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Etiology of inflammatory bowel disease: A unified hypothesis

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.
 
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.
 

Judith

Crohnsforum Science Advisor
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.
 
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!
 

Judith

Crohnsforum Science Advisor
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.
 
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...
 
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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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...
 

Judith

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

DustyKat

Super Moderator
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. :)
 
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.
 

DustyKat

Super Moderator
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. :)
 
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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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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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.
 
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.
 
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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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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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.

:poo:
 
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?
 
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.
 
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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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.
 
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
 
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.
 
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”.
 
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
 


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

thanks for your info Xiofa
 
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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.
 
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
 
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?
 
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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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.
 


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.
 
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.
 
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.
 
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.
 

Judith

Crohnsforum Science Advisor
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.
 
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.
 
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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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.
 
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.
 
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
 
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?
 
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 :)
 
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.
 
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
 
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.
 
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.
 
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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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.
 
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.
 
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.
 
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.
 
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.
 
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
 
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.
 
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
 
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.
 
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.
 
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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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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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.
 
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.
 
thanks for the reply Xiaofa Qin, you're one of the few researches who came here to openly discuss their paper, it's appreciated
 
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:
 
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.
 
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.
 
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
 
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
 
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
 
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.
 
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.
 
, 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.
 
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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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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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.
 
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.
 
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...
 
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.
 
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.
 
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?
 
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.
 
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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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
 
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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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.
 
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'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.
 
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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