• Welcome to Crohn's Forum, a support group for people with all forms of IBD. While this community is not a substitute for doctor's advice and we cannot treat or diagnose, we find being able to communicate with others who have IBD is invaluable as we navigate our struggles and celebrate our successes. We invite you to join us.

Etiology of inflammatory bowel disease: A unified hypothesis

Old Mike: I agree. The dramatic increase in low IBD countries like China may provide a chance to find out its cause. Hope people may put more efforts.

It would be no surprising that the unsterilized water may protective. However, drinking chlorination/boiling sterilized water seems not enough to cause IBD. In fact, drinking boiled water is a very old tradition and common practice in China. The unboiled water is called "raw water" and generally regarded as not safe. As the result, many people in China drink boiled water the whole life, even in hot summer. The recent increase in IBD in China is more likely related to changes such as the westernized life style and foodstaffs.
 
What about not looking at the clean water issue, but at the byproducts that these cause. Are they poisoning us slowly? Such as trihalomethanes, haloacetic acids, bromate, and chlorite?
 
If you combine sodium benzoates with vitamin C, you get benzene. So this very popular and natural preservative is being replaced by the industry for our health. I would like to see the same thing happen with other known chemistry issues that are common place, like chlorination without better filtration, flouride addition, chemical sweetening, and anything else "questionable". Until studies prove they are harmless, I will continue to assume that the combination of substance A with B is killing us.
 
I would be interested in matching particular products and distribution with health problems. Awareness would at least allow avoidance. I wonder if the grant to ask for isn't for bowel disease, but public health issues greater than just our symptoms, bowel issues becoming part of a bigger problem.
 
What about not looking at the clean water issue, but at the byproducts that these cause. Are they poisoning us slowly? Such as trihalomethanes, haloacetic acids, bromate, and chlorite?
Nothing seems simple. Talking about toxicity, anything we take would far less toxic than the endotoxin (also known as lipopolysaccharides, or LPS) possessed by the bacteria inside our body. A dose of 1 µg/kg can induce shock in humans, while 1 ml saliva or 1 g feces contains 1 mg endotoxin (here is a link), enough to cause many times of shock. However, multiple studies demonstrated use of antibiotics increased rather than decreased the risk of IBD. People are trying using fecal transplant or probiotics to treat IBD. Similar as antibiotics, dietary chemicals like saccharin and sucralose have very little effect on the body, as almost all of them are eliminated from the body without any metabolism. However, they may have a big impact on gut bacteria.


I would be interested in matching particular products and distribution with health problems.
I also think we at least need to see a match, i.e., a correlation, before we may further determine if this is the causation. We can raise a lot of possibilities and suspects for IBD, but they would have to be checked against the peculiar temporal and geographical distributions of the disease. As demonstrated in Figure 2A in my paper, data collected over 60 years in Monroe County in New York showed a dramatic increase in both ulcerative colitis and Crohn's disease during early 1960s to middle 1970s, then a remarkable drop during later 1970s and early 1980s. Now it seems a new round of increase of IBD in US since early 2000s (Qin X. When and How Was the New Round of Increase in Inflammatory Bowel Disease in the United States Started? J Clin Gastroenterol. 2013 Nov 13. [Epub ahead of print]). I think we would have to take into consideration of these peculiar features when we seek an answer for the mystery.
 
there's this expression

"For every complex problem there is an answer that is clear, simple, and wrong."
“Truth is ever to be found in the simplicity, and not in the multiplicity and confusion of things.”
― Isaac Newton

In my experience, mediocre academics spend their careers obsessing over irrelevant complexity unable to see the simple patterns in what they studying...
 
Measured objectively, what a man can wrest from Truth by passionate striving is utterly infinitesimal. But the striving frees us from the bonds of the self and makes us comrades of those who are the best and the greatest.

― Albert Einstein
 
“Truth is ever to be found in the simplicity, and not in the multiplicity and confusion of things.”
― Isaac Newton

In my experience, mediocre academics spend their careers obsessing over irrelevant complexity unable to see the simple patterns in what they studying...
they are biased to do so, for it is their profession, but i will never belittle their work.

So this in some cases is true. But the process of abstraction and theorizing, is a the process of simplification, to find the underlying common concepts of causes that link a multitude of observations. the end goal is ultimately to simplify and give meaning to previously meaninglessness processes.

one major issue that may be related to your point is with reductionism and current limitations of inductive reasoning. The simulation of natural environments from which we gather data, data to be taken with a grain of salt regarding if that is the true behavior of the cell within the organism, but it helps us build theoretical models to test them in vivo. For my own intellectual progress, i sought to take science back out into the real world and consider the most general rather then the smallest parts, for a different perspective. but there is no difference, an empirical observation is an empirical observation whether the parts are small or large, it all counts. For me this was a matter of empowerment, i thought science was only done somewhere in a lab, i thought, can i gather knowledge too? can i propose a hypothesis to? do my own observations count too? i used this as a starting point to direct all my research, then, to outline different theories with high tech experiments i found online. all that work brought me to............ fecal transplants!!!

http://www.crohnsforum.com/showthread.php?t=52400
 
Last edited:
Xiaofa:You might be interested in this old paper,if you have not seen it in
the past.
These findings indicate that inactivation of pancreas tryptic activity is mainly carried out by the intestinal microbial flora.
Old Mike
http://www.microbecolhealthdis.net/index.php/mehd/article/viewFile/7395/8728
Old Mike: Thank you very much for sharing the paper. Although I have collected quite a number of research papers from Drs. Norin and Midtvedt, the one you listed above is out of my radar. I usually use pubmed to check out references. It seems this one is out of their collection. Yes, I take a great interest in this paper. I always would like to have some new inputs and, as stated early, adjust my thoughts against the new facts. This paper, although published more than two decades ago, would still bring me some fresh new thoughts:

1) As large amounts of digestive proteases can be found in the large intestine of animals raised under germ-free but not conventional condition, I have thought most, if not all, antibiotics would be able to cause dramatic reduction in gut bacteria and thus severely impaired inactivation of digestive proteases. However, as demonstrated in Table 2 of this paper, this seems not the case – among the ten antibiotics tested only doxycycline showed an increase in faecal tryptic activity during the treatment period compared to the two samples before the treatment. Interestingly, doxycycline is also the best know antibiotics that increased the risk of inflammatory bowel disease, especially Crohn’s disease (see: Inflammatory bowel disease linked to antibiotic treatment for acne).

2) Study showed that putting saccharin in the diet can cause more than 10 fold increase in trypsin activity in the feces and contents of large intestine (Naim M, Brand JG, Kare MR. Effect of unpalatable diets, food restriction and saccharin-adulterated diet on tryptic, chymotryptic, and amylolytic activity in pancreas, intestine and feces of rats. J Nutr. 1982 Nov;112(11):2104-15), suggesting dietary chemicals like saccharin may cause even big impairment than antibiotics on the inactivation of digestive proteases, which may be one of the reasons for the much higher use of antibiotics but still lower incidence of IBD in China compared with the western countries as discussed in some early posts (on 11-17-2012, 07:52 PM, on 11-17-2012, 10:52 PM, and on 11-18-2012, 05:30 PM).

Here is a very recent paper showing the reduced alpha1-antitrypsin in serum and colon of ulcerative colitis patients (Wang JY, et al. Correlation between pulmonary function impairment and levels of alpha1-antitrypsin in serum and colon of ulcerative colitis patients: a clinical research]. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2014 Jan;34(1):20-6). The more severe of the disease is, the longer the disease lasts, the lower the alpha1-antitrypsin is in the body, suggesting the likely gradual exhaustion of the endogenous anti-trypsin capacity of the body.

Thanks again for sharing the info.
 
Xiaofa: Thank You.
As you can see pubmed/medline does not have everything we might be looking for,you must use google with some specific search terms.

Here is the path I went down yesterday,which I copy and paste from another
forum I frequent. I went down the path of antibiotics and gut bacteria,
and then found the paper on tryptic activity. Then I came across the non
human protein in red meat and milk.


Influence of antibiotics on intestinal mucin in healthy subjects
www.ncbi.nlm.nih.gov/pubmed/3492375


more on antibiotics and gut bacteria.

It seems that after antibiotics the gut bacteria can be disturbed for a very long time.

Of course UC started to increase before antibiotic use.

But I also have to wonder with the advent of antibiotics in pill form as opposed to injection, like when I was a kid,

might have led to the explosion of IBD.

I might speculate that when taking a pill there might be more antibiotic in the gut than with an injection.



http://mic.sgmjournals.org/content/156/11/3216.full



Something on tryptic activity.

These findings indicate that inactivation of pancreas tryptic activity is mainly carried out by the intestinal microbial flora.
Old Mike
http://www.microbecolhealthdis.net/i...File/7395/8728



more,if it says page not found just google this

Breakdown of Mucin as Barrier to Digestive Enzymes in the Ischemic Rat Small Intestine

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040087

Now this one is real interesting,quite a few people indicate their UC started after antibiotic use.

You can get a little more info by clicking on the read cube section.

Seems that sialic acid in the diet might not be good, at least after taking antibiotics, red meat and dairy.

Old Mike



http://www.nature.com/nature/journal/vaop/ncurrent/full/nature12503.html



more

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2752721/



gets even more interesting,normal humans make antibodies to it,wonder if UC people make more.

Wonder if cooking denatures it.

Of course the Masai eat lots of meat,blood and milk, and don't have inflammatory disease.

http://www.pnas.org/content/100/21/12045.long



more stuff

http://www.pnas.org/content/early/2010/05/04/0914634107.full.pdf
 
http://articles.mercola.com/sites/a...ows-link-between-mmr-vaccine-and-autism.aspx#!
So far 70 of 82 have tested positive for vaccine measles in the gut tissue. No cases of wild measles. This could point to batches of the vaccines being a cause of one form of bowel disease. I'm glad they are revisiting this. In order to come back to this point, we all know that the public, and researchers have to agree something warrants a study.
If vaccines or illness have lasting effects, it may at least lead to creating a different vaccine so future generations don't suffer.
The studies are far too many to be ignored, but the connections are still fuzzy.
 
http://articles.mercola.com/sites/a...ows-link-between-mmr-vaccine-and-autism.aspx#!
So far 70 of 82 have tested positive for vaccine measles in the gut tissue. No cases of wild measles. This could point to batches of the vaccines being a cause of one form of bowel disease. I'm glad they are revisiting this. In order to come back to this point, we all know that the public, and researchers have to agree something warrants a study.
If vaccines or illness have lasting effects, it may at least lead to creating a different vaccine so future generations don't suffer.
The studies are far too many to be ignored, but the connections are still fuzzy.
Here is an example how a controversy, no matter how many evidences highly suggestive one side likely wrong, can still last forever. From the link above, we can see it was mainly based on a Daily Mail report back to 28/05/2006 (here is the link: Scientists fear MMR link to autism) regarding a study by Dr. Stephen Walker at Wake Forest University. According to a post on April 30, 2013 at the Autism Science, News and Opinions website entitled “A few points about Steve Walker’s measles/autism study”, this study was never published and actually failed to replicate and dismissed. In fact, shortly after the appearance of the article on Daily Mail, Wake Forest University Baptist Medical Center where Dr. Walker was working made a press release entitled “Wake Forest Researcher Warns Against Making Connection Between Presence of Measles Virus and Autism”, and quoted what Dr. Walker said as “That is not what our research is showing”. According to another post entitled “The Daily Mail (UK) continuing sorry contribution to fear, uncertainty, doubt, and vaccine fears”, Daily Mail also deeply regretted for what it did.


According to a recent review that included five randomised controlled trials (RCTs), one controlled clinical trial (CCT), 27 cohort studies, 17 case-control studies, five time-series trials, one case cross-over trial, two ecological studies, six self controlled case series studies involving in all about 14,700,000 children, exposure to the MMR vaccine was unlikely to be associated with diseases like autism and Crohn's disease. (Demicheli V, Rivetti A, Debalini MG, Di Pietrantonj C. Vaccines for measles, mumps and rubella in children. Cochrane Database Syst Rev. 2012 Feb 15;2:CD004407).

In facing these discrepancies, which one should we prefer to believe? As discussed in my early post on 07-10-2013, we live in the age of information explosion that made it a big challenge to find out those evidences that may help solving instead of adding the mystery. Hope the exchange of info and views may sharp our vision.
 
