeability, visceral sensitivity, faecal proteolytic activity and PAR-2 expression at all post-TNBS points. All FSG effects were reversed by the ICI 182.780 except the decrease in faecal proteolytic activity and PAR-2 expression. 

In conclusion, the anti-inflammatory properties of FSG treatment result from two distinct but synergic pathways i.e an ER-ligand and a PAR-2 mediated pathway, providing rationale for potential use as adjuvant therapy in IBD.


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## Xiaofa Qin

*Immunol Lett. 2015 Mar 28. pii: S0165-2478(15)00048-6. doi: 10.1016/j.imlet.2015.03.007. PMID:25827759*

*Can inflammatory bowel disease really be solved by the multiple -omics and meta-omics analyses?*

Xiaofa Qin, M.D., Ph.D
Founder/President
GI Biopharma Inc
New Jersey
USA

I read with great interest the paper by Huang et al. [1] regarding the multi -omics analysis of inflammatory bowel disease (IBD). This paper as well as multiple others on this topic [2–4] represented the current mainstream notion that IBD is extremely complex that can only be elucidated through extensive research by sophisticated methods such as the multi -omics (genomics, transcriptomics, proteomics, metabolomics, etc.) and meta-omics analyses of the host and microbiota, to which I have a totally different perception. 

In fact, at about the same time when the first risk gene of IBD was found more than a decade ago [5,6], I had found evidence suggesting a possible simple cause and mechanism of IBD – impaired inactivation of digestive proteases mediated by deconjugated bilirubin as the result of inhibition of gut bacteria by dietary chemicals such as saccharin [7]. It provided simple explanations for many puzzles in IBD such as the emerging of clustered cases of IBD around the beginning of last century, the dramatic increase of IBD in the western countries since 1950s, and the leveling off or decrease of IBD as observed in multiple studies during later 1970s and early 1980s at the time when saccharin was found capable of causing cancer in animals. Later, I further found evidence suggesting sucralose, a new generation of artificial sweetener that was first approved in Canada in 1991 followed by many other countries, may also linked to IBD through a similar mechanism as saccharin, which may have contributed to the recent worldwide increase of IBD [8,9]. This led me eventually coming up with a unified hypothesis on the etiology of IBD, including the cause and mechanism of IBD as well as the relationship between ulcerative colitis (UC) and Crohn’s disease(CD) [10]. It provided further explanations for the many puzzles in IBD such as the mysterious remarkable increase of IBD in Alberta of Canada since early 1990s, in Brisbane of Australia since middle 1990s, in north California of the United these since the end of 1990s, and in South-Eastern Norway since middle 2000s, shortly after the approval of sucralose in Canada in 1991, in Australia in 1993, in the United States in 1998, and by the European Union in 2004, as well as the especially remarkable recent increase of IBD in children, the shift in the occurrence from UC to CD over time, the increased appearance of CD in the colon, etc. [10,11]. This possible link was further demonstrated by multiple more epidemiological studies published thereafter from countries across the world such as the United States [12], Canada [13], Ireland [14], Sweden [15],Singapore [16], Saudi Arabia [17], China [18], etc. [19]. More importantly, some peculiar changes in IBD such as the recent decrease in CD but increase in UC in the children in Sweden [15] as well as the shared trend of change of pediatric IBD in Sweden with the general population IBD in Denmark but not pediatric IBD in Norway[20], and even higher incidence of IBD in Guangzhou, China than the adjacent more developed Hong Kong and Macau [19] can also be easily explained by the unified hypothesis through the pattern of consumption of those dietary chemicals.

Thus, the statement in the paper [1] that much of the etiology of IBD remained unexplained seems not accurate. There were indeed simple explanations on the etiology of IBD as shown in the series publications listed above, but all these evidences are just ignored or neglected, intentionally or unintentionally, by the authors of the paper as well as the general society. This is not surprising, as all the evidence presented in my publications was collected by me as an amateur IBD researcher during my spare time from the literature, while the ultimate finding of the nearly 200 risk IBD genes were the result of decade long multiple millions, if not billions, effort of elite IBD professionals all over the world accompanied by series publications in most prestigious scientific journals like Nature [5,6,21–32]. However, time again, the truth usually comes out from theories with the best explanation of the real world rather than those favored by fashion and power. Finding of the 200 risk genes have time and again celebrated as great achievements, but none of these genes, alone or in combinations, can really explain what happened in the real world. This failure may have just reflected the fact that some agents in the environment but not the gene have played a predominant role in the development of IBD, as demonstrated by the fact that IBD emerged and dramatically increased just for about a century.

Although it failed to explain what happened in the real world, this tremendous effort indeed made the significant finding of the considerable overlap among these nearly 200 risk genes between susceptibility loci for IBD and mycobacterial infection with pathways shared between host responses to mycobacteria and those predisposing to IBD [21], thus proposed the direction for further research. However, this notion that IBD is caused by an infection would be strongly contradicted by those facts such as the effective treatment of IBD by immune suppressors and anti-TNF-alpha agents [33]. As demonstrated above, the dietary chemicals theory seems also explained more puzzles of IBD than any pathogens can and is supported by the most recent publications in Nature showing saccharin and other dietary chemicals can increase the risk of colitis, diabetes, and even obesity by altering gut microbiota [34,35]. The links between NOD2 and autophagy-related genes and IBD may just reflected the increased infiltration of gut bacteria and their debris secondary of the increased gut permeability as the result of damage of gut barrier by the poorly inactivated digestive proteases,  rather than uncontrolled infection of pathogens in the mucosa [36]. 

Thus, we should realize that many of the changes revealed by -omics and meta-omics would be just consequence rather than the cause of the disease, while the crucial primary event may be subtle, transient and yet simple. A superficial explanation of data could be misleading or even detrimental for an easy solution of the disease. In my opinion, we should track down the root toward the primary cause of disease rather than just explore up and likely get lost among the small branches and leaves. Therefore, as suggested years ago [37,38] I advocate here again sparing a little bit more efforts finding out the possible causative factors in the environment. Only then we may found the root mechanism, a cure and ultimate prevention of IBD.

*References*

[1] H. Huang, P. Vangay, C.E. McKinlay, D. Knights, Multi-omics analysis of inflammatory bowel disease, Immunol. Lett. 162 (2014) 62–68.

[2] C. Fiocchi, Integrating omics: the future of IBD? Dig. Dis. 32 (Suppl. 1) (2014)96–102.

[3] Y. Yau, R.W. Leong, M. Zeng, V.C. Wasinger, Proteomics and metabolomics in inflammatory bowel disease, J. Gastroenterol. Hepatol. 28 (2013) 1076–1086.

[4] A.R. Erickson, B.L. Cantarel, R. Lamendella, Y. Darzi, E.F. Mongodin, C. Pan, et al.,Integrated metagenomics/metaproteomics reveals human host-microbiota signatures of Crohn’s disease, PLoS ONE 7 (2012) e49138.

[5] J.P. Hugot, M. Chamaillard, H. Zouali, S. Lesage, J.P. Cezard, J. Belaiche, et al.,Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease, Nature 411 (2001) 599–603.

[6] Y. Ogura, D.K. Bonen, N. Inohara, D.L. Nicolae, F.F. Chen, R. Ramos, et al., Aframeshift mutation in NOD2 associated with susceptibility to Crohn’s disease, Nature 411 (2001) 603–606.

[7] X.F. Qin, Impaired inactivation of digestive proteases by deconjugated bilirubin:the possible mechanism for inflammatory bowel disease, Med. Hypotheses 59(2002) 159–163.

[8] X. Qin, What made Canada become a country with the highest incidence of inflammatory bowel disease: could sucralose be the culprit? Can. J. Gastroenterol. 25 (2011) 511.

[9] X. Qin, What caused the recent worldwide increase of inflammatory bowel disease: should sucralose be added as a suspect? Inflamm. Bowel Dis. 17 (2011)E139.

[10] X. Qin, Etiology of inflammatory bowel disease: a unified hypothesis, World J. Gastroenterol. 18 (2012) 1708–1722.

[11] X. Qin, Food additives: possible cause for recent remarkable increase of inflammatory bowel disease in children, J. Pediatr. Gastroenterol. Nutr. 54 (2012)564.

[12] X. Qin, When and how was the new round of increase in inflammatory bowel disease in the United States started? J. Clin. Gastroenterol. 48 (2014) 564–565.

[13] X. Qin, How to explain recent multiple reports on the decline of inflammatory bowel disease in Canada, Can. J. Gastroenterol. Hepatol. 28 (2014) 620.

[14] X. Qin, The possible cause for the rapid rise in incidence of Irish paediatric inflammatory bowel disease. Response to: Hope B, et al. Rapid rise in incidence of Irish paediatric inflammatory bowel disease, Arch. Dis. Child 97 (7) (2012)590–594.

[15] X. Qin, How to explain the discordant change of ulcerative colitis and Crohn disease in adjacent or even the same regions and time periods, J. Pediatr. Gastroenterol. Nutr. 57 (2013) e30.

[16] X. Qin, Comment on: paediatric inflammatory bowel disease in a multiracial Asian country, Singap. Med. J. 54 (2013) 716.

[17] X. Qin, What might be the cause for the emerging inflammatory bowel disease in Saudi outpatients? Saudi J. Gastroenterol. 20 (2014) 75.

[18] X. Qin, May artificial sweeteners not sugar be the culprit of dramatic increase of inflammatory bowel disease in China? Chin. Med. J. 127 (2014) 3196–3197.

[19] X. Qin, Is the gap between the developed and developing countries in the incidence of inflammatory bowel disease disappearing? Gastroenterology 145(2013) 912.

[20] X. Qin, Why pediatric inflammatory bowel disease (IBD) in Sweden shared similar trend of change as general population IBD in Denmark but not pediatric IBD in Norway? Scand. J. Gastroenterol. 49 (2014) 1268–1269.