I posted a reply and it got lost in the Internet.... LOL
What if, the kids were already sick, and the vaccines are the straw that breaks the camel's back?
Is there screening before vaccines? If so, they could see some kind of relative connection between those that got ill, and those that don't. In any case, the good outweighs the bad, sad to say, in the case of vaccines. And we know that any bugs seem to accumulate in the tissues when the immune system is shut off, or busy fighting. Or perpetually burned out.

It isn't really adding to the mystery. Look at the breed of dogs that seem to perpetually suffer with similar disease issues? What is that connection? It isn't just a human one.
It is most likely a hereditary issue, of which then a correction using stem cells might work. Just what are we correcting? Is it a pancreas enzyme balance issue? Is it a cellular component and function issue?
I think some of the clinics have good ideas, they see that the ability to fight C-Diff and MAP are dead, that infusion with stool from healthy people works at times, that worms from pigs work at times, that drugs work at times. But is anyone really healed? Or are they just setting the stage so we can go back to fighting constantly for our health?
The healthy system compared to the sick system should give us the difference to correct, and I know it is much more complicated than just turn number 2 off and number 9 on. But I do think that we should stop trying to find more symptomatic and related issues, and get to what is really malfunctioning, the correct cell and chemistry response to life as we live it. If that is hereditary, then it can probably be corrected soon. I'm putting my money on stem cell research.
 
Thanks for sharing the thoughts.

Theoretically, if vaccine really increased the risk of autism or Crohn’s disease, no matter worked primarily or secondarily, it should be shown up in the many epidemiological studies.

Talking about the dog, I have actually suspected that IBD in human might be more like IBD in dogs and cats more than Johne’s disease in cattle (Qin X. What is human inflammatory bowel disease (IBD) more like: Johne's disease in cattle or IBD in dogs and cats? Inflamm Bowel Dis. 2008 Jan;14(1):138)

IBD just emerged and became more and more popular for about a century. In my opinion, environmental factors would have played the predominant role, although genetic and hereditary factors may also be involved in its display. I agree on the notion that we should stop trying to find more symptomatic and related issues, and get to what is really malfunctioning, the correct cell and chemistry response to life as we live it. However, without a clear understanding of the whole process especially the primary cause, we may even not be able to tell what we see is a malfunction or a normal reaction. I suspected that the inflammation in IBD might be just a natural reaction of the immune system to the infiltrated bacterial and dietary components from the lumen due to a weakening in gut barrier (Qin X. What caused the increase of autoimmune and allergic diseases: a decreased or an increased exposure to luminal microbial components? World J Gastroenterol. 2007 Feb 28;13(8):1306-7), just like an inflammation of the skin in response to an infection after the cut, as discussed in my early post on 11-25-2012. I am afraid if the original causative factor is not identified and got rid of, the “good” cells generated from the stem cells may just react the same way and became “bad” again. Any way, stem cell is a hot area of study, it would be sure people will pursue in this area. More studies and clinical trials will eventually tell.
 
Xiaofa: This just came out,about an hour ago.
Popular artificial sweetener not so sweet.
As you may have guessed before reading the article, sucralose.
Hopefully this is new work and not the older paper.
Old Mike

http://medicalxpress.com/news/2014-06-popular-artificial-sweetener-sweet.html
Thanks Old Mike for sharing the info. I think we should take a more prudent attitude toward the safety of artificial sweeteners and other dietary chemicals. At least, their effect on gut bacteria has never been taken into account when assessing their toxicity. Based on early discussion on the possible link between spicy food and sugar and IBD in China (see post on 02-01-2014), I submitted a paper to Chinese Medical Journal entitled “May artificial sweeteners not sugar be the culprit of dramatic increase of inflammatory bowel disease in China?”, and it has been accepted for publication.

As for the paper I communicated with you early, now it is published online (Qin X. May bacterial or pancreatic proteases play a critical role in IBD World Journal of Gastroenterology 2014 (in press)). The full article as well as Peer-review Report from the reviewers, etc, can be found there. As stated in the ACKNOWLEGEMENTS section of the paper (just before the references), thank you Old Mike for sharing the original paper with me on this forum.

Xiaofa
 
Xiaofa: Thank you again.

This might be another interesting aspect of the western diet which has been overlooked, over eating.
Throughout history humans did not always eat 3 meals a day, really started
in England with industrialization. As you know from the history of IBD,the increase in incidence started also in England.
Fasting may in fact be a necessary control on the immune system,by getting
rid of damaged cells, or even erasing some memory cells that are defective.
Then again are we also over feeding the gut bacteria.

As a tie in with your theory,over eating/excessive amount of food too many times a day, might produce a constant load of pancreatic protease,which may overwhelm our colon anti-protease enzymes.
Perhaps an answer to many of our so called idiopathic diseases.
Old Mike
http://medicalxpress.com/news/2014-06-fasting-triggers-stem-cell-regeneration.html



full text

http://www.cell.com/cell-stem-cell/fulltext/S1934-5909(14)00151-9

Few more thoughts.
I have to imagine in paleo times, there were many years of intermittent fasting throughout a persons life.

Makes you wonder if over eating is perhaps a cause of autoimmune disease.

Then again do we want to generate new high powered immune cells,might not be good,dont know.

I quess will have to start to look at this more,perhaps fasting is normal for humans,and perhaps even necessary.

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



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

Autophagy.
http://www.ncbi.nlm.nih.gov/pubmed/9003009

http://www.ncbi.nlm.nih.gov/pubmed/23295687



autophagy seems to be mostly involved with crohn's at least for a defect in infected cell clearance

but at this point who knows what other defects are in the immune system cells that might be cleared.

http://www.herbalzym.com/2013/02/ul...hagy-and-innate-immunity-in-ibd-pathogenesis/

Another case for fasting. Got to wonder if we eat too much to often. New info.

Also too much fortification/vitamins/antioxidants.



http://medicalxpress.com/news/2014-06-theory-diabetic-complications-therapeutic-approach.html

older paper might even be dangerous if old,unless of course you get new immune cells

http://ajcn.nutrition.org/content/74/5/670.full

some history of breakfast.
http://www.bbc.com/news/magazine-20243692



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



animal overeating

http://www.aces.edu/pubs/docs/U/UNP-0089/UNP-0089.pdf



people,perhaps depending on genetics some get overweight some get IBD

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3650896/
 
Last edited:
Being reported on the BBC website today. I am not sure the connection with "junk food" is helpful or accurate, but good to see this problem getting the attention it deserves.
As described in the paper discussed here and multiple papers published afterwards (Here is the link), I have suspected that sucralose may be the important causative factor for the recent worldwide increase of IBD. I have found evidence for countries like Canada, the US, Australia, Norway, Ireland, Singapore, Saudi, etc. I have wondered for a long time why we did not see an increase in IBD in UK after its approval of sucralose in 2002. Well, here comes the evidence. Now we have another “coincidence”.
 
As described in the paper discussed here and multiple papers published afterwards (Here is the link), I have suspected that sucralose may be the important causative factor for the recent worldwide increase of IBD. I have found evidence for countries like Canada, the US, Australia, Norway, Ireland, Singapore, Saudi, etc. I have wondered for a long time why we did not see an increase in IBD in UK after its approval of sucralose in 2002. Well, here comes the evidence. Now we have another “coincidence”.
check this out, maybe this is the data you need.

http://www.crohnsforum.com/showthread.php?t=64770
 
I've never used saccharin or sucralose and have probably had Crohn's since 1970 - but wasn't diagnosed until 1987. Some family members had it back before WWII, and they certainly didn't use any artificial sweeteners then.

I suspect this is just another dead end, caused mostly by the improved diagnosis and reporting of IBD that coincided with the introduction of artificial sweeteners.

No doubt any "evidence" is caused by an inevitable biased treatment of the individual data points to support the hypothesis. Even scientists and physicians are human and can't help but support their pet ideas that they have a lot invested in.
 
I've never used saccharin or sucralose and have probably had Crohn's since 1970 - but wasn't diagnosed until 1987. Some family members had it back before WWII, and they certainly didn't use any artificial sweeteners then.

I suspect this is just another dead end, caused mostly by the improved diagnosis and reporting of IBD that coincided with the introduction of artificial sweeteners.

No doubt any "evidence" is caused by an inevitable biased treatment of the individual data points to support the hypothesis. Even scientists and physicians are human and can't help but support their pet ideas that they have a lot invested in.
Saccharin I think came out in late 1800's, i think i may have been popularized during world war 1, it was also used as a preservative for canning as it was very good at inhibiting the growth of bacteria.These properties make it a good candidate for disturbing the intestinal bacteria, which is now suspected to be the prime cause of IBD, recent success in fecal transplants seem to suggest this is all true. lack of bacterial diversity is likely the prime cause of IBD, regardless of the toxin that is secondary to its disturbance such as antibiotics, saccharin, sucralose, carrageenan etc.
 
I've never used saccharin or sucralose and have probably had Crohn's since 1970 - but wasn't diagnosed until 1987. Some family members had it back before WWII, and they certainly didn't use any artificial sweeteners then.
As explicitly described in the paper discussed here (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3332284/pdf/WJG-18-1708.pdf ), saccharin was introduced into the market in 1887, decades before even World War I (WWI). It had been used in thousands of kinds of foods, beverages and other things like tooth pastes. Learn to read more and think more, before claim an assumption as CERTAIN.
 
Thanks Old Mike for sharing the info. It is indeed a very interesting study. I do not think artificial sweeteners are the sole cause of IBD. However, as for the wide use, I believe they could be one of the major causative factors for the disease. In China, the highest incidence of IBD including both Crohn’s disease and ulcerative colitis occurred in Guangzhou, one of the most southern cities of China, which is totally opposite to the general North-South gradient of IBD. However, Guangzhou is well know for the sweet taste of the dishes. As discussed in the early posts, I suspected that artificial sweeteners might be the possible cause for the high incidence of IBD there. I submitted a paper to Chinese Medical Journal and it is just published (Qin X. May artificial sweeteners not sugar be the culprit of dramatic increase of inflammatory bowel disease in China? Chin Med J (Engl). 2014 Sep;127(17):3196-7).

Recently there was also a paper regarding nationwide study of IBD in Denmark (Nørgård BM, et al. The incidence of ulcerative colitis (1995-2011) and Crohn's disease (1995-2012) - Based on nationwide Danish registry data. J Crohns Colitis. 2014 Mar 24. pii:S1873-9946(14)00103-2. [Epub ahead of print]). Interestingly, if we check it against the studies on incidence of IBD in the same period in the adjacent countries, we can find that pediatric IBD in Sweden shared similar trend of change as the general population IBD in Denmark but not pediatric IBD in Norway (see the figure below):



Again these peculiar phenomena fit into the pattern of consumption of some artificial sweeteners, but seems difficult to be explained by many current popular hypotheses such as hygiene condition, vitamin D and sunshine (Stockholm shared similar latitude with Oslo but not Denmark), smoking, Mycobacterium avium subspecies paratuberculosis (MAP, which is very low in Sweden but high in Denmark and Norway), worms, etc. I wrote a paper on this and it is just published (Qin X. Why pediatric inflammatory bowel disease (IBD) in Sweden shared similar trend of change as general population IBD in Denmark but not pediatric IBD in Norway? Scand J Gastroenterol. 2014 Oct;49(10):1268-1269). Right now, there are many theories regarding the cause of IBD. I believe each hypothesis would have to be checked constantly against what happened in the real world where lays the clues to differentiate real from tale.
 
Last edited:
Xiaofa:Just an aside.
I quite smoking 1977 UC 1980.
My wife quit smoking at the same time, no IBD.
She also drinks about a 12 pack of diet pepsi a week,no IBD.
There is of course something else going on as risk factors,such as genetics,MAP infections.

Also this was off my radar, MAP is in fruits and vegetables,which might
confound some of the thinking on MAP in herds and high IBD rates,
versus areas with low MAP in animal herds and high IBD rates.
here is a
LINK
Old Mike
 
Xiaofa:Just an aside.
I quite smoking 1977 UC 1980.
My wife quit smoking at the same time, no IBD.
She also drinks about a 12 pack of diet pepsi a week,no IBD.
There is of course something else going on as risk factors,such as genetics,MAP infections.

Also this was off my radar, MAP is in fruits and vegetables,which might
confound some of the thinking on MAP in herds and high IBD rates,
versus areas with low MAP in animal herds and high IBD rates.
here is a
LINK
Old Mike
There is definitely reason for the striking increase of IBD since last century. I would be happy to see explanations better than mine.

However, to my knowledge, large amounts of MAP are only generated by animals with Johne’s disease and shed into the environment through feces. Then MAP will eventually die (although that may take months) but WITHOUT the capability of replication/proliferation in the environment. If these would be the case, MAP on the vegetable or fruit would be more likely just the result of contamination from those animals, making the scenario of low MAP in animal herds (but high MAP in vegetables and fruits) in high IBD areas seems unlikely. Do you have any evidence other than this?
 
Xiaofa: There is no doubt in my mind that artificial sweeteners disrupt gut bacteria, so therefore they would seem to be a risk factor for IBD. Yet multiple millions ingest sweeteners and do not have IBD. Of course there are multiple millions that have IBS which might be a mild form of gut disease that has not manifested into IBD. I know you are saying that sweeteners are not the only cause of IBD,and other risk factors must be involved.
At some point the risk factors add up and IBD manifests.

In the case of my wife,she has at least two risk factors for IBD, quitting smoking and ingesting a large amount of artificial sweetners,and she lives with me which may also be a risk factor, yet she has no IBD,or IBS.

I forgot to mention in my other post that we moved into my current house in
1979,which is a 1/4 mile from a working dairy farm, I drank their milk she did not, my UC came on in 1980.

What I was trying to say in my other post is that importation of MAP contaminated vegetables may somehow confound IBD incidence patterns.
Also MAP has now been found in domestic shower water.

If I remember correctly in about 28% of non IBD people they find MAP in the colons,yet they do not have IBD,so again one possible risk factor is not sufficient to cause IBD.

How do we explain IBD clustering, of course it might be chance but unlikely.
Here is a quote from someone on this forum,from about 2 weeks ago.

"Up until about 2 years ago, I had never heard of Crohn's Disease. Since I've been diagnosed, off the top of my head I know now of 10 people within my workplace who also have it. For a relatively small staff pool, that ratio raises concern for me.

I work within the animal care industry which makes me believe that whilst predisposition to the disease may exist, a form of bacteria may "activate" the disease."


Here is an interesting cluster.
http://www.ncbi.nlm.nih.gov/pubmed/21703899

As we can see here MAP was first discovered in South Korea in 1967.
http://www.ncbi.nlm.nih.gov/pubmed/22749233
By the way I spent the year 1971 in Korea.

From this we learn an low but increasing incidence.
Now I have to suspect there is also increasing consumption of sweeteners.
Have to look for data on this.
http://www.ncbi.nlm.nih.gov/pubmed/17941073

All that being said. MAP may also just be a bystander bacteria,and that
is why it is so difficult to determine what is really going on.

Old Mike
 
Last edited:
Thanks Old Mike for sharing the thought and info. I share the same notion with you that IBS might be just a mild form of gut disease that has not manifested into IBD. As discussed in my early posts, I think even some artificial sweeteners or something else indeed the main culprit of IBD, the relationship between these agents and IBD would be more like those between smoking and lung cancer. Although more than 90% lung cancer attribute to smoking, most smokers did not develop the disease and lung cancer definitely can also be caused by other factors like radon. Yes, there are many factors that may have participated in the eventual manifestation of the disease in a certain individual. However, there may be still some primary cause(s) and shared root mechanism we may need to find out for the effective treatment and prevention of the disease. For instance, although I also believe gut bacteria played a critical for the sustained inflammation of gut in IBD patients. However, in my opinion, the increased infiltration of gut bacteria and their debris may be just the consequence secondary to the impaired inactivation of digestive proteases and the resultant damage of gut barrier due to reduction of some kinds of gut bacteria. Therefore, I believe giving back certain kinds of bacteria capable of doing so (probably one or two strains might be enough, which would be much better than the poorly defined cumbersome FMT from randomly selected donors) such as same strains of probiotics would be a simple and potentially highly effective approach. This is in contrast to the notion that this disease is caused primarily by uncontrolled infection by some pathogens and thus a cure can only be achieved by eliminating the bacteria via agents like high doses of combined antibiotics, which may result in further reduction in gut bacteria and, if my notion would be true, exacerbate the disease. So, finding the cause of IBD would be an important issue. However, it seems still a long way to go.


As for MAP, I deeply respected the great endeavor of some researchers in this area and the high enthusiasm of the patients. However, I personally feel there are still many questions we may have to face for the asserted causal relationship. For instance, you mentioned the finding of MAP in domestic shower water in recent reports, which had caused panic in some people. That study is done by quantitative PCR (http://www.mdpi.com/2076-0817/3/3/577) that detects a tiny piece of DNA, not the living bacteria. Even what they found is indeed livable MAP, the treatment of the open water by filtration and chlorination at water plants would have greatly reduced the amount of MAP. However, multiple studies had well documented long time ago that people with tap water had increased risk of IBD than those drinking raw water where the amount of MAP would be likely even much higher, indicating there seems actually a negative correlation between the amount of MAP in drinking water and the risk of IBD. It was also claimed that MAP may get into the aerosols that may be associated with the clustered cases of CD along the river adjacent to some farms or increased incidence of CD at the downwind side of the river. However, on the other hand, it is also documented that Johne’s disease in a farm can be even eliminated by just designating the newly born MAP-negative and positive calves into separated pens (http://www.johnes.org/dairy/control.html), indicating not only the aerosols but even the potentially heavily contaminated dusts, grass, leaves, etc, floating over the farm are not enough to cause the real infection of MAP to the healthy but highly susceptible calves in the adjacent pen. How come people can so easily catch the disease, even by the trace amount of MAP in the aerosol generated from the water of river far away from the farm? Usually increased susceptibility is accompanied with augmented proliferation of the pathogen. However, MAP in patients is barely detectable, not because the method is not available, rather because the amount is too little. We have no problem to detect many kinds of virus that are much smaller than bacteria. Now we can see atoms through a microscope. How come it turns out to be so difficult to detect the bacteria that caused such massive damage of the gut as seen in CD patients? There are multiple well-established methods to identify MAP infected animal in herds. Large amounts of MAP can be found in the tissue or feces of animal with Johne’s disease and the disease can be easily transmitted from one animal to another and from the mother to the calve. However, CD is still regarded as noncontagious among people or mother to the babe. Apparently, there are actually some fundamental differences between Johne’s disease and CD we may have to face. It has also been claimed that more than 90% of Crohn’s disease may attribute to MAP. As we know, places such as Sweden and Western Australia have very low MAP contamination but high rates of CD. As shown in the figure in the early post above, Sweden has pediatric IBD even higher than the adjacent Norway, indicating also a negative correlation between the incidence of IBD and prevalence of MAP that seems difficult to be explained by importation of vegetables, fruits, etc, from the adjacent MAP contaminated areas. In facing these conflicting “facts”, we may have to take into account all the evidences to make a sagacious judgment. Hopefully, those ongoing clinical trials would provide us with more valuable information. The possible link between some artificial sweeteners and IBD is also just a hypothesis. As constantly advocated during the more than a decade, I hope those capable checking out this possibility. Despite the long effort, it still failed to raise any action. This made me strongly feel that IBD remains a mystery not because the disease and the cause is too complicated, rather too little efforts was spent on the right approach. Therefore, it may still take some time to determine the cause of IBD, but we will eventually reach the goal.
 
Here is a new study showing that little effect of vitamin D on colitis in IL-10 deficient mice (Glenn AJ, et al. Long-Term Vitamin D3 Supplementation Does Not Prevent Colonic Inflammation or Modulate Bone Health in IL-10 Knockout Mice at Young Adulthood. Nutrients. 2014 Sep 22;6(9):3847-3862), suggesting minimal role of vitamin D/sunshine in IBD. This is in striking contrast with the recently envisioned critical role of vitamin D in the disease. Evidence for both sides would be definitely accumulating and it just served as another example of controversy that may again last incessantly. So, many of the current medical research is not bring a solution to the problem rather generating a lot of conflicting “facts”.
 

Lady Organic

Moderator
Staff member
thx, I ve never really believed vitamine D played a role in triggering IBD. I dont think southern USA states (very sunny and hot) have lower prevalence of IBD, and mostly the prevalence of IBD in developping countries such as India, China and arabic countries is dramatically increasing since a decade; countries where sweets, transformed and processed food sold in groceries are gainning popularity over home cooked meals with all natural ingredients. Countries and cities where access to groceries is limited have lower prevalence of IBD.
 
Yes, the recent striking increase of IBD in many countries over the world seems unlikely to be explained by sunshine/vitamin D. Interestingly, there are multiple recent reports on decrease in the incidence of IBD including both Crohn’s disease and ulcerative colitis in Canada (Leddin D, et al. Decreasing incidence of inflammatory bowel disease in Eastern Canada: a population database study. BMC Gastroenterol. 2014 Aug 9;14:140 AND Bitton A, et al. Epidemiology of inflammatory bowel disease in Québec: recent trends. Inflamm Bowel Dis. 2014 Oct;20(10):1770-6), suggesting this disease would be indeed preventable once we find out what caused it.
 
Xiaofa Qin, your mention the reduced incidence of CD/UC is preventable once we know what caused it, which goes without saying. And you point to this study as evidence. Yet I cannot believe that the Canadians have figured out how to reduce the incidence rate and are holding out on the rest of the world. Will you please expand on your reasoning regarding this?
 

Lady Organic

Moderator
Staff member
Thanks a lot Xiaofa.

thats quite interesting... these two research go really against what I had thought! One fact that has not been mentionned in the discussions of both papers, and that couls also account for this decrease is that the waiting list to see a GI is extremly long here in Québec. Not sure about Nova Scotia, but Im guessing it would be the same. A patient with mild to moderate symptoms of possible CD can wait for longer than 6 months to meet a GI. Gi's have been super loaded having to screen and scope colo-rectal cancer which had been largely pushed and advertized in general 50+ population for prevention in the last decade. THe trend has just shut down now, and since a year, its litteraly impossible for a healthy patient without risk factors to be screened at public hospital endoscopy. I put my father on a waiting list 2 years ago upon recommendation of my GI and finally, the hospital cancelled his demand, telling him, the rules have changed. I guess they realized GIs were overwhelmed and needed more time for the really sick people and no more for general prevention...

So do these patients on long waiting lists seek alternative treatments? with naturopaths, natural remedies, diets, etc? have they been lost? The system is overwhelmed here, its a possibility. Im wondering. it will be interesting to see additional epidemiologic research after this recent stop in universal coloscopy colorectal-cancer screening. Maybe Im off target and wrong, but thats what crossed my mind when I tried to explain why there would be a decrease in incidence of reported IBD. Yet, Im truly hoping Im wrong, and that there is a real decrease in population. future will tell. thanks again for your participation in the forum.
 
Xiaofa Qin, your mention the reduced incidence of CD/UC is preventable once we know what caused it, which goes without saying. And you point to this study as evidence. Yet I cannot believe that the Canadians have figured out how to reduce the incidence rate and are holding out on the rest of the world. Will you please expand on your reasoning regarding this?
I am not implying some people have figured out the cause of the disease and held it out. Rather I am suggesting the need to put more efforts to find out the cause of the disease.

Thanks a lot Xiaofa.

thats quite interesting... these two research go really against what I had thought! One fact that has not been mentionned in the discussions of both papers, and that couls also account for this decrease is that the waiting list to see a GI is extremly long here in Québec. Not sure about Nova Scotia, but Im guessing it would be the same. A patient with mild to moderate symptoms of possible CD can wait for longer than 6 months to meet a GI. Gi's have been super loaded having to screen and scope colo-rectal cancer which had been largely pushed and advertized in general 50+ population for prevention in the last decade. THe trend has just shut down now, and since a year, its litteraly impossible for a healthy patient without risk factors to be screened at public hospital endoscopy. I put my father on a waiting list 2 years ago upon recommendation of my GI and finally, the hospital cancelled his demand, telling him, the rules have changed. I guess they realized GIs were overwhelmed and needed more time for the really sick people and no more for general prevention...