[21] L. Jostins, S. Ripke, R.K. Weersma, R.H. Duerr, D.P. McGovern, K.Y. Hui, et al.,Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease, Nature 491 (2012) 119–124.

[22] K. Cadwell, J.Y. Liu, S.L. Brown, H. Miyoshi, J. Loh, J.K. Lennerz, et al., A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells, Nature 456 (2008) 259–263.

[23] Wellcome Trust Case Control Consortium, Genome-wide association study of14,000 cases of seven common diseases and 3,000 shared controls, Nature 447(2007) 661–678.

[24] Z. Liu, J. Lee, S. Krummey, W. Lu, H. Cai, M.J. Lenardo, The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease, Nat. Immunol. 12 (2011) 1063–1070.

[25] M.A. Rivas, M. Beaudoin, A. Gardet, C. Stevens, Y. Sharma, C.K. Zhang, et al., Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease, Nat. Genet. 43 (2011) 1066–1073.

[26] C.A. Anderson, G. Boucher, C.W. Lees, A. Franke, M. D’Amato, K.D. Taylor, et al.,Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47, Nat. Genet. 43 (2011) 246–252.

[27] Y. Momozawa, M. Mni, K. Nakamura, W. Coppieters, S. Almer, L. Amininejad,et al., Resequencing of positional candidates identifies low frequency IL23Rcoding variants protecting against inflammatory bowel disease, Nat. Genet. 43(2011) 43–47.

[28] K. Asano, T. Matsushita, J. Umeno, N. Hosono, A. Takahashi, T. Kawaguchi, et al.,A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population, Nat. Genet. 41 (2009) 1325–1329.

[29] S. Kugathasan, R.N. Baldassano, J.P. Bradfield, P.M. Sleiman, M. Imielinski, S.L.Guthery, et al., Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease, Nat. Genet. 40 (2008) 1211–1215.

[30] S.A. Fisher, M. Tremelling, C.A. Anderson, R. Gwilliam, S. Bumpstead, N.J.Prescott, et al., Genetic determinants of ulcerative colitis include the ECM1locus and five loci implicated in Crohn’s disease, Nat. Genet. 40 (2008) 710–712.

[31] M. Stoll, B. Corneliussen, C.M. Costello, G.H. Waetzig, B. Mellgard, W.A. Koch,et al., Genetic variation in DLG5 is associated with inflammatory bowel disease,Nat. Genet. 36 (2004) 476–480.

[32] V.D. Peltekova, R.F. Wintle, L.A. Rubin, C.I. Amos, Q. Huang, X. Gu, et al., Functional variants of OCTN cation transporter genes are associated with Crohn disease, Nat. Genet. 36 (2004) 471–475.

[33] X. Qin, Does the association with NOD2, autophagy and some pathogens really mean Crohn’s disease is caused by uncontrolled infection? J. Crohn’s Colitis 8(2014) 87.

[34] J. Suez, T. Korem, D. Zeevi, G. Zilberman-Schapira, C.A. Thaiss, O. Maza, et al.,Artificial sweeteners induce glucose intolerance by altering the gut microbiota,Nature 514 (2014) 181–186.

[35] B. Chassaing, O. Koren, J.K. Goodrich, A.C. Poole, S. Srinivasan, R.E. Ley, et al.,Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome, Nature 519 (2015) 92–96.

[36] X. Qin, How NOD2 and autophagy may be related to Crohn’s disease? A view shifted from live microbes to luminal bacterial debris, J. Crohn’s Colitis 8 (2013) 88.

[37] X. Qin, How can we really reduce the morbidity of inflammatory bowel disease – research on genes and cytokines, or find out the causative factors in the environment? J. Crohn’s Colitis 3 (2009) 315.

[38] X. Qin, With the great complexity unveiling, can we still decipher the interaction between gut flora and the host in inflammatory bowel disease to find out the mechanism and cause? How? Inflamm. Bowel Dis. 14 (2008) 1607–1608.


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## InstantCoffee

This has been an interesting read. Sucralose has been a known trigger food for me for over a year. 

Ingesting it in small amounts produces some noticeable bad effects including diarrhea. I can't remember what else, it's been a long time.

Old Mike mentioned intermittent fasting which is interesting. I think if overeating was the problem you would see larger incidence of IBD and much lower of obesity.

However intermittent fasting has shown great results in my Crohn's when I experimented with it.

We know that fasting stimulates apoptosis. It also stimulates production of seratonin in the gut as well as catecholamines. Maintaining proper neurotransmitter balance between seratonin and dopamine has been shown to be an effective therapeutic treatment for Crohn's in some trials. 

In a fast we also see Bacteroidetes becoming the dominant gut bacteria as the others starve (including harmful pathogenic bacteria). Bacteroidetes feeds on the intestinal mucins and creates butyric acid which helps heal the gut, however I would fear losing the diversity of other probiotic species like the clostridia groups might encourage more loss of food tolerances. 

Ultimately I think this all goes back to gut bacteria.


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## Xiaofa Qin

Regarding the decreased risk of inflammatory bowel disease (IBD) with increased intake of milk that was published recently on Inflammatory Bowel Disease (Opstelten JL, Leenders M, Dik VK, et al. Dairy Products, Dietary Calcium, and Risk of Inflammatory Bowel Disease: Results From a European Prospective Cohort Investigation. Inflammatory bowel diseases 2016;22:1403-1411. http://www.ncbi.nlm.nih.gov/pubmed/27120568 ), I wrote a letter to the editors entitled” Increased milk consumption but decreased risk of Crohn’s disease (CD): Critical evidence negated causative role of Mycobacterium avium subspecies paratuberculosis (MAP) in CD”, which was recently published online (http://www.ncbi.nlm.nih.gov/pubmed/27542142 ). Below is the text of the paper:

*Increased milk consumption but decreased risk of Crohn’s disease (CD): Critical evidence negated causative role of Mycobacterium avium subspecies paratuberculosis (MAP) in CD*

_To the Editors:_
          I read with great interest the paper by Opstelten et al published recently in this journal regarding the intake of dairy products and the risk of inflammatory bowel disease (IBD) [1]. This a large scale prospective cohort epidemiological study by scientists and doctors of countries across Europe and beyond such as the Netherlands, United Kingdom, Sweden, Germany, Denmark, Italy, France, Greece, and Malaysia, reflected the great efforts and high quality of the study. It is found that, compared with nonconsumers, individuals consuming milk had significantly reduced odds of Crohn’s disease (CD) (OR 0.30, 95% CI, 0.13–0.65) and nonsignificantly reduced odds of ulcerative colitis (UC) (OR 0.85, 95% CI, 0.49–1.47), with a conclusion that milk consumption may be associated with decreased risk of developing CD. I think an important aspect the paper failed to address is the century long Mycobacterium avium subsp. paratuberculosis (MAP) and CD controversy. Up to date, there are still deep believers that MAP is the causative factor for CD and even beyond, attributing the increase of these diseases to the widespread of hardly killed MAP through milk [2-4]. Apparently, this is an issue worthwhile to address as it not only affected the diary, herds, and food industry but also showed a tendency of escalation of the MAP panic in the general public from CD to many other diseases. With the evidence I collected during the last fifteen years, I proposed that the impaired inactivation of digestive proteases as the result of reduction in gut bacteria in modern society rather than any pathogens may have played a primary causative role in IBD, as discussed in detail in the paper with a unified hypothesis on the etiology of IBD [5].  The result of the current paper by Opstelten et al provided another critical piece of evidence negate the causative role of MAP in CD. Hope these results may bring in more stringent studies to end the century long MAP/CD controversy and find out the real cause of IBD. 

Xiaofa Qin, MD, PhD
GI Biopharam Inc.
Westfield, New Jersey

 
REFERENCES
1. Opstelten JL, Leenders M, Dik VK, et al. Dairy Products, Dietary Calcium, and Risk of Inflammatory Bowel Disease: Results From a European Prospective Cohort Investigation. Inflammatory bowel diseases 2016;22:1403-1411
2. Davis WC. On deaf ears, Mycobacterium avium paratuberculosis in pathogenesis Crohn's and other diseases. World J Gastroenterol 2015; 21(48): 13411-7.
3. Sechi LA, Dow CT. Mycobacterium avium ss. paratuberculosis Zoonosis - The Hundred Year War - Beyond Crohn's Disease. Front Immunol 2015; 6: 96.
4. Waddell LA, Rajic A, Stark KD, Mc ES. The zoonotic potential of Mycobacterium avium ssp. paratuberculosis: a systematic review and meta-analyses of the evidence. Epidemiol Infect 2015; 143(15): 3135-57.
5. Qin X. Etiology of inflammatory bowel disease: a unified hypothesis. World J Gastroenterol 2012; 18(15): 1708-22.


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## Xiaofa Qin

I believe the reverse relationship between milk consumption and the risk of inflammatory bowel disease (IBD) as revealed in the recently published European study (Opstelten JL, Leenders M, Dik VK, et al. Dairy Products, Dietary Calcium, and Risk of Inflammatory Bowel Disease: Results From a European Prospective Cohort Investigation. Inflammatory bowel diseases 2016;22:1403-1411. http://www.ncbi.nlm.nih.gov/pubmed/27120568 ) provided critical evidence that negated the causative role of Mycobacterium avium subspecies paratuberculosis (MAP) in Crohn’s disease (CD) (http://www.ncbi.nlm.nih.gov/pubmed/27542142 ). The result of the European study encouraged me to write a review with my view on the long controversy regarding MAP as the cause of CD, which has been published online in the open access journal of International Journal of Clinical & Medical Microbiology (http://www.graphyonline.com/journal/journal_article_inpress.php?journalid=IJCMM ). 