So do these patients on long waiting lists seek alternative treatments? with naturopaths, natural remedies, diets, etc? have they been lost? The system is overwhelmed here, its a possibility. Im wondering. it will be interesting to see additional epidemiologic research after this recent stop in universal coloscopy colorectal-cancer screening. Maybe Im off target and wrong, but thats what crossed my mind when I tried to explain why there would be a decrease in incidence of reported IBD. Yet, Im truly hoping Im wrong, and that there is a real decrease in population. future will tell. thanks again for your participation in the forum.
Thanks for sharing the thoughts. As a chronic disease without a cure, I do not think workload of GI may result in missed diagnose of IBD over a decade that attributed to the reported decline of IBD in Canada. As shown in the Figure in the paper discussed here, a decline or plateau in incidence of IBD had also been observed during later 1970s and early 1980s in multiple studies from many countries such as Canada, the United States, Demark, Germany, Japan, Israel, Sweden, and United Kingdom, but those declines were followed by striking increase again in IBD in these countries and all over the world afterwards. These multiple ups and downs of IBD seems more likely caused by dynamically changed exposure to some agents in the environment. Therefore, I advocate sparing more efforts to find out these environmental causative factors that may be critical not only for the cure but also effective prevention of the disease.
 
A large scale multi-countries prospective epidemiological study just comes out (Chan SS, et al. Carbohydrate Intake in the Etiology of Crohn's Disease and Ulcerative Colitis. Inflamm Bowel Dis. 2014 Sep 26. [Epub ahead of print] ), showing no association between the intakes of carbohydrates, sugar, starch, and inflammatory bowel disease (IBD) including both Crohn's disease (CD) or ulcerative colitis (UC). Again, this would be another strong controversy with the claimed critical role of carbohydrate (sugar, starch, etc) in IBD and the asserted miracle efficacy of some special carbohydrate diet (SCD) on the disease.

**************************************************

Inflamm Bowel Dis. 2014 Sep 26. [Epub ahead of print]

Carbohydrate Intake in the Etiology of Crohn's Disease and Ulcerative Colitis.

Chan SS1, Luben R, van Schaik F, Oldenburg B, Bueno-de-Mesquita HB, Hallmans G, Karling P, Lindgren S, Grip O, Key T, Crowe FL, Bergmann MM, Overvad K, Palli D, Masala G, Khaw KT, Racine A, Carbonnel F, Boutron-Ruault MC, Olsen A, Tjonneland A, Kaaks R, Tumino R, Trichopoulou A, Hart AR.

Author information
1Norwich Medical School, Department of Medicine, University of East Anglia, Norwich, United Kingdom; 2Department of Gastroenterology, Norfolk and Norwich University Hospital NHS Trust, Norwich, United Kingdom; 3Strangeways Research Laboratory, Institute of Public Health, University of Cambridge, United Kingdom; 4University Medical Center Utrecht, Department of Gastroenterology and Hepatology, Utrecht, the Netherlands; 5National Institute of Public Health and the Environment (RIVM), Bilthoven, the Netherlands; 6Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, United Kingdom; 7Department of Public Health and Clinical Medicine, Nutritional Research, Umeå University, Umeå, Sweden; 8Department of Public Health and Clinical Medicine, GI Unit, Umeå University, Umeå, Sweden; 9Department of Clinical Sciences, University Hospital, Malmö, Sweden; 10Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom; 11Department of Epidemiology, German Institute of Human Nutrition, Potsdam, Germany; 12Department of Clinical Epidemiology, University of Aarhus, Denmark; 13Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Centre, Florence, Italy; 14INSERM, Centre for Research in Epidemiology and Population Health, Institut Gustave Roussy, Paris, France; 15Université Paris Sud, UMRS 1018, Paris, France; 16Department of Gastroenterology, Bicêtre University Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France; 17Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark; 18Division of Clinical Epidemiology, DKFZ-German Cancer Research Centre, Heidelberg, Germany; 19Cancer Registry and Histopathology Unit, "Civic - M.P.Arezzo" Hospital, Ragusa, Italy; 20WHO Collaborating Center for Food and Nutrition Policies, Athens, Greece.

Abstract

BACKGROUND:
Diet may have a role in the etiology of inflammatory bowel disease. In previous studies, the associations between increased intakes of carbohydrates, sugar, starch, and inflammatory bowel disease are inconsistent. However, few prospective studies have investigated the associations between these macronutrients and incident Crohn's disease (CD) or ulcerative colitis (UC).

METHODS:
A total of 401,326 men and women were recruited between 1991 and 1998. At recruitment, dietary intakes of carbohydrate, sugar, and starch were measured using validated food frequency questionnaires. The cohort was monitored identifying participants who developed incident CD or UC. Cases were matched with 4 controls, and odds ratios were calculated for quintiles of total carbohydrate, sugar, and starch intakes adjusted for total energy intake, body mass index, and smoking.

RESULTS:
One hundred ten participants developed CD, and 244 participants developed UC during follow-up. The adjusted odds ratio for the highest versus the lowest quintiles of total carbohydrate intake for CD was 0.87, 95% CI = 0.24 to 3.12 and for UC 1.46, 95% CI = 0.62 to 3.46, with no significant trends across quintiles for either (CD, Ptrend = 0.70; UC, Ptrend = 0.41). Similarly, no associations were observed with intakes of total sugar (CD, Ptrend = 0.50; UC, Ptrend = 0.71) or starch (CD, Ptrend = 0.69; UC, Ptrend = 0.17).

CONCLUSIONS:
The lack of associations with these nutrients is in agreement with many case-control studies that have not identified associations with CD or UC. As there is biological plausibility for how specific carbohydrates could have an etiological role in inflammatory bowel disease, future epidemiological work should assess individual carbohydrates, although there does not seem to be a macronutrient effect.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.
 
Read these two again.

http://www.ncbi.nlm.nih.gov/pubmed/8358131
http://www.ncbi.nlm.nih.gov/pubmed/17551835



It now occurs to me that if UC people can be put into remission just with the camostat or BBI,there are implications.

Excess protease can come from digestive enzymes that are not deactivated, bacteria, and immune cells.

The proteases are dissolving the mucus and I guess any part of the colon they can contact,UC people also have excess

proteases in stools.



Implications:

By inhibiting protease/keeping the mucus intact you can go into remission, regardless if UC is autoimmune,or biofilms or bacteria are driving the inflammation.




We have an, alpha 1-proteinase inhibitor system which can become overwhelmed and allow protease to attack the mucus and tissue.


This is a way to perhaps accomplish the same thing without taking protease inhibitors.

http://www.ncbi.nlm.nih.gov/pubmed/2833080
 
Microb Cell Fact. 2015 Feb 26;14(1):26. doi: 10.1186/s12934-015-0198-4.

Serine protease inhibitors protect better than IL-10 and TGF-β anti-inflammatory cytokines against mouse colitis when delivered by recombinant lactococci.

Bermúdez-Humarán LG1,2, Motta JP3,4,5,6, Aubry C7,8, Kharrat P9,10, Rous-Martin L11,12,13, Sallenave JM14,15,16, Deraison C17,18,19, Vergnolle N20,21,22,23, Langella P24,25.

Abstract

BACKGROUND: Different studies have described the successful use of recombinant lactic acid bacteria (recLAB) to deliver anti-inflammatory molecules at the mucosal level to treat Inflammatory Bowel Disease (IBD).

METHODS: In order to identify the best strategy to treat IBD using recLAB, we compared the efficacy of different recombinant strains of Lactococcus lactis (the model LAB) secreting two types of anti-inflammatory molecules: cytokines (IL-10 and TGF-β1) and serine protease inhibitors (Elafin and Secretory Leukocyte Protease Inhibitor: SLPI), using a dextran sulfate sodium (DSS)-induced mouse model of colitis.

RESULTS: Our results show that oral administration of recombinant L. lactis strains expressing either IL-10 or TGF-β1 display moderate anti-inflammatory effects in inflamed mice and only for some clinical parameters. In contrast, delivery of either serine protease inhibitors Elafin or SLPI by recLAB led to a significant reduction of intestinal inflammation for all clinical parameters tested. Since the best results were obtained with Elafin-producing L. lactis strain, we then tried to enhance Elafin expression and hence its delivery rate by producing it in a L. lactis mutant strain inactivated in its major housekeeping protease, HtrA. Strikingly, a higher reduction of intestinal inflammation in DSS-treated mice was observed with the Elafin-overproducing htrA strain suggesting a dose-dependent Elafin effect.

CONCLUSIONS: Altogether, these results strongly suggest that serine protease inhibitors are the most efficient anti-inflammatory molecules to be delivered by recLAB at the mucosal level for IBD treatment.
 
This might be related I'm not sure.

PLoS One. 2012;7(11):e49547. doi: 10.1371/journal.pone.0049547. Epub 2012 Nov 14.
A low dose of fermented soy germ alleviates gut barrier injury, hyperalgesia and faecal protease activity in a rat model of inflammatory bowel disease.


Abstract
Pro-inflammatory cytokines like macrophage migration inhibitory factor (MIF), IL-1β and TNF-α predominate in inflammatory bowel diseases (IBD) and TNBS colitis. Increased levels of serine proteases activating protease-activated receptor 2 (PAR-2) are found in the lumen and colonic tissue of IBD patients. PAR-2 activity and pro-inflammatory cytokines impair epithelial barrier, facilitating the uptake of luminal aggressors that perpetuate inflammation and visceral pain. Soy extracts contain phytoestrogens (isoflavones) and serine protease inhibitors namely Bowman-Birk Inhibitors (BBI). Since estrogens exhibit anti-inflammatory and epithelial barrier enhancing properties, and that a BBI concentrate improves ulcerative colitis, we aimed to evaluate if a fermented soy germ extract (FSG) with standardized isoflavone profile and stable BBI content exert cumulative or synergistic protection based on protease inhibition and estrogen receptor (ER)-ligand activity in colitic rats. Female rats received orally for 15 d either vehicle or FSG with or without an ER antagonist ICI 182.780 before TNBS intracolonic instillation. Macroscopic and microscopic damages, myeloperoxidase activity, cytokine levels, intestinal paracellular permeability, visceral sensitivity, faecal proteolytic activity and PAR-2 expression were assessed 24 h, 3 d and 5 d post-TNBS. FSG treatment improved the severity of colitis, by decreasing the TNBS-induced rise in gut permeability, visceral sensitivity, faecal proteolytic activity and PAR-2 expression at all post-TNBS points. All FSG effects were reversed by the ICI 182.780 except the decrease in faecal proteolytic activity and PAR-2 expression.

In conclusion, the anti-inflammatory properties of FSG treatment result from two distinct but synergic pathways i.e an ER-ligand and a PAR-2 mediated pathway, providing rationale for potential use as adjuvant therapy in IBD.
 
Last edited:
Immunol Lett. 2015 Mar 28. pii: S0165-2478(15)00048-6. doi: 10.1016/j.imlet.2015.03.007. PMID:25827759

Can inflammatory bowel disease really be solved by the multiple -omics and meta-omics analyses?

Xiaofa Qin, M.D., Ph.D
Founder/President
GI Biopharma Inc
New Jersey
USA

I read with great interest the paper by Huang et al. [1] regarding the multi -omics analysis of inflammatory bowel disease (IBD). This paper as well as multiple others on this topic [2–4] represented the current mainstream notion that IBD is extremely complex that can only be elucidated through extensive research by sophisticated methods such as the multi -omics (genomics, transcriptomics, proteomics, metabolomics, etc.) and meta-omics analyses of the host and microbiota, to which I have a totally different perception.

In fact, at about the same time when the first risk gene of IBD was found more than a decade ago [5,6], I had found evidence suggesting a possible simple cause and mechanism of IBD – impaired inactivation of digestive proteases mediated by deconjugated bilirubin as the result of inhibition of gut bacteria by dietary chemicals such as saccharin [7]. It provided simple explanations for many puzzles in IBD such as the emerging of clustered cases of IBD around the beginning of last century, the dramatic increase of IBD in the western countries since 1950s, and the leveling off or decrease of IBD as observed in multiple studies during later 1970s and early 1980s at the time when saccharin was found capable of causing cancer in animals. Later, I further found evidence suggesting sucralose, a new generation of artificial sweetener that was first approved in Canada in 1991 followed by many other countries, may also linked to IBD through a similar mechanism as saccharin, which may have contributed to the recent worldwide increase of IBD [8,9]. This led me eventually coming up with a unified hypothesis on the etiology of IBD, including the cause and mechanism of IBD as well as the relationship between ulcerative colitis (UC) and Crohn’s disease(CD) [10]. It provided further explanations for the many puzzles in IBD such as the mysterious remarkable increase of IBD in Alberta of Canada since early 1990s, in Brisbane of Australia since middle 1990s, in north California of the United these since the end of 1990s, and in South-Eastern Norway since middle 2000s, shortly after the approval of sucralose in Canada in 1991, in Australia in 1993, in the United States in 1998, and by the European Union in 2004, as well as the especially remarkable recent increase of IBD in children, the shift in the occurrence from UC to CD over time, the increased appearance of CD in the colon, etc. [10,11]. This possible link was further demonstrated by multiple more epidemiological studies published thereafter from countries across the world such as the United States [12], Canada [13], Ireland [14], Sweden [15],Singapore [16], Saudi Arabia [17], China [18], etc. [19]. More importantly, some peculiar changes in IBD such as the recent decrease in CD but increase in UC in the children in Sweden [15] as well as the shared trend of change of pediatric IBD in Sweden with the general population IBD in Denmark but not pediatric IBD in Norway[20], and even higher incidence of IBD in Guangzhou, China than the adjacent more developed Hong Kong and Macau [19] can also be easily explained by the unified hypothesis through the pattern of consumption of those dietary chemicals.