The full text of this paper I wrote can be downloaded by this link:  www.graphyonline.com/archives/archivedownload.php?pid=IJCMM-109 


Below is the abstract of this paper:

*Can Crohn's Disease Really be Caused by Mycobacterium avium Subspecies Paratuberculosis?-With My Alternative Theory that Reduction in Commensal Gut Bacteria and Resultant Impaired Inactivation of Digestive Proteases as the Primary Cause*

Xiaofa Qin
GI Biopharma Inc, 918 Willow Grove Road, Westfield, NJ 07090, United States

*Abstract*

The role of Mycobacterium avium subspecies paratuberculosis (MAP) in Crohn's disease (CD) has been debated for more than a century. Up to date, it remains a highly controversy issue as there are a large amounts of “solid” scientific evidence on both sides. However, I feel many of these conflicts are superficial and the core issue is just the extreme scarcity of MAP in CD and thus the still unresolved conflict between sensitivity and specificity. Along with in-depth analyses of the likely intimate nature of CD, MAP, and the so-called cell-wall deficient spheroplasts, as well as weighted assessment of findings from treatment and epidemiology, here I suggested that the evidences against a critical role of MAP in CD greatly overweigh those support it. Here I also shared a unified hypothesis I developed during the last 15 years regarding the etiology of inflammatory bowel disease (IBD), including the cause and mechanism of IBD as well as the relationship between CD and ulcerative colitis (UC). I proposed that reduction in commensal microbiota in modern society and the resultant impairment in inactivation of pancreatic digestive protease in the lower gut rather than any specific pathogens may have played the primary causative role in both CD and UC.


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## Xiaofa Qin

In my opinion, there should be fervent discussions and debates among the different hypotheses and opinions regarding the possible cause and mechanism of IBD. I believe the cure and prevention of IBD largely depends on finding out the root cause and mechanism of disease, which might turn out to be very simple.


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## xeridea

Oh boy, Xiaofa Qin, you are going to rile up some of the MAP proponents with your follow-up posts. But some of these suggestions does fall in line with the argument asking why is it dairy farmers have lower incidence of CD if there's the higher MAP exposure. I'm curious to see what sort of discussions your post spurs...


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## irishgal

I read both of these articles with interest. I'm always open to hearing the pros and cons of the MAP debate. I agree - there should be debate and peer review on all of these theories. I guess we'll see what the stage 3 RedHill study says soon, which may clarify the flawed Selby study. A few questions from the above articles then: 

1. If Crohn's is based on a genetic predisposition of the immune system not to recognize intracellular pathogens (which is well researched), wouldn't it then follow that only patients with that genetic profile would be susceptible to MAP as a trigger? People whose immune system can recognize MAP and contain it would have no issue wth MAP, no matter how much dairy they consume. It will be really interesting to see if they do follow up studies on this dairy intake theory. Maybe dairy has both protective and harmful effects in CD. A lot of patients get leaky gut as a result of CD. In those cases, adding highly reactive proteins like dairy and gluten can make you feel worse. Cutting those out can relieve some symptoms of leaky gut. I've never thought that the MAP in dairy alone can trigger CD. I think it has to be some other event in a period of waning immunity, but as usual, more research is necessary! Interesting study though.

2. Farmers should get more CD by being in contact with MAP. Unless they don't have the genetics (see above) or if their bodies produce stronger antibodies to MAP by being in constant contact with it. They're less "hygenic" and that may provide some additional protection, right?

3. Clearly a HUGE issue with the whole MAP debate is the lack of any type of standard diagnostic. I agree that the IS900 series is probably not a great indicator (See this post:  http://thecrohnsinfection.org/john-...oimmune-diseases-are-they-zoonotic-in-origin/). But if someone could reliably culture and actually grow the spheroplastic form of human MAP (thus proving it's not a dead, leftover form), wouldn't that be the best place to start?

4. Lastly, I noticed that Dr. Qin states that there are no conflicts of interest. Hopefully he can shed some light on this, because I thought he was the sole owner of a Biopharma company formed to study this research? Is that not considered a conflict? Admittedly, this is not my area of expertise, so I will defer to Dr. Qin to clarify any conflicts. (Not trying to be rude or accusatory, I truly want to learn what is considered a conflict in this case.)

I certainly agree that artificial sweetners aren't good for people. I avoid them as much as possible, but it's hard since they're in everything! Certainly the Western diet doesn't seem to be helping IBD patients. It will be interesting to see if further research will show that sweeteners (along with the factors that Dr. Qin mentions) can cause the pathology seen in Crohn's. Are there any independant groups working on research surrounding this hypothesis?


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## Xiaofa Qin

xeridea said:


> Oh boy, Xiaofa Qin, you are going to rile up some of the MAP proponents with your follow-up posts. But some of these suggestions does fall in line with the argument asking why is it dairy farmers have lower incidence of CD if there's the higher MAP exposure. I'm curious to see what sort of discussions your post spurs...


Thanks for sharing your thoughts. I would be glad if any people would like to share their thoughts on this with different opinions, including insightful discussions over scientific journals with those firm proponents of prominent scientific and professional backgrounds. Debate may help to differentiate real versus tale, and truth versus false. In fact, the journal of Inflammatory Bowel Disease published several of my other papers recently (http://www.ncbi.nlm.nih.gov/pubmed/?term=xiaofa+qin ), behind which there are some stories the people here may be interested. 


In early 2015, a paper published in Inflammatory Bowel Disease showing remarkable increase of IBD in Korea: 

Kim HJ, Ahn HS et al. Incidence and natural course of inflammatory bowel disease in Korea, 2006-2012: a nationwide population-based study. Inflamm Bowel Dis. 2015 Mar;21(3):623-30. 

According to the data they cited, I found that the dramatic increase occurred in early 2000s, but leveled off in recent several years. As sucralose was approved in Korea around 2000, I suggested that they check out the possible link between IBD and dietary chemicals such as sucralose and saccharin. 

Qin X. How to Explain the Dramatic Increase Around 2000 but Recent Leveling Off of Inflammatory Bowel Disease in Korea? Inflamm Bowel Dis. 2015 Aug;21(8):E16-7. 

In the reply, they denied the possible link between food additives and IBD, with the fact that Korea adopted much more strict regulation since 1992 on the use of saccharin.  

Ahn HS. Increased Incidence of Inflammatory Bowel Disease in Korea May Not Be Explained by Food Additives. Inflamm Bowel Dis. 2015; 21(8):E17 

On checking out their data, it can be found a sudden decrease in IBD during 1992 and 1993, therefore I reminded them that the possible link between food additives and IBD should not be ruled out. 

Qin X. Food Additives Should Not Be Ruled Out as the Possible Causative Factors of Inflammatory Bowel Disease in Korea. Inflamm Bowel Dis. 2016 Jan;22(1):E1. 

In the reply, they argued that the decrease during 1992 and 1993 is more likely a random fluctuation due to the low number of cases.  

Ahn HS. Reply to: Food Additives Should Not be Ruled Out as the Possible Causative Factors of Inflammatory Bowel Disease in Korea. Inflamm Bowel Dis. 2016; 22(1):E1-2. 

But the population they studies is about one million. I believe such a large population made the observed decrease unlikely a random error. Along with the many evidences I collected during the last fifteen years I suggested the possible link between those artificial sweeteners and IBD deserved further study. 

Qin X. The Possible Link Between Artificial Sweeteners Such as Saccharin and Sucralose and Inflammatory Bowel Disease Deserves Further Study. Inflamm Bowel Dis. 2016; 22(6):E17. 

Shortly after the acceptance of publication by the journal of the above paper, the large-scale European study came out. It revealed a sole positive association between a "high sugar and soft drinks" pattern and IBD. 

Racine A, etc. Dietary Patterns and Risk of Inflammatory Bowel Disease in Europe: Results from the EPIC Study. Inflamm Bowel Dis. 2016 Feb;22(2):345-54.

The above paper provided another critical piece of evidence for the possible link between the artificial sweeteners and IBD, but I felt their discussion was pretty superficial. I wrote a letter with my view as how sugar and soft drinks may be associated with IBD. 

Qin X. How Sugar and Soft Drinks Are Related to Inflammatory Bowel Disease? Inflamm Bowel Dis. 2016 ; 22(6):E18-9. 


I believe this kind of exchanges of views would benefit the scientific community and the general society. It may help to clear our thoughts and vision and the ultimate solution of the problem.


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## JMC

xeridea said:


> But some of these suggestions does fall in line with the argument asking why is it dairy farmers have lower incidence of CD if there's the higher MAP exposure.


Humans have an adaptive immune system.  We also have genetic differences affecting the behaviour of our immune system with respect to pathogens.  Higher exposure does not imply higher incidence of disease.  End of debate.