Thus, the statement in the paper [1] that much of the etiology of IBD remained unexplained seems not accurate. There were indeed simple explanations on the etiology of IBD as shown in the series publications listed above, but all these evidences are just ignored or neglected, intentionally or unintentionally, by the authors of the paper as well as the general society. This is not surprising, as all the evidence presented in my publications was collected by me as an amateur IBD researcher during my spare time from the literature, while the ultimate finding of the nearly 200 risk IBD genes were the result of decade long multiple millions, if not billions, effort of elite IBD professionals all over the world accompanied by series publications in most prestigious scientific journals like Nature [5,6,21–32]. However, time again, the truth usually comes out from theories with the best explanation of the real world rather than those favored by fashion and power. Finding of the 200 risk genes have time and again celebrated as great achievements, but none of these genes, alone or in combinations, can really explain what happened in the real world. This failure may have just reflected the fact that some agents in the environment but not the gene have played a predominant role in the development of IBD, as demonstrated by the fact that IBD emerged and dramatically increased just for about a century.

Although it failed to explain what happened in the real world, this tremendous effort indeed made the significant finding of the considerable overlap among these nearly 200 risk genes between susceptibility loci for IBD and mycobacterial infection with pathways shared between host responses to mycobacteria and those predisposing to IBD [21], thus proposed the direction for further research. However, this notion that IBD is caused by an infection would be strongly contradicted by those facts such as the effective treatment of IBD by immune suppressors and anti-TNF-alpha agents [33]. As demonstrated above, the dietary chemicals theory seems also explained more puzzles of IBD than any pathogens can and is supported by the most recent publications in Nature showing saccharin and other dietary chemicals can increase the risk of colitis, diabetes, and even obesity by altering gut microbiota [34,35]. The links between NOD2 and autophagy-related genes and IBD may just reflected the increased infiltration of gut bacteria and their debris secondary of the increased gut permeability as the result of damage of gut barrier by the poorly inactivated digestive proteases, rather than uncontrolled infection of pathogens in the mucosa [36].

Thus, we should realize that many of the changes revealed by -omics and meta-omics would be just consequence rather than the cause of the disease, while the crucial primary event may be subtle, transient and yet simple. A superficial explanation of data could be misleading or even detrimental for an easy solution of the disease. In my opinion, we should track down the root toward the primary cause of disease rather than just explore up and likely get lost among the small branches and leaves. Therefore, as suggested years ago [37,38] I advocate here again sparing a little bit more efforts finding out the possible causative factors in the environment. Only then we may found the root mechanism, a cure and ultimate prevention of IBD.

References

[1] H. Huang, P. Vangay, C.E. McKinlay, D. Knights, Multi-omics analysis of inflammatory bowel disease, Immunol. Lett. 162 (2014) 62–68.

[2] C. Fiocchi, Integrating omics: the future of IBD? Dig. Dis. 32 (Suppl. 1) (2014)96–102.

[3] Y. Yau, R.W. Leong, M. Zeng, V.C. Wasinger, Proteomics and metabolomics in inflammatory bowel disease, J. Gastroenterol. Hepatol. 28 (2013) 1076–1086.

[4] A.R. Erickson, B.L. Cantarel, R. Lamendella, Y. Darzi, E.F. Mongodin, C. Pan, et al.,Integrated metagenomics/metaproteomics reveals human host-microbiota signatures of Crohn’s disease, PLoS ONE 7 (2012) e49138.

[5] J.P. Hugot, M. Chamaillard, H. Zouali, S. Lesage, J.P. Cezard, J. Belaiche, et al.,Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease, Nature 411 (2001) 599–603.

[6] Y. Ogura, D.K. Bonen, N. Inohara, D.L. Nicolae, F.F. Chen, R. Ramos, et al., Aframeshift mutation in NOD2 associated with susceptibility to Crohn’s disease, Nature 411 (2001) 603–606.

[7] X.F. Qin, Impaired inactivation of digestive proteases by deconjugated bilirubin:the possible mechanism for inflammatory bowel disease, Med. Hypotheses 59(2002) 159–163.

[8] X. Qin, What made Canada become a country with the highest incidence of inflammatory bowel disease: could sucralose be the culprit? Can. J. Gastroenterol. 25 (2011) 511.

[9] X. Qin, What caused the recent worldwide increase of inflammatory bowel disease: should sucralose be added as a suspect? Inflamm. Bowel Dis. 17 (2011)E139.

[10] X. Qin, Etiology of inflammatory bowel disease: a unified hypothesis, World J. Gastroenterol. 18 (2012) 1708–1722.

[11] X. Qin, Food additives: possible cause for recent remarkable increase of inflammatory bowel disease in children, J. Pediatr. Gastroenterol. Nutr. 54 (2012)564.

[12] X. Qin, When and how was the new round of increase in inflammatory bowel disease in the United States started? J. Clin. Gastroenterol. 48 (2014) 564–565.

[13] X. Qin, How to explain recent multiple reports on the decline of inflammatory bowel disease in Canada, Can. J. Gastroenterol. Hepatol. 28 (2014) 620.

[14] X. Qin, The possible cause for the rapid rise in incidence of Irish paediatric inflammatory bowel disease. Response to: Hope B, et al. Rapid rise in incidence of Irish paediatric inflammatory bowel disease, Arch. Dis. Child 97 (7) (2012)590–594.

[15] X. Qin, How to explain the discordant change of ulcerative colitis and Crohn disease in adjacent or even the same regions and time periods, J. Pediatr. Gastroenterol. Nutr. 57 (2013) e30.

[16] X. Qin, Comment on: paediatric inflammatory bowel disease in a multiracial Asian country, Singap. Med. J. 54 (2013) 716.

[17] X. Qin, What might be the cause for the emerging inflammatory bowel disease in Saudi outpatients? Saudi J. Gastroenterol. 20 (2014) 75.

[18] X. Qin, May artificial sweeteners not sugar be the culprit of dramatic increase of inflammatory bowel disease in China? Chin. Med. J. 127 (2014) 3196–3197.

[19] X. Qin, Is the gap between the developed and developing countries in the incidence of inflammatory bowel disease disappearing? Gastroenterology 145(2013) 912.

[20] X. Qin, Why pediatric inflammatory bowel disease (IBD) in Sweden shared similar trend of change as general population IBD in Denmark but not pediatric IBD in Norway? Scand. J. Gastroenterol. 49 (2014) 1268–1269.

[21] L. Jostins, S. Ripke, R.K. Weersma, R.H. Duerr, D.P. McGovern, K.Y. Hui, et al.,Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease, Nature 491 (2012) 119–124.

[22] K. Cadwell, J.Y. Liu, S.L. Brown, H. Miyoshi, J. Loh, J.K. Lennerz, et al., A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells, Nature 456 (2008) 259–263.

[23] Wellcome Trust Case Control Consortium, Genome-wide association study of14,000 cases of seven common diseases and 3,000 shared controls, Nature 447(2007) 661–678.

[24] Z. Liu, J. Lee, S. Krummey, W. Lu, H. Cai, M.J. Lenardo, The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease, Nat. Immunol. 12 (2011) 1063–1070.

[25] M.A. Rivas, M. Beaudoin, A. Gardet, C. Stevens, Y. Sharma, C.K. Zhang, et al., Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease, Nat. Genet. 43 (2011) 1066–1073.

[26] C.A. Anderson, G. Boucher, C.W. Lees, A. Franke, M. D’Amato, K.D. Taylor, et al.,Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47, Nat. Genet. 43 (2011) 246–252.

[27] Y. Momozawa, M. Mni, K. Nakamura, W. Coppieters, S. Almer, L. Amininejad,et al., Resequencing of positional candidates identifies low frequency IL23Rcoding variants protecting against inflammatory bowel disease, Nat. Genet. 43(2011) 43–47.

[28] K. Asano, T. Matsushita, J. Umeno, N. Hosono, A. Takahashi, T. Kawaguchi, et al.,A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population, Nat. Genet. 41 (2009) 1325–1329.

[29] S. Kugathasan, R.N. Baldassano, J.P. Bradfield, P.M. Sleiman, M. Imielinski, S.L.Guthery, et al., Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease, Nat. Genet. 40 (2008) 1211–1215.

[30] S.A. Fisher, M. Tremelling, C.A. Anderson, R. Gwilliam, S. Bumpstead, N.J.Prescott, et al., Genetic determinants of ulcerative colitis include the ECM1locus and five loci implicated in Crohn’s disease, Nat. Genet. 40 (2008) 710–712.

[31] M. Stoll, B. Corneliussen, C.M. Costello, G.H. Waetzig, B. Mellgard, W.A. Koch,et al., Genetic variation in DLG5 is associated with inflammatory bowel disease,Nat. Genet. 36 (2004) 476–480.

[32] V.D. Peltekova, R.F. Wintle, L.A. Rubin, C.I. Amos, Q. Huang, X. Gu, et al., Functional variants of OCTN cation transporter genes are associated with Crohn disease, Nat. Genet. 36 (2004) 471–475.

[33] X. Qin, Does the association with NOD2, autophagy and some pathogens really mean Crohn’s disease is caused by uncontrolled infection? J. Crohn’s Colitis 8(2014) 87.

[34] J. Suez, T. Korem, D. Zeevi, G. Zilberman-Schapira, C.A. Thaiss, O. Maza, et al.,Artificial sweeteners induce glucose intolerance by altering the gut microbiota,Nature 514 (2014) 181–186.

[35] B. Chassaing, O. Koren, J.K. Goodrich, A.C. Poole, S. Srinivasan, R.E. Ley, et al.,Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome, Nature 519 (2015) 92–96.

[36] X. Qin, How NOD2 and autophagy may be related to Crohn’s disease? A view shifted from live microbes to luminal bacterial debris, J. Crohn’s Colitis 8 (2013) 88.

[37] X. Qin, How can we really reduce the morbidity of inflammatory bowel disease – research on genes and cytokines, or find out the causative factors in the environment? J. Crohn’s Colitis 3 (2009) 315.

[38] X. Qin, With the great complexity unveiling, can we still decipher the interaction between gut flora and the host in inflammatory bowel disease to find out the mechanism and cause? How? Inflamm. Bowel Dis. 14 (2008) 1607–1608.
 
Last edited:
This has been an interesting read. Sucralose has been a known trigger food for me for over a year.

Ingesting it in small amounts produces some noticeable bad effects including diarrhea. I can't remember what else, it's been a long time.

Old Mike mentioned intermittent fasting which is interesting. I think if overeating was the problem you would see larger incidence of IBD and much lower of obesity.

However intermittent fasting has shown great results in my Crohn's when I experimented with it.

We know that fasting stimulates apoptosis. It also stimulates production of seratonin in the gut as well as catecholamines. Maintaining proper neurotransmitter balance between seratonin and dopamine has been shown to be an effective therapeutic treatment for Crohn's in some trials.

In a fast we also see Bacteroidetes becoming the dominant gut bacteria as the others starve (including harmful pathogenic bacteria). Bacteroidetes feeds on the intestinal mucins and creates butyric acid which helps heal the gut, however I would fear losing the diversity of other probiotic species like the clostridia groups might encourage more loss of food tolerances.

Ultimately I think this all goes back to gut bacteria.
 