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## JMC

Xiaofa Qin said:


> Thanks for sharing your thoughts. I would be glad if any people would like to share their thoughts on this with different opinions, including insightful discussions over scientific journals with those firm proponents of prominent scientific and professional backgrounds. Debate may help to differentiate real versus tale, and truth versus false. In fact, the journal of Inflammatory Bowel Disease published several of my other papers recently (http://www.ncbi.nlm.nih.gov/pubmed/?term=xiaofa+qin ), behind which there are some stories the people here may be interested.
> 
> 
> In early 2015, a paper published in Inflammatory Bowel Disease showing remarkable increase of IBD in Korea:
> 
> Kim HJ, Ahn HS et al. Incidence and natural course of inflammatory bowel disease in Korea, 2006-2012: a nationwide population-based study. Inflamm Bowel Dis. 2015 Mar;21(3):623-30.
> 
> According to the data they cited, I found that the dramatic increase occurred in early 2000s, but leveled off in recent several years. As sucralose was approved in Korea around 2000, I suggested that they check out the possible link between IBD and dietary chemicals such as sucralose and saccharin.
> 
> Qin X. How to Explain the Dramatic Increase Around 2000 but Recent Leveling Off of Inflammatory Bowel Disease in Korea? Inflamm Bowel Dis. 2015 Aug;21(8):E16-7.
> 
> In the reply, they denied the possible link between food additives and IBD, with the fact that Korea adopted much more strict regulation since 1992 on the use of saccharin.
> 
> Ahn HS. Increased Incidence of Inflammatory Bowel Disease in Korea May Not Be Explained by Food Additives. Inflamm Bowel Dis. 2015; 21(8):E17
> 
> On checking out their data, it can be found a sudden decrease in IBD during 1992 and 1993, therefore I reminded them that the possible link between food additives and IBD should not be ruled out.
> 
> Qin X. Food Additives Should Not Be Ruled Out as the Possible Causative Factors of Inflammatory Bowel Disease in Korea. Inflamm Bowel Dis. 2016 Jan;22(1):E1.
> 
> In the reply, they argued that the decrease during 1992 and 1993 is more likely a random fluctuation due to the low number of cases.
> 
> Ahn HS. Reply to: Food Additives Should Not be Ruled Out as the Possible Causative Factors of Inflammatory Bowel Disease in Korea. Inflamm Bowel Dis. 2016; 22(1):E1-2.
> 
> But the population they studies is about one million. I believe such a large population made the observed decrease unlikely a random error. Along with the many evidences I collected during the last fifteen years I suggested the possible link between those artificial sweeteners and IBD deserved further study.
> 
> Qin X. The Possible Link Between Artificial Sweeteners Such as Saccharin and Sucralose and Inflammatory Bowel Disease Deserves Further Study. Inflamm Bowel Dis. 2016; 22(6):E17.
> 
> Shortly after the acceptance of publication by the journal of the above paper, the large-scale European study came out. It revealed a sole positive association between a "high sugar and soft drinks" pattern and IBD.
> 
> Racine A, etc. Dietary Patterns and Risk of Inflammatory Bowel Disease in Europe: Results from the EPIC Study. Inflamm Bowel Dis. 2016 Feb;22(2):345-54.
> 
> The above paper provided another critical piece of evidence for the possible link between the artificial sweeteners and IBD, but I felt their discussion was pretty superficial. I wrote a letter with my view as how sugar and soft drinks may be associated with IBD.
> 
> Qin X. How Sugar and Soft Drinks Are Related to Inflammatory Bowel Disease? Inflamm Bowel Dis. 2016 ; 22(6):E18-9.
> 
> 
> I believe this kind of exchanges of views would benefit the scientific community and the general society. It may help to clear our thoughts and vision and the ultimate solution of the problem.


If this is the cause, then surely changing your diet should reverse the symptoms of IBD?  Theories are interesting, but we all want practical things we can do to cure ourselves or reduce symptoms.  What is your prescribed cure for Crohn's?


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## Xiaofa Qin

JMC said:


> Humans have an adaptive immune system.  We also have genetic differences affecting the behaviour of our immune system with respect to pathogens.  Higher exposure does not imply higher incidence of disease.  End of debate.


An interesting explanation. Could you give an example showing a reverse relationship between exposure to a pathogen and prevalence of the disease caused by the same pathogen?


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## Xiaofa Qin

JMC said:


> If this is the cause, then surely changing your diet should reverse the symptoms of IBD?  Theories are interesting, but we all want practical things we can do to cure ourselves or reduce symptoms.  What is your prescribed cure for Crohn's?


Depend on the extent of damage of the gut tissue and stage of the disease, it may not be easy or possible to reverse the course of the disease by just removing the  primary causative agents. In my opinion, if the damage of the gut tissue is still reversible (such as no severe fibrosis that greatly restricted the supply of blood and nutrients), a cure may probably be achieved by a complete control of the inflammation within the gut tissue and the restoration of gut bacteria in gut lumen with full functions in which an effective deactivation of digestive proteases in the low gut would be a critical one among them.


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## Xiaofa Qin

irishgal said:


> I read both of these articles with interest. I'm always open to hearing the pros and cons of the MAP debate. I agree - there should be debate and peer review on all of these theories. I guess we'll see what the stage 3 RedHill study says soon, which may clarify the flawed Selby study.


Thanks for sharing your thoughts. 

Due to the damage of gut barrier in IBD patients, to my perception, a reduction in gut bacteria and thus the luminal commensal bacterial toxicants by the antibiotics should have some beneficial effect even in the absence of MAP. I wonder the impaired inactivation of digestive proteases along with the reduction in gut bacteria may have confounded the efficacy of the antibiotics. See: Qin X. Impaired inactivation of digestive proteases: a factor that may have confounded the efficacy of antibiotics aimed at reducing the exposure to luminal bacteria and their components. Am J Gastroenterol. 2008 Nov;103(11):2955-6. So, it would be not easy to draw a conclusion, but time will eventually tell which side is right. 




irishgal said:


> A few questions from the above articles then:
> 
> 1. If Crohn's is based on a genetic predisposition of the immune system not to recognize intracellular pathogens (which is well researched), wouldn't it then follow that only patients with that genetic profile would be susceptible to MAP as a trigger? People whose immune system can recognize MAP and contain it would have no issue wth MAP, no matter how much dairy they consume. It will be really interesting to see if they do follow up studies on this dairy intake theory. Maybe dairy has both protective and harmful effects in CD. A lot of patients get leaky gut as a result of CD. In those cases, adding highly reactive proteins like dairy and gluten can make you feel worse. Cutting those out can relieve some symptoms of leaky gut. I've never thought that the MAP in dairy alone can trigger CD. I think it has to be some other event in a period of waning immunity, but as usual, more research is necessary! Interesting study though.


Even the nearly 200 risk genes together can only explain a small portion of the variance in disease risk. To my knowledge, there seem no people really resistant to CD. If MAP in the milk would be the cause for CD and proteins in the milk could exacerbate the symptom, there should be added increased risk of milk to CD. This seems not the case. 



irishgal said:


> 2. Farmers should get more CD by being in contact with MAP. Unless they don't have the genetics (see above) or if their bodies produce stronger antibodies to MAP by being in constant contact with it. They're less "hygenic" and that may provide some additional protection, right?


As discussed in my review (www.graphyonline.com/archives/archivedownload.php?pid=IJCMM-109), I do not think CD is caused by a pathogen, thus in my “biased” opinion, the   reduced risk of CD in farmers is more likely to be explained by a more functional microbiota as the result of increased exposure to microbes due to less hygiene condition.



irishgal said:


> 3. Clearly a HUGE issue with the whole MAP debate is the lack of any type of standard diagnostic. I agree that the IS900 series is probably not a great indicator (See this post:  http://thecrohnsinfection.org/john-...oimmune-diseases-are-they-zoonotic-in-origin/). But if someone could reliably culture and actually grow the spheroplastic form of human MAP (thus proving it's not a dead, leftover form), wouldn't that be the best place to start?


As discussed in the review, the spheroplastic form of MAP should be much less pathogenic to the acid fast bacteria. This makes it difficult to explain the much severe damage as seen in CD in human compared to Johne’s disease in cattle in spite of the scarcely existence of spheroplastic forms of MAP in CD and large amounts of acid fact bacteria in Johne's disease. 



irishgal said:


> 4. Lastly, I noticed that Dr. Qin states that there are no conflicts of interest. Hopefully he can shed some light on this, because I thought he was the sole owner of a Biopharma company formed to study this research? Is that not considered a conflict? Admittedly, this is not my area of expertise, so I will defer to Dr. Qin to clarify any conflicts. (Not trying to be rude or accusatory, I truly want to learn what is considered a conflict in this case.)


As stated in my early posts several years ago, I found the possible link between dietary chemicals such as saccharin and IBD by a series of accidentally findings and extensive pursuit in the literature. Shortly after that, I had contact multiple national and international agencies and IBD professionals advocating checking out this possibility, but failed to raise any action. I paid thousands of US dollars of publication fee by my own, including the above recent review on MAP, in hoping to draw more attention. I have expected some pharmaceutical companies would conduct some R & D toward this potentially important new mechanism and develop some new treatment for IBD, but also without seeing any action. I eventually realized that I would have to do something by myself and thus left the academic and started the company, named GI Biopharma Inc. Up to date, I still have not raise any capital or funding and do not get any pay from the disclosed company or any other resource for recent couples of years. I am very grateful for my wife for the full support of me and my family, which allow me to concentrate my strenuous efforts toward some fundamental issues of human health, including the true cause of IBD and role of MAP in CD. Is there anything wrong with such an endeavor?  Should I withdraw from this lonely arduous striving that is appreciated by nobody, but suspected and ridiculed by even the patients it aimed to help?



irishgal said:


> I certainly agree that artificial sweetners aren't good for people. I avoid them as much as possible, but it's hard since they're in everything! Certainly the Western diet doesn't seem to be helping IBD patients. It will be interesting to see if further research will show that sweeteners (along with the factors that Dr. Qin mentions) can cause the pathology seen in Crohn's. Are there any independant groups working on research surrounding this hypothesis?


From the evidences I collected during the last fifteen years, I proposed that sweeteners such as saccharin and sucralose could be important causative factors for IBD, due to their wide use in the general population. As stated above, although I had vigorously advocated from the very beginning, it still failed to raise any action by the governmental or international agencies or the mainstream of IBD research. Despite that, I indeed got a Chinese professor to conduct some research in this regard and we just published a paper (Li R, Zheng J, Jiang M, Liu Y, Qin X, Wang X. Increased Digestive Proteases and Decreased β-Glucuronidase in Feces of Rats Treated with Sucralose and Saccharin-Another Critical Evidence That These Dietary Chemicals May Be Important Causative Factors for Inflammatory Bowel Disease. Inflamm Bowel Dis. 2016 Aug;22(8):E29-30.) supportive of the proposed hypothesis.  It had taken decades to pin down the association between smoking and lung cancer. Apparent, much more efforts would be needed to get a clear picture regarding the relationship between those artificial sweeteners and IBD.

Thanks you again for sharing your thoughts and questions. Above is just my personal opinion.


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## irishgal

Dr. Qin - thank you for sharing your thoughts. I believe that any research on Crohn's is beneficial, and applying the scientific method by experimentation of these theories is critical. It seems that you have experienced a lot of the same issues that the group of MAP researchers have: no funding stream, ridiculed for your beliefs and overall unappreciated by the people you are trying to help. I do not intend to minimize your contribution, and I appreciate your effort. 

My question on the conflict issue stems from what I observed at the Chicago symposium on MAP in 2015. Before they spoke, the speakers disclosed to the audience that they were working on behalf of whatever research group, and some may have had a financial stake as well. Disclosing conflicts is not intended to minimize or discount the research of the speaker, but to allow the audience to put it in the correct context. The most famous example of this is the Andrew Wakefield debacle on autism. He reported his findings in the Lancet without disclosing that he was conducting the study for a group of patients who were suing the MMR manufacturer. His findings were therefore more suspect since he had been paid to find a link. It would have become really interesting had others been able to validate his work, though I wonder if he had disclosed this conflict up front if his research may have appeared more valid.

I think nearly all researchers have conflicts, because they are paid by someone or they have a stake in the outcome of the research. That is why all published research has a conflicts disclosure. I don't think you should stop seeking funding for your work or stop trying to prove your theory, but I'm confused as to what consitutes a conflict in medical research here. It would seem like the standard disclosure about your company would be in that conflicts section. Again, not trying to say your research isn't valid, just trying to understand the obligation to disclose conflicts. 

Lastly, these recent two articles don't seem as much about promoting your theory as they seem to be attacking the MAP theory. To me, the MAP theory makes more sense (from my own personal case), or at least that there's some pathogenic involvement in CD, whatever that may end up to be. I'm not sure what role the overall microbiome plays. I don't think anyone really understands the microbiome, and it will be very interesting to see what that research yields. But I'd love to do the conclusive research which tells us that MAP is involved or not first. It seems like a viable culprit, so why not figure that one out, and if it's not MAP, move on to the next theory. Of course, different groups testing different theories is beneficial for all. But I'd wish those groups would stick to the research on their theory, instead of spending their time opining about why another group's theory is junk.

I truly hope that you get the funding you need to either prove or disprove your theory on Crohn's. I always wonder if it may be more than one theory that turns up correct. The more people working on it, the better!


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## JMC

Xiaofa Qin said:


> An interesting explanation. Could you give an example showing a reverse relationship between exposure to a pathogen and prevalence of the disease caused by the same pathogen?


Vaccination


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## Xiaofa Qin

Xiaofa Qin said:


> An interesting explanation. Could you give an example showing a reverse relationship between exposure to a pathogen and prevalence of the disease caused by the same pathogen?





JMC said:


> Vaccination


Here is a link with the introduction to vaccine: https://en.wikipedia.org/wiki/Vaccine

As stated, "a vaccine is a biological preparation that provides active acquired immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing micro-organism and is often made from weakened or killed forms of the microbe, its toxins or one of its surface proteins". 

Vaccine is not the original pathogen. It may reduce the susceptibility to the original pathogen, but still the more the exposure to the virulent pathogen, the more the disease


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## Xiaofa Qin

irishgal:

Thank you for sharing your thoughts and statements. I understand and agree for many of what you said, but not for all, especially in some key issues you are addressing. For instance:



irishgal said:


> It would seem like the standard disclosure about your company would be in that conflicts section.


I do not think what you suggested is the standard way of disclosure of confliction. I have explicated listed the company in the author institution section despite that up to date I do not get any financial benefit from the company. Have you really seen any scientific paper in which they listed their institution in the author section, then state again in the Conflict of Interest section that they have a connection with the same institution? 



irishgal said:


> Lastly, these recent two articles don't seem as much about promoting your theory as they seem to be attacking the MAP theory.


Expression, discussion, comments and exchange of views over scientific journals should not be cynically regarded as an attack. They are normal scientific activities that would benefit for all parties involved, as well as the scientific community and the whole society. As you may know, Dr. Andrew Wakefield’s paper on Lancet was followed by many studies. Some of them claimed they found the same connection, but much more large-scale more stringent studies negated the connection between MMR and autism, which would be the just thing to do but not malicious attack. It finally restricted the escalation of disaster incurred by the reduced immunization of children due to fear, which would not be achieved by just leaving alone the proponent side to do their job. 

After I found the possible link between saccharin and IBD fifteen years ago, I contact multiple national and international agencies and IBD professions advocating them to check out this possibility. Failed to raise any action, I feel obligated to write an publication to warn the public for such a potential risk, although I knew this may potentially get me into some trouble. During these years I advocate again and again to those with the resource to conduct a check. I know it may turn out I am wrong, but I still would be glad to see the result. 

I expressed my view on the relationship between MAP and CD as well as my own hypothesis regarding the cause and mechanism of IBD in the two papers as publications in the scientific journals. So I am inviting the "attack" and would glad to see others including the firm MAP/CD proponents to response with their different thoughts and opinions. We should have nothing to fear, as the truth is already there hiding, we can reveal it but nobody can change it. I am sure the new thoughts expressed in these two papers will benefit those engaged in MAP/CD research with more broad thinking, more comprehensive and accurate evaluation of their results. I also would be glad to see any kind of feedback or inputs, including those from you, along with different thoughts and opinions that would enhance my thinking and vision and benefit the whole society as well. Thanks.


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## irishgal

Xiaofa Qin said:


> Here is a link with the introduction to vaccine: https://en.wikipedia.org/wiki/Vaccine
> 
> As stated, "a vaccine is a biological preparation that provides active acquired immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing micro-organism and is often made from weakened or killed forms of the microbe, its toxins or one of its surface proteins".
> 
> Vaccine is not the original pathogen. It may reduce the susceptibility to the original pathogen, but still the more the exposure to the virulent pathogen, the more the disease


Saw this interesting research about TB (also a mycobacteria) where for some people, more exposure could lead to better immunity:

"Clinical studies suggest that there are individuals who are highly exposed to M. tuberculosis but remain persistently tuberculin skin test (TST) negative, and thus presumably uninfected. These individuals raise the possibility that at still-earlier points in the course of infection, it is possible for the host to fully clear the bacteria and that this early bactericidal response could be harnessed through vaccination."
http://mbio.asm.org/content/7/2/e00342-16.full

Also, there's the standard argument which includes the hygiene hypothesis that exposure to everyday pathogens early on prevents diseases (including "autoimmune" diseases) later in life. 
https://www.sciencedaily.com/releases/2009/12/091208192005.htm


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## irishgal

I think my issue with the conflict issue can be summed up by this article:

"Researchers with conflicts of interest were found to be more likely to choose comparators that would produce favorable results [29], selectively include only certain outcomes in published reports [30], publish conclusions that are inconsistent with the study results [31, 32], or complete a clinical trial without subsequent publication of the results [33]. These types of biases can also impact the quality and reliability of systematic reviews, arguably the most critical publications guiding clinical care."
https://researchintegrityjournal.biomedcentral.com/articles/10.1186/s41073-016-0006-7

The journal itself has this statement on Competing Interests:
"Competing interests
A competing interest exists when your interpretation of data or presentation of information may be influenced by your personal or financial relationship with other people or organizations. Authors must disclose any financial competing interests; they should also reveal any non-financial competing interests that may cause them embarrassment were they to become public after the publication of the manuscript.
Authors are required to complete a declaration of competing interests. All competing interests that are declared will be listed at the end of published articles. Where an author gives no competing interests, the listing will read 'The author(s) declare that they have no competing interests'."

Again, not trying to be accusatory, but truly trying to understanding why this article didn't have a section about competing interests.

The reason why I may have seen this as more of an attack and less as an invitation to open discourse, was that it seemed that your review of the MAP research didn't include studies which showed evidence contrary to your position. Which is partially understandable in your position since you are admirably attempting to find funding to study a theory of Crohn's in which you wholeheartedly believe, but it has the danger of misleading the reader if they believe you have no financial interest. For example, in your analysis of AMAT, you rely on the Selby study, which while it's the only blind study on AMAT, was rejected by peers due to it's many errors. The sole fact that the antibiotic capsules didn't rupture, thus not delivering the stated medication, should have been enough to invalidate it, but it had other flaws besides that. (See this peer review about half way down the page: http://thecrohnsinfection.org/clinician-information/.) There are many smaller studies which show that AMAT used correctly, over a longer period of time in higher doses can be effective for some CD patients. And RedHill is currently running a large scale stage 3 trial on it, but none of this was mentioned in your review of the MAP research. I believe this is a critical and misleading deletion that causes harm to patients by not providing the full body of data.

Here is an example of an article where a researcher disclosed conflicts (if you can see the full article)
http://www.futuremedicine.com/doi/pdf/10.2217/fmb.14.133

But I understand out of fairness to you, the company affiliation was disclosed up front which may the obligation that the journal requires.


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## Zim

Xiaofa Qin said:


> An interesting explanation. Could you give an example showing a reverse relationship between exposure to a pathogen and prevalence of the disease caused by the same pathogen?





irishgal said:


> Also, there's the standard argument which includes the hygiene hypothesis that exposure to everyday pathogens early on prevents diseases (including "autoimmune" diseases) later in life.
> https://www.sciencedaily.com/releases/2009/12/091208192005.htm


Also:

Can Being Exposed to Cows Boost Your Immunity?
http://www.hull-o.com/can-being-exposed-to-cows-boost-your-immunity/

Here's why farm kids have fewer allergies and less asthma
http://www.theverge.com/2015/9/3/9256955/allergies-asthma-farm-kids-dust-endotoxins-a20


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## InstantCoffee

Xiaofa Qin I was wondering your thoughts on a theory I've had regarding a possible link to Crohn's.

In Crohn's we see one of the genetic factors is the poor function of the OCTN cation transport proteins responsible for transporting Serotonin out of the gut. 