Regarding the decreased risk of inflammatory bowel disease (IBD) with increased intake of milk that was published recently on Inflammatory Bowel Disease (Opstelten JL, Leenders M, Dik VK, et al. Dairy Products, Dietary Calcium, and Risk of Inflammatory Bowel Disease: Results From a European Prospective Cohort Investigation. Inflammatory bowel diseases 2016;22:1403-1411. http://www.ncbi.nlm.nih.gov/pubmed/27120568 ), I wrote a letter to the editors entitled” Increased milk consumption but decreased risk of Crohn’s disease (CD): Critical evidence negated causative role of Mycobacterium avium subspecies paratuberculosis (MAP) in CD”, which was recently published online (http://www.ncbi.nlm.nih.gov/pubmed/27542142 ). Below is the text of the paper:

Increased milk consumption but decreased risk of Crohn’s disease (CD): Critical evidence negated causative role of Mycobacterium avium subspecies paratuberculosis (MAP) in CD

To the Editors:
I read with great interest the paper by Opstelten et al published recently in this journal regarding the intake of dairy products and the risk of inflammatory bowel disease (IBD) [1]. This a large scale prospective cohort epidemiological study by scientists and doctors of countries across Europe and beyond such as the Netherlands, United Kingdom, Sweden, Germany, Denmark, Italy, France, Greece, and Malaysia, reflected the great efforts and high quality of the study. It is found that, compared with nonconsumers, individuals consuming milk had significantly reduced odds of Crohn’s disease (CD) (OR 0.30, 95% CI, 0.13–0.65) and nonsignificantly reduced odds of ulcerative colitis (UC) (OR 0.85, 95% CI, 0.49–1.47), with a conclusion that milk consumption may be associated with decreased risk of developing CD. I think an important aspect the paper failed to address is the century long Mycobacterium avium subsp. paratuberculosis (MAP) and CD controversy. Up to date, there are still deep believers that MAP is the causative factor for CD and even beyond, attributing the increase of these diseases to the widespread of hardly killed MAP through milk [2-4]. Apparently, this is an issue worthwhile to address as it not only affected the diary, herds, and food industry but also showed a tendency of escalation of the MAP panic in the general public from CD to many other diseases. With the evidence I collected during the last fifteen years, I proposed that the impaired inactivation of digestive proteases as the result of reduction in gut bacteria in modern society rather than any pathogens may have played a primary causative role in IBD, as discussed in detail in the paper with a unified hypothesis on the etiology of IBD [5]. The result of the current paper by Opstelten et al provided another critical piece of evidence negate the causative role of MAP in CD. Hope these results may bring in more stringent studies to end the century long MAP/CD controversy and find out the real cause of IBD.

Xiaofa Qin, MD, PhD
GI Biopharam Inc.
Westfield, New Jersey


REFERENCES
1. Opstelten JL, Leenders M, Dik VK, et al. Dairy Products, Dietary Calcium, and Risk of Inflammatory Bowel Disease: Results From a European Prospective Cohort Investigation. Inflammatory bowel diseases 2016;22:1403-1411
2. Davis WC. On deaf ears, Mycobacterium avium paratuberculosis in pathogenesis Crohn's and other diseases. World J Gastroenterol 2015; 21(48): 13411-7.
3. Sechi LA, Dow CT. Mycobacterium avium ss. paratuberculosis Zoonosis - The Hundred Year War - Beyond Crohn's Disease. Front Immunol 2015; 6: 96.
4. Waddell LA, Rajic A, Stark KD, Mc ES. The zoonotic potential of Mycobacterium avium ssp. paratuberculosis: a systematic review and meta-analyses of the evidence. Epidemiol Infect 2015; 143(15): 3135-57.
5. Qin X. Etiology of inflammatory bowel disease: a unified hypothesis. World J Gastroenterol 2012; 18(15): 1708-22.
 
I believe the reverse relationship between milk consumption and the risk of inflammatory bowel disease (IBD) as revealed in the recently published European study (Opstelten JL, Leenders M, Dik VK, et al. Dairy Products, Dietary Calcium, and Risk of Inflammatory Bowel Disease: Results From a European Prospective Cohort Investigation. Inflammatory bowel diseases 2016;22:1403-1411. http://www.ncbi.nlm.nih.gov/pubmed/27120568 ) provided critical evidence that negated the causative role of Mycobacterium avium subspecies paratuberculosis (MAP) in Crohn’s disease (CD) (http://www.ncbi.nlm.nih.gov/pubmed/27542142 ). The result of the European study encouraged me to write a review with my view on the long controversy regarding MAP as the cause of CD, which has been published online in the open access journal of International Journal of Clinical & Medical Microbiology (http://www.graphyonline.com/journal/journal_article_inpress.php?journalid=IJCMM ).

The full text of this paper I wrote can be downloaded by this link: www.graphyonline.com/archives/archivedownload.php?pid=IJCMM-109


Below is the abstract of this paper:

Can Crohn's Disease Really be Caused by Mycobacterium avium Subspecies Paratuberculosis?-With My Alternative Theory that Reduction in Commensal Gut Bacteria and Resultant Impaired Inactivation of Digestive Proteases as the Primary Cause

Xiaofa Qin
GI Biopharma Inc, 918 Willow Grove Road, Westfield, NJ 07090, United States

Abstract

The role of Mycobacterium avium subspecies paratuberculosis (MAP) in Crohn's disease (CD) has been debated for more than a century. Up to date, it remains a highly controversy issue as there are a large amounts of “solid” scientific evidence on both sides. However, I feel many of these conflicts are superficial and the core issue is just the extreme scarcity of MAP in CD and thus the still unresolved conflict between sensitivity and specificity. Along with in-depth analyses of the likely intimate nature of CD, MAP, and the so-called cell-wall deficient spheroplasts, as well as weighted assessment of findings from treatment and epidemiology, here I suggested that the evidences against a critical role of MAP in CD greatly overweigh those support it. Here I also shared a unified hypothesis I developed during the last 15 years regarding the etiology of inflammatory bowel disease (IBD), including the cause and mechanism of IBD as well as the relationship between CD and ulcerative colitis (UC). I proposed that reduction in commensal microbiota in modern society and the resultant impairment in inactivation of pancreatic digestive protease in the lower gut rather than any specific pathogens may have played the primary causative role in both CD and UC.
 
In my opinion, there should be fervent discussions and debates among the different hypotheses and opinions regarding the possible cause and mechanism of IBD. I believe the cure and prevention of IBD largely depends on finding out the root cause and mechanism of disease, which might turn out to be very simple.
 
Oh boy, Xiaofa Qin, you are going to rile up some of the MAP proponents with your follow-up posts. But some of these suggestions does fall in line with the argument asking why is it dairy farmers have lower incidence of CD if there's the higher MAP exposure. I'm curious to see what sort of discussions your post spurs...
 
I read both of these articles with interest. I'm always open to hearing the pros and cons of the MAP debate. I agree - there should be debate and peer review on all of these theories. I guess we'll see what the stage 3 RedHill study says soon, which may clarify the flawed Selby study. A few questions from the above articles then:

1. If Crohn's is based on a genetic predisposition of the immune system not to recognize intracellular pathogens (which is well researched), wouldn't it then follow that only patients with that genetic profile would be susceptible to MAP as a trigger? People whose immune system can recognize MAP and contain it would have no issue wth MAP, no matter how much dairy they consume. It will be really interesting to see if they do follow up studies on this dairy intake theory. Maybe dairy has both protective and harmful effects in CD. A lot of patients get leaky gut as a result of CD. In those cases, adding highly reactive proteins like dairy and gluten can make you feel worse. Cutting those out can relieve some symptoms of leaky gut. I've never thought that the MAP in dairy alone can trigger CD. I think it has to be some other event in a period of waning immunity, but as usual, more research is necessary! Interesting study though.

2. Farmers should get more CD by being in contact with MAP. Unless they don't have the genetics (see above) or if their bodies produce stronger antibodies to MAP by being in constant contact with it. They're less "hygenic" and that may provide some additional protection, right?

3. Clearly a HUGE issue with the whole MAP debate is the lack of any type of standard diagnostic. I agree that the IS900 series is probably not a great indicator (See this post: http://thecrohnsinfection.org/john-...oimmune-diseases-are-they-zoonotic-in-origin/). But if someone could reliably culture and actually grow the spheroplastic form of human MAP (thus proving it's not a dead, leftover form), wouldn't that be the best place to start?

4. Lastly, I noticed that Dr. Qin states that there are no conflicts of interest. Hopefully he can shed some light on this, because I thought he was the sole owner of a Biopharma company formed to study this research? Is that not considered a conflict? Admittedly, this is not my area of expertise, so I will defer to Dr. Qin to clarify any conflicts. (Not trying to be rude or accusatory, I truly want to learn what is considered a conflict in this case.)

I certainly agree that artificial sweetners aren't good for people. I avoid them as much as possible, but it's hard since they're in everything! Certainly the Western diet doesn't seem to be helping IBD patients. It will be interesting to see if further research will show that sweeteners (along with the factors that Dr. Qin mentions) can cause the pathology seen in Crohn's. Are there any independant groups working on research surrounding this hypothesis?
 
Last edited:
Oh boy, Xiaofa Qin, you are going to rile up some of the MAP proponents with your follow-up posts. But some of these suggestions does fall in line with the argument asking why is it dairy farmers have lower incidence of CD if there's the higher MAP exposure. I'm curious to see what sort of discussions your post spurs...
Thanks for sharing your thoughts. I would be glad if any people would like to share their thoughts on this with different opinions, including insightful discussions over scientific journals with those firm proponents of prominent scientific and professional backgrounds. Debate may help to differentiate real versus tale, and truth versus false. In fact, the journal of Inflammatory Bowel Disease published several of my other papers recently (http://www.ncbi.nlm.nih.gov/pubmed/?term=xiaofa+qin ), behind which there are some stories the people here may be interested.


In early 2015, a paper published in Inflammatory Bowel Disease showing remarkable increase of IBD in Korea:

Kim HJ, Ahn HS et al. Incidence and natural course of inflammatory bowel disease in Korea, 2006-2012: a nationwide population-based study. Inflamm Bowel Dis. 2015 Mar;21(3):623-30.

According to the data they cited, I found that the dramatic increase occurred in early 2000s, but leveled off in recent several years. As sucralose was approved in Korea around 2000, I suggested that they check out the possible link between IBD and dietary chemicals such as sucralose and saccharin.

Qin X. How to Explain the Dramatic Increase Around 2000 but Recent Leveling Off of Inflammatory Bowel Disease in Korea? Inflamm Bowel Dis. 2015 Aug;21(8):E16-7.

In the reply, they denied the possible link between food additives and IBD, with the fact that Korea adopted much more strict regulation since 1992 on the use of saccharin.

Ahn HS. Increased Incidence of Inflammatory Bowel Disease in Korea May Not Be Explained by Food Additives. Inflamm Bowel Dis. 2015; 21(8):E17

On checking out their data, it can be found a sudden decrease in IBD during 1992 and 1993, therefore I reminded them that the possible link between food additives and IBD should not be ruled out.

Qin X. Food Additives Should Not Be Ruled Out as the Possible Causative Factors of Inflammatory Bowel Disease in Korea. Inflamm Bowel Dis. 2016 Jan;22(1):E1.

In the reply, they argued that the decrease during 1992 and 1993 is more likely a random fluctuation due to the low number of cases.

Ahn HS. Reply to: Food Additives Should Not be Ruled Out as the Possible Causative Factors of Inflammatory Bowel Disease in Korea. Inflamm Bowel Dis. 2016; 22(1):E1-2.

But the population they studies is about one million. I believe such a large population made the observed decrease unlikely a random error. Along with the many evidences I collected during the last fifteen years I suggested the possible link between those artificial sweeteners and IBD deserved further study.

Qin X. The Possible Link Between Artificial Sweeteners Such as Saccharin and Sucralose and Inflammatory Bowel Disease Deserves Further Study. Inflamm Bowel Dis. 2016; 22(6):E17.

Shortly after the acceptance of publication by the journal of the above paper, the large-scale European study came out. It revealed a sole positive association between a "high sugar and soft drinks" pattern and IBD.

Racine A, etc. Dietary Patterns and Risk of Inflammatory Bowel Disease in Europe: Results from the EPIC Study. Inflamm Bowel Dis. 2016 Feb;22(2):345-54.

The above paper provided another critical piece of evidence for the possible link between the artificial sweeteners and IBD, but I felt their discussion was pretty superficial. I wrote a letter with my view as how sugar and soft drinks may be associated with IBD.

Qin X. How Sugar and Soft Drinks Are Related to Inflammatory Bowel Disease? Inflamm Bowel Dis. 2016 ; 22(6):E18-9.