Serotonin is synthesized from 5-HTP / tryptophan in foods from the bacteria in the gut. 

Serotonin toxicity is known to have many adverse effects including inflammation and mood disorders.

Crohn's has been linked to hormonal disruptions and it has been possible to achieve remission in some patients both with SSRIs and with specialized doses of 5-HTP and L-Tyrosine to 'reactivate' the OCTN transport proteins.

We also see remission achieved through antibiotics.

If antibiotics were simply suppressing the Serotonin synthesizing bacteria in the gut, this wouldn't be a far fetched result would it? 

I think it's one of the only reasonable explanations that ties together both dietary treatment, hormonal treatment and antibiotic treatment all being effective against the same disease.


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## Xiaofa Qin

Thanks irishgal, Zim, InstantCoffee for sharing the thoughts and info. 

More and more studies showed changes in gut bacteria along with changes in the hygiene condition, or use of antibiotics or some diets may have played critical role in IBD and multiple other diseases. To my knowledge, I know serotonin is mainly produced in in the enterochromaffin cells in the GI, but frankly I have no idea as how serotonin produced by gut bacteria may contribute to inflammation and other functions in the body. Hope studies in the future may shade light on all these issues related to dysbiosis of gut bacteria.  




irishgal said:


> The reason why I may have seen this as more of an attack and less as an invitation to open discourse, was that it seemed that your review of the MAP research didn't include studies which showed evidence contrary to your position. Which is partially understandable in your position since you are admirably attempting to find funding to study a theory of Crohn's in which you wholeheartedly believe, but it has the danger of misleading the reader if they believe you have no financial interest. For example, in your analysis of AMAT, you rely on the Selby study, which while it's the only blind study on AMAT, was rejected by peers due to it's many errors. The sole fact that the antibiotic capsules didn't rupture, thus not delivering the stated medication, should have been enough to invalidate it, but it had other flaws besides that. (See this peer review about half way down the page: http://thecrohnsinfection.org/clinician-information/.) There are many smaller studies which show that AMAT used correctly, over a longer period of time in higher doses can be effective for some CD patients. And RedHill is currently running a large scale stage 3 trial on it, but none of this was mentioned in your review of the MAP research. I believe this is a critical and misleading deletion that causes harm to patients by not providing the full body of data.


This cynical accusation is simply not true. If you really carefully read through my paper (www.graphyonline.com/archives/archivedownload.php?pid=IJCMM-109), you should find that I have included as many as nearly fifty reviews alone (Ref. 2 – 48) at the very beginning of my paper, including most, if not all, of the key reviews from the eminent MAP/CD proponent scholars in the world, in which there were thorough discussions over the study by Dr. Selby et al in Australia.  

As for TB, I think you would probably know TB is a disease most prevalent in poor countries and poor regions where there is high TB exposure. If not know, I suggest you easily check these data out through internet or other resource and get a sense of what occurred in the real world. This would avoid the mistake of presenting erroneous misleading info to the readers as the result of distort interpretation or extrapolation of limited piece of peculiarly selected material but putting aside the vast amount of evidences that are more pertinent and stringent and readily available, a behavior you have bitterly denounced.

If you have different thoughts or opinions that you think of a value to express, I suggested you write a rebuttal to the journal, so we can have a formal discussion there that can be judged by the world and future.


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## DustyKat

Not wishing to sideline the discussion but just curious about something: 

My son had an ileocaecal resection in 2011. His pathology report on the resected bowel stated that there was no evidence of MAP infection. Is this routinely tested for in the resected bowel of Crohn’s patients? 

As a side note: He had his surgery at Royal Prince Alfred Hospital in Sydney and Dr Selby was his gastroenterologist whilst he was an inpatient there.


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## irishgal

DustyKat said:


> Not wishing to sideline the discussion but just curious about something:
> 
> My son had an ileocaecal resection in 2011. His pathology report on the resected bowel stated that there was no evidence of MAP infection. Is this routinely tested for in the resected bowel of Crohn’s patients?
> 
> As a side note: He had his surgery at Royal Prince Alfred Hospital in Sydney and Dr Selby was his gastroenterologist whilst he was an inpatient there.


Dusty - this is really interesting. As far as I'm aware, testing for MAP in resection tissue is generally not done, even when a patient requests it. In fact, five years ago I'm not sure how they would have tested for it, since the available tests for use in humans produced many false negatives. The MAP tests in cattle seem to be more advanced. John Aitken is now able to culture human MAP reliably, but this has just been in the past few years, maybe 2014? I've always wondered what happened to Dr. Selby after his famous study, and I wonder if he requested the sample be tested for MAP. How is your son doing now? Hopefully really well. Have you considered seeing Prof. Borody sine you're in AUS. Will have to read some of your recent posts to catch up!

Dr. Qin - I could continue, but I don't think this is productive. I can see we will continue to disagree. I meant no offense to you and your work, and was attempting to have a civil discourse. I know that tone does not come across well on the internet and I see you have taken offense, which I did not intend. I understand you fully believe in your hypothesis, and I look forward to reading your future research on this. I think all CD research is of value to elucidate the puzzle that is sitting there hidden, as you mention. However, as a patient who went from severe CD to a full absence of symptoms in 6 weeks on AMAT (and then histological healing in 6 months), I have become a believer. Especially because I have before and after cultures of my human MAP infection which shows a significant decrease in the pathogen (along with a wealth of other labs, histology and procedure reports) that corresponds to my healing. If one patient can be healed in this way, it only requires figuring out the mechanism to heal others as well.


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## DustyKat

In that case it was probably a pretty crude test then. :lol: It was also the pathology that said he had no convincing evidence of Crohn’s disease either but that was only because of an absence of granulomas. Yeah, I’m not sure who requested it but it was negative as was TB. I know the doc was doing research at the time, not sure for what though, as he was interested in my son taking part but we lived too far away and frequent, regular testing and annual scoping was required. Since he was not candidate I didn’t delve deeper into what it was all about. 

My son did well for 4 years post surgery but flared last year. He was commenced on Humira and that has pulled things back into line and he is doing well.  

I have two kids and they both have Crohn’s. I do believe in their case it is genetic, both have ileal Crohn’s and until more recently I also thought they had the same phenotype but now I am not so convinced. My daughter had a long undiagnosed period so her disease was left to run rampant with her only receiving her diagnosis on the operating table. That was 10 years ago and she has remained in remission since and has not taken medication for about 6 years I think, her choice. She now lives in Japan. 
My son on the other hand was diagnosed very quickly, within 2 weeks, and with next to no symptoms however his disease and complications developed very quickly despite intervention. I now think his phenotype is far more aggressive than his sister’s. 

Neither has ever fitted the more common denominators that spring up occasionally as to what may cause Crohn’s or trigger it. Both were normal vaginal births, both were breastfed for at least 12 months, neither had prescribed antibiotics until diagnosed with Crohn’s at 14 years (daughter) and 17 years (son) respectively, we live in a small rural town so limited access to fast food growing up, neither like fizzy drinks, had pets when growing up and access to farm animals and farm life. But had quite significant diversity in what they each liked in a dietary sense and what their interests were that I would question how much a part environment would play. 

My kids are now 24 and 23 years old. My son knows about Prof Borody and his research but I don’t know if he will make the move to see him. I know his current GI does not hold the same beliefs about Crohn’s that Prof Borody does and both being in the same state I know they have met at conferences etc.


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## InstantCoffee

Xiaofa Qin said:


> Thanks irishgal, Zim, InstantCoffee for sharing the thoughts and info.
> 
> More and more studies showed changes in gut bacteria along with changes in the hygiene condition, or use of antibiotics or some diets may have played critical role in IBD and multiple other diseases. To my knowledge, I know serotonin is mainly produced in in the enterochromaffin cells in the GI, but frankly I have no idea as how serotonin produced by gut bacteria may contribute to inflammation and other functions in the body. Hope studies in the future may shade light on all these issues related to dysbiosis of gut bacteria.


https://www.caltech.edu/news/microbes-help-produce-serotonin-gut-46495

Here is an article on a study done on the bacteria that synthesize serotonin in the gut



> The researchers found that the EC cells from germ-free mice produced approximately 60 percent less serotonin than did their peers with conventional bacterial colonies. When these germ-free mice were recolonized with normal gut microbes, the serotonin levels went back up—showing that the deficit in serotonin can be reversed.


I'll see if I can find the source but I believe Crohns usually presents with abnormally high gut serotonin levels.

Here's an article exploring the connection between IBD and gut serotonin http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3977648/


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## Xiaofa Qin

InstantCoffee said:


> https://www.caltech.edu/news/microbes-help-produce-serotonin-gut-46495
> 
> Here is an article on a study done on the bacteria that synthesize serotonin in the gut
> 
> 
> 
> I'll see if I can find the source but I believe Crohns usually presents with abnormally high gut serotonin levels.
> 
> Here's an article exploring the connection between IBD and gut serotonin http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3977648/


Thanks for sharing these info. From these materials we can learn that more than 90% of the serotonin in the body is located in gut tissue and mainly produced by the EC cells in the mucosa, with the materials generated within the body rather than exogenous sources like diet. Gut bacteria may significantly affect serotonin level, but still by impact on EC cells. Production of serotonin by gut bacteria in the lumen is likely minimal, which would be even lower along with the use of antibiotics and the resultant decrease in gut bacteria. Serotonin is pro-inflammation. Therefore, we may expect to see decreased risk of IBD by antibiotics if the production of serotonin in the lumen by gut bacteria may play important role, but this seems in contrary to the increased risk of IBD by antibiotics as reported in multiple studies. It may need more studies to elucidate the relationship among gut bacteria, diet, serotonin, and IBD.