I believe this kind of exchanges of views would benefit the scientific community and the general society. It may help to clear our thoughts and vision and the ultimate solution of the problem.
 
But some of these suggestions does fall in line with the argument asking why is it dairy farmers have lower incidence of CD if there's the higher MAP exposure.
Humans have an adaptive immune system. We also have genetic differences affecting the behaviour of our immune system with respect to pathogens. Higher exposure does not imply higher incidence of disease. End of debate.
 
Thanks for sharing your thoughts. I would be glad if any people would like to share their thoughts on this with different opinions, including insightful discussions over scientific journals with those firm proponents of prominent scientific and professional backgrounds. Debate may help to differentiate real versus tale, and truth versus false. In fact, the journal of Inflammatory Bowel Disease published several of my other papers recently (http://www.ncbi.nlm.nih.gov/pubmed/?term=xiaofa+qin ), behind which there are some stories the people here may be interested.


In early 2015, a paper published in Inflammatory Bowel Disease showing remarkable increase of IBD in Korea:

Kim HJ, Ahn HS et al. Incidence and natural course of inflammatory bowel disease in Korea, 2006-2012: a nationwide population-based study. Inflamm Bowel Dis. 2015 Mar;21(3):623-30.

According to the data they cited, I found that the dramatic increase occurred in early 2000s, but leveled off in recent several years. As sucralose was approved in Korea around 2000, I suggested that they check out the possible link between IBD and dietary chemicals such as sucralose and saccharin.

Qin X. How to Explain the Dramatic Increase Around 2000 but Recent Leveling Off of Inflammatory Bowel Disease in Korea? Inflamm Bowel Dis. 2015 Aug;21(8):E16-7.

In the reply, they denied the possible link between food additives and IBD, with the fact that Korea adopted much more strict regulation since 1992 on the use of saccharin.

Ahn HS. Increased Incidence of Inflammatory Bowel Disease in Korea May Not Be Explained by Food Additives. Inflamm Bowel Dis. 2015; 21(8):E17

On checking out their data, it can be found a sudden decrease in IBD during 1992 and 1993, therefore I reminded them that the possible link between food additives and IBD should not be ruled out.

Qin X. Food Additives Should Not Be Ruled Out as the Possible Causative Factors of Inflammatory Bowel Disease in Korea. Inflamm Bowel Dis. 2016 Jan;22(1):E1.

In the reply, they argued that the decrease during 1992 and 1993 is more likely a random fluctuation due to the low number of cases.

Ahn HS. Reply to: Food Additives Should Not be Ruled Out as the Possible Causative Factors of Inflammatory Bowel Disease in Korea. Inflamm Bowel Dis. 2016; 22(1):E1-2.

But the population they studies is about one million. I believe such a large population made the observed decrease unlikely a random error. Along with the many evidences I collected during the last fifteen years I suggested the possible link between those artificial sweeteners and IBD deserved further study.

Qin X. The Possible Link Between Artificial Sweeteners Such as Saccharin and Sucralose and Inflammatory Bowel Disease Deserves Further Study. Inflamm Bowel Dis. 2016; 22(6):E17.

Shortly after the acceptance of publication by the journal of the above paper, the large-scale European study came out. It revealed a sole positive association between a "high sugar and soft drinks" pattern and IBD.

Racine A, etc. Dietary Patterns and Risk of Inflammatory Bowel Disease in Europe: Results from the EPIC Study. Inflamm Bowel Dis. 2016 Feb;22(2):345-54.

The above paper provided another critical piece of evidence for the possible link between the artificial sweeteners and IBD, but I felt their discussion was pretty superficial. I wrote a letter with my view as how sugar and soft drinks may be associated with IBD.

Qin X. How Sugar and Soft Drinks Are Related to Inflammatory Bowel Disease? Inflamm Bowel Dis. 2016 ; 22(6):E18-9.


I believe this kind of exchanges of views would benefit the scientific community and the general society. It may help to clear our thoughts and vision and the ultimate solution of the problem.
If this is the cause, then surely changing your diet should reverse the symptoms of IBD? Theories are interesting, but we all want practical things we can do to cure ourselves or reduce symptoms. What is your prescribed cure for Crohn's?
 
Humans have an adaptive immune system. We also have genetic differences affecting the behaviour of our immune system with respect to pathogens. Higher exposure does not imply higher incidence of disease. End of debate.
An interesting explanation. Could you give an example showing a reverse relationship between exposure to a pathogen and prevalence of the disease caused by the same pathogen?
 
If this is the cause, then surely changing your diet should reverse the symptoms of IBD? Theories are interesting, but we all want practical things we can do to cure ourselves or reduce symptoms. What is your prescribed cure for Crohn's?
Depend on the extent of damage of the gut tissue and stage of the disease, it may not be easy or possible to reverse the course of the disease by just removing the primary causative agents. In my opinion, if the damage of the gut tissue is still reversible (such as no severe fibrosis that greatly restricted the supply of blood and nutrients), a cure may probably be achieved by a complete control of the inflammation within the gut tissue and the restoration of gut bacteria in gut lumen with full functions in which an effective deactivation of digestive proteases in the low gut would be a critical one among them.
 
I read both of these articles with interest. I'm always open to hearing the pros and cons of the MAP debate. I agree - there should be debate and peer review on all of these theories. I guess we'll see what the stage 3 RedHill study says soon, which may clarify the flawed Selby study.
Thanks for sharing your thoughts.

Due to the damage of gut barrier in IBD patients, to my perception, a reduction in gut bacteria and thus the luminal commensal bacterial toxicants by the antibiotics should have some beneficial effect even in the absence of MAP. I wonder the impaired inactivation of digestive proteases along with the reduction in gut bacteria may have confounded the efficacy of the antibiotics. See: Qin X. Impaired inactivation of digestive proteases: a factor that may have confounded the efficacy of antibiotics aimed at reducing the exposure to luminal bacteria and their components. Am J Gastroenterol. 2008 Nov;103(11):2955-6. So, it would be not easy to draw a conclusion, but time will eventually tell which side is right.


A few questions from the above articles then:

1. If Crohn's is based on a genetic predisposition of the immune system not to recognize intracellular pathogens (which is well researched), wouldn't it then follow that only patients with that genetic profile would be susceptible to MAP as a trigger? People whose immune system can recognize MAP and contain it would have no issue wth MAP, no matter how much dairy they consume. It will be really interesting to see if they do follow up studies on this dairy intake theory. Maybe dairy has both protective and harmful effects in CD. A lot of patients get leaky gut as a result of CD. In those cases, adding highly reactive proteins like dairy and gluten can make you feel worse. Cutting those out can relieve some symptoms of leaky gut. I've never thought that the MAP in dairy alone can trigger CD. I think it has to be some other event in a period of waning immunity, but as usual, more research is necessary! Interesting study though.
Even the nearly 200 risk genes together can only explain a small portion of the variance in disease risk. To my knowledge, there seem no people really resistant to CD. If MAP in the milk would be the cause for CD and proteins in the milk could exacerbate the symptom, there should be added increased risk of milk to CD. This seems not the case.

2. Farmers should get more CD by being in contact with MAP. Unless they don't have the genetics (see above) or if their bodies produce stronger antibodies to MAP by being in constant contact with it. They're less "hygenic" and that may provide some additional protection, right?
As discussed in my review (www.graphyonline.com/archives/archivedownload.php?pid=IJCMM-109), I do not think CD is caused by a pathogen, thus in my “biased” opinion, the reduced risk of CD in farmers is more likely to be explained by a more functional microbiota as the result of increased exposure to microbes due to less hygiene condition.

3. Clearly a HUGE issue with the whole MAP debate is the lack of any type of standard diagnostic. I agree that the IS900 series is probably not a great indicator (See this post: http://thecrohnsinfection.org/john-...oimmune-diseases-are-they-zoonotic-in-origin/). But if someone could reliably culture and actually grow the spheroplastic form of human MAP (thus proving it's not a dead, leftover form), wouldn't that be the best place to start?
As discussed in the review, the spheroplastic form of MAP should be much less pathogenic to the acid fast bacteria. This makes it difficult to explain the much severe damage as seen in CD in human compared to Johne’s disease in cattle in spite of the scarcely existence of spheroplastic forms of MAP in CD and large amounts of acid fact bacteria in Johne's disease.

4. Lastly, I noticed that Dr. Qin states that there are no conflicts of interest. Hopefully he can shed some light on this, because I thought he was the sole owner of a Biopharma company formed to study this research? Is that not considered a conflict? Admittedly, this is not my area of expertise, so I will defer to Dr. Qin to clarify any conflicts. (Not trying to be rude or accusatory, I truly want to learn what is considered a conflict in this case.)
As stated in my early posts several years ago, I found the possible link between dietary chemicals such as saccharin and IBD by a series of accidentally findings and extensive pursuit in the literature. Shortly after that, I had contact multiple national and international agencies and IBD professionals advocating checking out this possibility, but failed to raise any action. I paid thousands of US dollars of publication fee by my own, including the above recent review on MAP, in hoping to draw more attention. I have expected some pharmaceutical companies would conduct some R & D toward this potentially important new mechanism and develop some new treatment for IBD, but also without seeing any action. I eventually realized that I would have to do something by myself and thus left the academic and started the company, named GI Biopharma Inc. Up to date, I still have not raise any capital or funding and do not get any pay from the disclosed company or any other resource for recent couples of years. I am very grateful for my wife for the full support of me and my family, which allow me to concentrate my strenuous efforts toward some fundamental issues of human health, including the true cause of IBD and role of MAP in CD. Is there anything wrong with such an endeavor? Should I withdraw from this lonely arduous striving that is appreciated by nobody, but suspected and ridiculed by even the patients it aimed to help?

I certainly agree that artificial sweetners aren't good for people. I avoid them as much as possible, but it's hard since they're in everything! Certainly the Western diet doesn't seem to be helping IBD patients. It will be interesting to see if further research will show that sweeteners (along with the factors that Dr. Qin mentions) can cause the pathology seen in Crohn's. Are there any independant groups working on research surrounding this hypothesis?
From the evidences I collected during the last fifteen years, I proposed that sweeteners such as saccharin and sucralose could be important causative factors for IBD, due to their wide use in the general population. As stated above, although I had vigorously advocated from the very beginning, it still failed to raise any action by the governmental or international agencies or the mainstream of IBD research. Despite that, I indeed got a Chinese professor to conduct some research in this regard and we just published a paper (Li R, Zheng J, Jiang M, Liu Y, Qin X, Wang X. Increased Digestive Proteases and Decreased β-Glucuronidase in Feces of Rats Treated with Sucralose and Saccharin-Another Critical Evidence That These Dietary Chemicals May Be Important Causative Factors for Inflammatory Bowel Disease. Inflamm Bowel Dis. 2016 Aug;22(8):E29-30.) supportive of the proposed hypothesis. It had taken decades to pin down the association between smoking and lung cancer. Apparent, much more efforts would be needed to get a clear picture regarding the relationship between those artificial sweeteners and IBD.

Thanks you again for sharing your thoughts and questions. Above is just my personal opinion.
 
Dr. Qin - thank you for sharing your thoughts. I believe that any research on Crohn's is beneficial, and applying the scientific method by experimentation of these theories is critical. It seems that you have experienced a lot of the same issues that the group of MAP researchers have: no funding stream, ridiculed for your beliefs and overall unappreciated by the people you are trying to help. I do not intend to minimize your contribution, and I appreciate your effort.

My question on the conflict issue stems from what I observed at the Chicago symposium on MAP in 2015. Before they spoke, the speakers disclosed to the audience that they were working on behalf of whatever research group, and some may have had a financial stake as well. Disclosing conflicts is not intended to minimize or discount the research of the speaker, but to allow the audience to put it in the correct context. The most famous example of this is the Andrew Wakefield debacle on autism. He reported his findings in the Lancet without disclosing that he was conducting the study for a group of patients who were suing the MMR manufacturer. His findings were therefore more suspect since he had been paid to find a link. It would have become really interesting had others been able to validate his work, though I wonder if he had disclosed this conflict up front if his research may have appeared more valid.

I think nearly all researchers have conflicts, because they are paid by someone or they have a stake in the outcome of the research. That is why all published research has a conflicts disclosure. I don't think you should stop seeking funding for your work or stop trying to prove your theory, but I'm confused as to what consitutes a conflict in medical research here. It would seem like the standard disclosure about your company would be in that conflicts section. Again, not trying to say your research isn't valid, just trying to understand the obligation to disclose conflicts.