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## Xiaofa Qin

irishgal said:


> Dr. Qin - I could continue, but I don't think this is productive. I can see we will continue to disagree. I meant no offense to you and your work, and was attempting to have a civil discourse. I know that tone does not come across well on the internet and I see you have taken offense, which I did not intend. I understand you fully believe in your hypothesis, and I look forward to reading your future research on this. I think all CD research is of value to elucidate the puzzle that is sitting there hidden, as you mention. However, as a patient who went from severe CD to a full absence of symptoms in 6 weeks on AMAT (and then histological healing in 6 months), I have become a believer. Especially because I have before and after cultures of my human MAP infection which shows a significant decrease in the pathogen (along with a wealth of other labs, histology and procedure reports) that corresponds to my healing. If one patient can be healed in this way, it only requires figuring out the mechanism to heal others as well.


I think we all share the same goal of ending the suffering of disease imposed on human being. 

I know even some minor personal experiences may greatly affect the belief of an individual on something. However, this kind of belief is also the most unreliable. You have mentioned in other post that you was on Remicade just prior to AMAT. Frankly, I do not know why you have such a deep belief that your remission was due to AMAT rather than the well-known currently most effective CD drug Remicade? 

Not only the personal experience of an individual, even the many of the open-label clinical trials in this days become so unreliable. One example would be the attempt to use Trichuris suis ova (TSO) to treat CD and other diseases. The miracle effect of the worm eggs has been shown in so many studies publish in many of most prestigious scientific journals and discussed in the many major social media, but it turn out complete fail when tested by the stringent double-blinded clinical trials ( See: Coronado crashes as Crohn’s disease trial fails and Coronado Biosciences (CNDO) No Longer Pursuing Trichuris Suis Ova Program, resulting in heavy costs for both the company to develop the product as well as the public.  

As for Dr. Selby’s study you mentioned, the doses for those antibiotics would be selected with a thorough understanding and review of the multiple studies before that. Although the 50 mg/day of clofazamine used in the first 10 months may not be fully released due to some defects in the capsule as you mentioned, there are still other two antibiotics, Clarithromycin 750mg/day and Rifabutin 450mg/day, would be fully functional and all these three antibiotics would have worked well for the remaining 14 months in the two year study. In fact, multiple clinical trials had claimed wonderful efficacy with fewer and even lower dose of these antibiotics and shorter treatment time. For instance:

*500 mg/day Clarithromycin alone for 4 – 12 weeks*
Leiper K, Morris AI, Rhodes JM. Open label trial of oral clarithromycin in active Crohn's disease. Aliment Pharmacol Ther. 2000 Jun;14(6):801-6. 

*Clarithromycin 500mg/d + rifabutin 300mg/d for 4 – 17 months*
Shafran I, Kugler L, El-Zaatari FA, Naser SA, Sandoval J. Open clinical trial of rifabutin and clarithromycin therapy in Crohn's disease. Dig Liver Dis. 2002 Jan;34(1):22-8. 

As discussed in my paper, MAP is actually much sensitive to the antibiotics such as clarithromycin than M. tuberculosis. However, as we know, most of the patients with TB (and also leprosy) can be effective cured by antibiotics but nothing else. Why MAP in CD is so difficult to be killed? Real or tale? The new clinical trials in future may eventually bring us the answer. Let’s see.

The accidental findings of the possible cause and mechanism of IBD fifteen years ago led me a great interest in IBD. I tried to exchange thoughts and views with others that I believe this would benefit for all. The recent two papers on MAP/CD among the much more of others (http://www.ncbi.nlm.nih.gov/pubmed/?term=xiaofa+qin) just reflected such an effort. Hope people may work together to bring an end to the disease.


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## Charlotte.

Haven't gone through the whole threat but just want to remind of something:

Correlation is not the same as causality. *nerd-mode off lol*

So even if a study or 10 studies can determine one factor that seems to correlate with the outcome it does not mean that there are 10 other factors that would correlate with the outcome as well but have just not been investigated for that. 

Don't ever trust statistics that you haven't falsified yourself. ;-)


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## irishgal

Hi Dr. Qin - thank you for your thoughts. I certainly agree that the RedHill study will determine if AMAT is beneficial in CD, and that is the type of rigorous, long term study that is necessary. As for my case and Remicade, I failed Remicade prior to starting AMAT. It worked for about 6 months to alleviate symptoms (though I had little healing) and it wore off quicker and quicker after each dose. Then I would flare even worse until I could get my next dose. The blood test showed I had built significant antibodies and I didn't have a clinical level in my body. This was all prior to AMAT, and I had fully stopped Remicade prior to AMAT, so there is no way my healing could have come from Remicade. Trust me - I was so sick at that point that I was bitterly disappointed that Remicade failed, which was my last treatment. I was terrified of going on something experimental. Reading the research and having it make sense in an intellectual way and actually making the leap to take heavy duty antibiotics which you know your GI is against was amazingly frightening. But I had no other viable options (and I considered helminths, SSI and FMT as well). Everything was experimental for me! And then to have AMAT work in only 6 weeks was emotionally disorienting. Then I found others like me, and wondered how many more were out there who had been told by their doc that they were out of treatments. Even if it worked in some, those patients would have their life back!

And I agree - single patient experiences are terribly unreliable in the scientific context. I shared my person story to provide some background as to why I thought AMAT may be a viable treatment for some CD patients. Certainly continued research needs to be done to find out why some experience healing like I did solely on antibiotics. I'm hoping the advent of a reliable diagnositic will answer some of these questions.

I will look forward to reading the future research on your hypothesis.


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## Xiaofa Qin

Hi, irishgal – Thank you for the explanation. Wish you keep on this wonderful good health all the time. Admire your great enthusiasm for helping others. Hope we may find out the root cause and mechanism of  this dreadful disease sooner, no matter what it would be, and provide not only a cure but also effective prevention of it, and eventually make the world IBD free.


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## xeridea

irishgal said:


> .And then to have AMAT work in only 6 weeks was emotionally disorienting. Then I found others like me, and wondered how many more were out there who had been told by their doc that they were out of treatments. Even if it worked in some, those patients would have their life back!


From what I've read on RHB-104 recently, a couple of the ABX in AMAT also have anti-inflammatory and immunomodulatory effects. Clarithromycin, a macrolide, is known to have anti-inflammatory properties by suppressing various inflammatory IL-x cytokines and TNF-alpha. And clofazamine modifies macrophage aptosis. 

These are some of the rationale Redhill is using to expand their research on RHB-104 into MS and RA.

It'd be interesting if they can show conclusively whether RHB-104 works by killing MAP, or if it works due to these other immune modifying properties. If it's the latter, in my mind at least, it sort of explains why David in this Prof. Borody Interview video has stayed on AMAT for 12 years.


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## irishgal

xeridea - that would be really interesting, and so confusing if the antibiotics were working not only on a MAP killing theory but also on an anti-inflammatory model. I guess the only way to sort that out would to be with reliable before and after MAP load testing. I think RedHill is doing that - or attempting it. Or at least collecting the before and after samples, then will test them eventually when they have a reliable diagnostic. I'll have to look into it more to see what they say, but I did see they just pushed back their timelines, which I know happens in these large trials. But interestingly, their press release said they are still blinded as to effectiveness, so it can't be because it either works/doesn't. 

I seen that interview with David too, and I think now he's been on for nearly 20 years! If it's the same guy, I saw an old news story about how his bones were destroyed by pred, so he's sticking with AMAT as long as he's allowed. Probably not a bad theory if it's working that well for him! I can only hope it works that long for me.


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## xeridea

Here is at least one paper on this topic:

_3. Immunoregulation and Anti-Inflammatory Action of Macrolides

In recent years, it has been shown that macrolides beyond the bacteriostatic and bactericidal effect have also anti-inflammatory effect, which was used in chronic inflammatory diseases such as atopic dermatitis, nonspecific inflammatory bowel disease, psoriasis, and arthritis. The effect of macrolides on the inflammatory cell activity by influencing the production and release of proinflammatory cytokines has been demonstrated in many studies. Cytokines and chemokines play a key role in regulating both the proinflammatory immune response—tumour necrosis factor (TNF-), granulocyte—macrophage colony-stimulating factor (GM-CSF), interleukin-L IL-1, IL-6, IL-8, and interferon gamma (IFN-) and anti-inflammatory (e.g., IL-10).

It was shown that macrolides inhibit the production and secretion of IL-1SS and TNF-. in monocytes [5] and IL-1SS, IL-6, TNF-., and GM-CSF in mast cells [6], and IL-8 protein epithelial neutrophil-activating (ENA-78) macrophage inflammatory protein (MIP-1) in macrophages and leukocytes [7]. It was also shown that clarithromycin suppresses the production of IL-6 and IL-1SS by fibroblast-like cells of the synovial membrane [8]. Therapeutic concentrations of erythromycin and clarithromycin reduce the expression of IL-8 mRNA level in bronchial epithelial cells of patients with chronic inflammatory airway disease [9].​_


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## xeridea

And this, another writeup looking at use of another macrolide, rapamycin, in pediatric refractory IBD. It's a small cohort, but they demonstrated 67% mucosal healing. Not bad for a compound produced by a species of Streptomyces bacteria you find in soil.

_
The records of 14 patients were analyzed. Eleven of them had ulcerative colitis (UC) and 3 Crohn's disease (CD); mean age at diagnosis was 9.1 years (standard deviation 3.8). Of UC patients, 5 (45%) achieved clinical remission and 2 (18%) showed clinical response. All CD patients went into clinical remission. Mucosal healing was achieved by 5 children (45%) with UC and 2 (67%) with CD patients. One child with ulcerative colitis was weaned off adalimumab, while 2 children with CD were weaned off prednisolone and methotrexate successfully._​
For what it's worth, rapamycin, and more generally, a class of 100 or so analogs of this compound, are having a renaissance of sorts in areas of cancer and longevity research. I'm kind of fascinated by this compound at the moment. Yay macrolides?


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## wildbill_52280

xeridea said:


> And this, another writeup looking at use of another macrolide, rapamycin, in pediatric refractory IBD. It's a small cohort, but they demonstrated 67% mucosal healing. Not bad for a compound produced by a species of Streptomyces bacteria you find in soil.
> 
> _
> The records of 14 patients were analyzed. Eleven of them had ulcerative colitis (UC) and 3 Crohn's disease (CD); mean age at diagnosis was 9.1 years (standard deviation 3.8). Of UC patients, 5 (45%) achieved clinical remission and 2 (18%) showed clinical response. All CD patients went into clinical remission. Mucosal healing was achieved by 5 children (45%) with UC and 2 (67%) with CD patients. One child with ulcerative colitis was weaned off adalimumab, while 2 children with CD were weaned off prednisolone and methotrexate successfully._​
> For what it's worth, rapamycin, and more generally, a class of 100 or so analogs of this compound, are having a renaissance of sorts in areas of cancer and longevity research. I'm kind of fascinated by this compound at the moment. Yay macrolides?


I vaguely recall one report of a women who used either rapamycin or something like that and achieved remission, I thought it was the only case that existed until i read this link. I use autophagy stimulators lithium and resveratrol to reduce some of my symptoms, they are similar to rapamycin at least in regards to their ability to stimulate autophagy. Stimulating autophagy as you may already know, can help eliminate intercellular bacteria like MAP or AEIC, something that crohn's patients seem to have a problem with.


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## A.Sharifi

Hello there

You may also consider this paper (search the title for full-text):

A randomized controlled trial on the effect of  vitamin D3 on  inflammation and cathelicidin gene expression in  ulcerative colitis  patients

*Background:* Inflammatory bowel disease (IBD) is an intestinal   chronic inflammatory condition and includes Crohn's disease (CD) and   ulcerative colitis (UC). It has been proposed that Vitamin D   supplementation may have a beneficial role in IBD. *Aim:* To characterize the effects of Vitamin D on cathelicidin (hCAP/LL37) gene expression, ESR, and serum hs-CRP levels. *Materials and Methods:*   Ninety UC patients on remission were randomized to receive 300,000 IU   intramuscular Vitamin D or 1 mL normal saline as placebo, respectively.   Before and 90 days after intervention, serum levels of 25 (OH)-Vitamin   D3, PTH, Calcium, ESR, and hs-CRP were measured. Cathelicidin gene   expression was also quantified using qRT-PCR. *Results:* Baseline   serum 25-OH-Vitamin D3 levels were not different between the two groups   and after intervention, increased only in Vitamin D group (_P_ < 0.001). Hs-CRP levels were lower in Vitamin D group after intervention (Before: 3.43 ± 3.47 vs 3.86 ± 3.55 mg/L, _P_ = 0.56; after: 2.31 ± 2.25 vs 3.90 ± 3.97 mg/L, _P_= 0.023). ESR decreased significantly in Vitamin D group (Before: 12.4 ± 6.1 vs 12.1 ± 5.3 mm/h, _P_= 0.77; after: 6.7 ± 4.5 vs 11.4 ± 5.5 mm/h, _P_<   0.001). The mean fold change in hCAP18 gene expression in Vitamin D   group was significantly higher than placebo group. (Mean ± SD: 3.13 ±   2.56 vs 1.09 ± 0.56; median ± interquartile range: 2.17 ± 3.81 vs 0.87 ±   0.53, _P_<,; 0.001). 
*Conclusion:* Decreases in ESR  and hs-CRP levels and increase in  LL37 gene expression support the  hypothesis that Vitamin D  supplementation may have a beneficial role in  UC patients.


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## JMC

Xiaofa Qin said:


> Here is a link with the introduction to vaccine: https://en.wikipedia.org/wiki/Vaccine
> 
> As stated, "a vaccine is a biological preparation that provides active acquired immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing micro-organism and is often made from weakened or killed forms of the microbe, its toxins or one of its surface proteins".


Obviously, I know what a vaccine is and how it works...



Xiaofa Qin said:


> Vaccine is not the original pathogen. It may reduce the susceptibility to the original pathogen,


It "may" reduce susceptibility because we have differences in own immune systems.  It is not usually the original pathogen in its entirety, but from your link:

"A vaccine typically contains an agent that resembles a disease-causing micro-organism and *is often made from weakened or killed forms of the microbe*, its toxins or one of its surface proteins



Xiaofa Qin said:


> but still the more the exposure to the virulent pathogen, the more the disease


It isn't that simple.  Exposure does not imply infection.  Infection does not imply disease.  You are drawing the wrong conclusions because of over-simplistic and wrong assumptions.


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## Xiaofa Qin

JMC said:


> It isn't that simple.  Exposure does not imply infection.  Infection does not imply disease.  You are drawing the wrong conclusions because of over-simplistic and wrong assumptions.


It seems you still disparate over the papers I wrote regarding the inverse relationship between milk consumption and the risk of IBD negated the causative role of MAP in CD (Qin X. Increased Milk Consumption but Decreased Risk of Crohn's Disease (CD): Critical Evidence Negated Causative Role of Mycobacterium avium Subspecies paratuberculosis (MAP) in CD. Inflamm Bowel Dis. 2016 Sep;22(9):E37-8.) and my view that the evidence against the causative role of MAP in CD greatly over-weigh those support it (Qin X. Can Crohn's Disease Really be Caused by Mycobacterium avium Subspecies Paratuberculosis?-With My Alternative Theory that Reduction in Commensal Gut Bacteria and Resultant Impaired Inactivation of Digestive Proteases as the Primary Cause. Int J Clin Med Microbiol,  1: IJCMM-109). Frankly, I do not have the interest to argue. Again, if you feel you have a thought that is of a value to express, I suggest you write a rebuttal to the journal. Or if you feel difficult to do so due to the lack of background and training in medicine, I suggest you advocating those eminent MAP/CD proponent scholars you highly admired and were familiar with to do it together. So we may have formal professional discussions there that can be judged by the world and future, and may also possibly draw more attention and studies in this area that may help to bring an end to this controversy early.


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## mf15

I see this thread is still going.
I posted this info back in 2013 or so.
Seems overlooked by the GI community.
Old Mike

yes only 2 people but it worked
https://www.jstage.jst.go.jp/article/internalmedicine1992/32/4/32_4_350/_pdf

BBI
http://www.ncbi.nlm.nih.gov/pubmed/17551835

potato juice
what I find interesting is that

Faecal protease activity in faeces from patients with intestinal resections and healthy infants was found to be significantly higher than in healthy adults. 

Brings up the question as to why infants don't get colitis, generally.
Perhaps mucosal anti trypsin activity is quite effective, in infants.

http://www.ncbi.nlm.nih.gov/pubmed/15086363

just to cover another base
Disease associations in alpha-1-antitrypsin deficiency
http://www.ncbi.nlm.nih.gov/pubmed/24176989

another
http://www.ncbi.nlm.nih.gov/pubmed/10807072


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## mf15

I searched this one does not seem to be in the thread.
Induction of Intestinal Inflammation in Mouse by Activation of Proteinase-Activated Receptor-2
From 2002
Old Mike
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1850779/

What we have going on here is PAR-2 activation by trypsin and mast cell tryptase which are elevated
in UC. While our alpha-1 antitrypsin is low.

Quercetin is both a mast cell stabilizer/trypsin/tryptase inhibitor.

The problem is you cant get quercetin to the colon unless you I guess overload dosage
with like 50/mg/kg or about 3 grams for a 60 kg person.

But if you take quercitrin it will pass into the colon and breakdown into quercetin.
But you cant get quercitrin as a supplement, except perhaps as dried apple peel will look
at that more. But you can get Rutin which will do the same thing.

Here is the explanation of what is going on,with guercetin,which works in a test tube,but not 
in UC models unless you over load to get it to the colon.
http://hera.ugr.es/doi/15772342.pdf

What else is going on of which I will have to track down again if I can find it is that the trypsin
is auto digesting our colon cells,some of the trypsin is also from bacteria .

Will fill out more as I get organized with this info.
Auto digestion.
/www.ncbi.nlm.nih.gov/pmc/articles/PMC3288241/

Protective effect of quercetin not seen at lower doses than 50mg/kg in mice.
www.omicsonline.org/proceedings/pro...ogical-and-biochemical-alterations-13963.html

Rutin
/www.ncbi.nlm.nih.gov/pubmed/15652231

might also need high does rutin
/www.ncbi.nlm.nih.gov/pubmed/25281414

Just another thought many of the quercetin supplements now have bromalein, don't think this
is a good idea, you want to get the quercetin into the lower gut, not perhaps into the blood stream.

rutin give extended exposure of quercetin in the gut even may help ileitis
www.sciencedirect.com/science/article/pii/S1756464614004204

rutin metabolism
/www.drrathresearch.org/images/attachments/education/Phytobiology/Rutin_2015.pdf

I see Briggs beat me to it, but he mentions it as an antioxidant
thepowerofpoop.com/wp/wp-content/uploads/2015/07/IBD-Briggs-July-21-2015-1-1.pdf

My angle is down regulation of protease activity.
Old Mike


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## gordan

This is interesting.  I wonder what other types of artificial sweeteners are guilty of this?  

Regardless, I personally know I'm going to really look into this.  Perhaps it's the cause of my issues.  Anything new to explore is better than a dead end.


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## Xiaofa Qin

Several years past since the last post. More studies emerge. I have also had more publications that can be found at: https://pubmed.ncbi.nlm.nih.gov/?term=Xiaofa+Qin

Recently, I also put a video on YouTube with my simple explanation as how changes of gut microbiota in modern society may associated with IBD and other diseases. The video can be found at: 




Welcome critiques, comments and discussion.


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     Company website: https://GI-Biopharma.com/our-products

    Amazon: https://www.amazon.com/GI-GI001-Probiotics/dp/B08NFKTF3G/

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If interest, please contact me, I may give some discounts.


----------