Lastly, these recent two articles don't seem as much about promoting your theory as they seem to be attacking the MAP theory. To me, the MAP theory makes more sense (from my own personal case), or at least that there's some pathogenic involvement in CD, whatever that may end up to be. I'm not sure what role the overall microbiome plays. I don't think anyone really understands the microbiome, and it will be very interesting to see what that research yields. But I'd love to do the conclusive research which tells us that MAP is involved or not first. It seems like a viable culprit, so why not figure that one out, and if it's not MAP, move on to the next theory. Of course, different groups testing different theories is beneficial for all. But I'd wish those groups would stick to the research on their theory, instead of spending their time opining about why another group's theory is junk.

I truly hope that you get the funding you need to either prove or disprove your theory on Crohn's. I always wonder if it may be more than one theory that turns up correct. The more people working on it, the better!
 
An interesting explanation. Could you give an example showing a reverse relationship between exposure to a pathogen and prevalence of the disease caused by the same pathogen?
Vaccination
Here is a link with the introduction to vaccine: https://en.wikipedia.org/wiki/Vaccine

As stated, "a vaccine is a biological preparation that provides active acquired immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing micro-organism and is often made from weakened or killed forms of the microbe, its toxins or one of its surface proteins".

Vaccine is not the original pathogen. It may reduce the susceptibility to the original pathogen, but still the more the exposure to the virulent pathogen, the more the disease
 
irishgal:

Thank you for sharing your thoughts and statements. I understand and agree for many of what you said, but not for all, especially in some key issues you are addressing. For instance:

It would seem like the standard disclosure about your company would be in that conflicts section.
I do not think what you suggested is the standard way of disclosure of confliction. I have explicated listed the company in the author institution section despite that up to date I do not get any financial benefit from the company. Have you really seen any scientific paper in which they listed their institution in the author section, then state again in the Conflict of Interest section that they have a connection with the same institution?

Lastly, these recent two articles don't seem as much about promoting your theory as they seem to be attacking the MAP theory.
Expression, discussion, comments and exchange of views over scientific journals should not be cynically regarded as an attack. They are normal scientific activities that would benefit for all parties involved, as well as the scientific community and the whole society. As you may know, Dr. Andrew Wakefield’s paper on Lancet was followed by many studies. Some of them claimed they found the same connection, but much more large-scale more stringent studies negated the connection between MMR and autism, which would be the just thing to do but not malicious attack. It finally restricted the escalation of disaster incurred by the reduced immunization of children due to fear, which would not be achieved by just leaving alone the proponent side to do their job.

After I found the possible link between saccharin and IBD fifteen years ago, I contact multiple national and international agencies and IBD professions advocating them to check out this possibility. Failed to raise any action, I feel obligated to write an publication to warn the public for such a potential risk, although I knew this may potentially get me into some trouble. During these years I advocate again and again to those with the resource to conduct a check. I know it may turn out I am wrong, but I still would be glad to see the result.

I expressed my view on the relationship between MAP and CD as well as my own hypothesis regarding the cause and mechanism of IBD in the two papers as publications in the scientific journals. So I am inviting the "attack" and would glad to see others including the firm MAP/CD proponents to response with their different thoughts and opinions. We should have nothing to fear, as the truth is already there hiding, we can reveal it but nobody can change it. I am sure the new thoughts expressed in these two papers will benefit those engaged in MAP/CD research with more broad thinking, more comprehensive and accurate evaluation of their results. I also would be glad to see any kind of feedback or inputs, including those from you, along with different thoughts and opinions that would enhance my thinking and vision and benefit the whole society as well. Thanks.
 
Last edited:
Here is a link with the introduction to vaccine: https://en.wikipedia.org/wiki/Vaccine

As stated, "a vaccine is a biological preparation that provides active acquired immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing micro-organism and is often made from weakened or killed forms of the microbe, its toxins or one of its surface proteins".

Vaccine is not the original pathogen. It may reduce the susceptibility to the original pathogen, but still the more the exposure to the virulent pathogen, the more the disease
Saw this interesting research about TB (also a mycobacteria) where for some people, more exposure could lead to better immunity:

"Clinical studies suggest that there are individuals who are highly exposed to M. tuberculosis but remain persistently tuberculin skin test (TST) negative, and thus presumably uninfected. These individuals raise the possibility that at still-earlier points in the course of infection, it is possible for the host to fully clear the bacteria and that this early bactericidal response could be harnessed through vaccination."
http://mbio.asm.org/content/7/2/e00342-16.full

Also, there's the standard argument which includes the hygiene hypothesis that exposure to everyday pathogens early on prevents diseases (including "autoimmune" diseases) later in life.
https://www.sciencedaily.com/releases/2009/12/091208192005.htm
 
I think my issue with the conflict issue can be summed up by this article:

"Researchers with conflicts of interest were found to be more likely to choose comparators that would produce favorable results [29], selectively include only certain outcomes in published reports [30], publish conclusions that are inconsistent with the study results [31, 32], or complete a clinical trial without subsequent publication of the results [33]. These types of biases can also impact the quality and reliability of systematic reviews, arguably the most critical publications guiding clinical care."
https://researchintegrityjournal.biomedcentral.com/articles/10.1186/s41073-016-0006-7

The journal itself has this statement on Competing Interests:
"Competing interests
A competing interest exists when your interpretation of data or presentation of information may be influenced by your personal or financial relationship with other people or organizations. Authors must disclose any financial competing interests; they should also reveal any non-financial competing interests that may cause them embarrassment were they to become public after the publication of the manuscript.
Authors are required to complete a declaration of competing interests. All competing interests that are declared will be listed at the end of published articles. Where an author gives no competing interests, the listing will read 'The author(s) declare that they have no competing interests'."

Again, not trying to be accusatory, but truly trying to understanding why this article didn't have a section about competing interests.

The reason why I may have seen this as more of an attack and less as an invitation to open discourse, was that it seemed that your review of the MAP research didn't include studies which showed evidence contrary to your position. Which is partially understandable in your position since you are admirably attempting to find funding to study a theory of Crohn's in which you wholeheartedly believe, but it has the danger of misleading the reader if they believe you have no financial interest. For example, in your analysis of AMAT, you rely on the Selby study, which while it's the only blind study on AMAT, was rejected by peers due to it's many errors. The sole fact that the antibiotic capsules didn't rupture, thus not delivering the stated medication, should have been enough to invalidate it, but it had other flaws besides that. (See this peer review about half way down the page: http://thecrohnsinfection.org/clinician-information/.) There are many smaller studies which show that AMAT used correctly, over a longer period of time in higher doses can be effective for some CD patients. And RedHill is currently running a large scale stage 3 trial on it, but none of this was mentioned in your review of the MAP research. I believe this is a critical and misleading deletion that causes harm to patients by not providing the full body of data.

Here is an example of an article where a researcher disclosed conflicts (if you can see the full article)
http://www.futuremedicine.com/doi/pdf/10.2217/fmb.14.133

But I understand out of fairness to you, the company affiliation was disclosed up front which may the obligation that the journal requires.
 
An interesting explanation. Could you give an example showing a reverse relationship between exposure to a pathogen and prevalence of the disease caused by the same pathogen?
Also, there's the standard argument which includes the hygiene hypothesis that exposure to everyday pathogens early on prevents diseases (including "autoimmune" diseases) later in life.
https://www.sciencedaily.com/releases/2009/12/091208192005.htm
Also:

Can Being Exposed to Cows Boost Your Immunity?
http://www.hull-o.com/can-being-exposed-to-cows-boost-your-immunity/

Here's why farm kids have fewer allergies and less asthma
http://www.theverge.com/2015/9/3/9256955/allergies-asthma-farm-kids-dust-endotoxins-a20
 
Xiaofa Qin I was wondering your thoughts on a theory I've had regarding a possible link to Crohn's.

In Crohn's we see one of the genetic factors is the poor function of the OCTN cation transport proteins responsible for transporting Serotonin out of the gut.

Serotonin is synthesized from 5-HTP / tryptophan in foods from the bacteria in the gut.

Serotonin toxicity is known to have many adverse effects including inflammation and mood disorders.

Crohn's has been linked to hormonal disruptions and it has been possible to achieve remission in some patients both with SSRIs and with specialized doses of 5-HTP and L-Tyrosine to 'reactivate' the OCTN transport proteins.

We also see remission achieved through antibiotics.

If antibiotics were simply suppressing the Serotonin synthesizing bacteria in the gut, this wouldn't be a far fetched result would it?

I think it's one of the only reasonable explanations that ties together both dietary treatment, hormonal treatment and antibiotic treatment all being effective against the same disease.
 
Thanks irishgal, Zim, InstantCoffee for sharing the thoughts and info.

More and more studies showed changes in gut bacteria along with changes in the hygiene condition, or use of antibiotics or some diets may have played critical role in IBD and multiple other diseases. To my knowledge, I know serotonin is mainly produced in in the enterochromaffin cells in the GI, but frankly I have no idea as how serotonin produced by gut bacteria may contribute to inflammation and other functions in the body. Hope studies in the future may shade light on all these issues related to dysbiosis of gut bacteria.


The reason why I may have seen this as more of an attack and less as an invitation to open discourse, was that it seemed that your review of the MAP research didn't include studies which showed evidence contrary to your position. Which is partially understandable in your position since you are admirably attempting to find funding to study a theory of Crohn's in which you wholeheartedly believe, but it has the danger of misleading the reader if they believe you have no financial interest. For example, in your analysis of AMAT, you rely on the Selby study, which while it's the only blind study on AMAT, was rejected by peers due to it's many errors. The sole fact that the antibiotic capsules didn't rupture, thus not delivering the stated medication, should have been enough to invalidate it, but it had other flaws besides that. (See this peer review about half way down the page: http://thecrohnsinfection.org/clinician-information/.) There are many smaller studies which show that AMAT used correctly, over a longer period of time in higher doses can be effective for some CD patients. And RedHill is currently running a large scale stage 3 trial on it, but none of this was mentioned in your review of the MAP research. I believe this is a critical and misleading deletion that causes harm to patients by not providing the full body of data.
This cynical accusation is simply not true. If you really carefully read through my paper (www.graphyonline.com/archives/archivedownload.php?pid=IJCMM-109), you should find that I have included as many as nearly fifty reviews alone (Ref. 2 – 48) at the very beginning of my paper, including most, if not all, of the key reviews from the eminent MAP/CD proponent scholars in the world, in which there were thorough discussions over the study by Dr. Selby et al in Australia.

As for TB, I think you would probably know TB is a disease most prevalent in poor countries and poor regions where there is high TB exposure. If not know, I suggest you easily check these data out through internet or other resource and get a sense of what occurred in the real world. This would avoid the mistake of presenting erroneous misleading info to the readers as the result of distort interpretation or extrapolation of limited piece of peculiarly selected material but putting aside the vast amount of evidences that are more pertinent and stringent and readily available, a behavior you have bitterly denounced.

If you have different thoughts or opinions that you think of a value to express, I suggested you write a rebuttal to the journal, so we can have a formal discussion there that can be judged by the world and future.
 

DustyKat

Super Moderator
Not wishing to sideline the discussion but just curious about something:

My son had an ileocaecal resection in 2011. His pathology report on the resected bowel stated that there was no evidence of MAP infection. Is this routinely tested for in the resected bowel of Crohn’s patients?

As a side note: He had his surgery at Royal Prince Alfred Hospital in Sydney and Dr Selby was his gastroenterologist whilst he was an inpatient there.
 
Not wishing to sideline the discussion but just curious about something:

My son had an ileocaecal resection in 2011. His pathology report on the resected bowel stated that there was no evidence of MAP infection. Is this routinely tested for in the resected bowel of Crohn’s patients?

As a side note: He had his surgery at Royal Prince Alfred Hospital in Sydney and Dr Selby was his gastroenterologist whilst he was an inpatient there.
Dusty - this is really interesting. As far as I'm aware, testing for MAP in resection tissue is generally not done, even when a patient requests it. In fact, five years ago I'm not sure how they would have tested for it, since the available tests for use in humans produced many false negatives. The MAP tests in cattle seem to be more advanced. John Aitken is now able to culture human MAP reliably, but this has just been in the past few years, maybe 2014? I've always wondered what happened to Dr. Selby after his famous study, and I wonder if he requested the sample be tested for MAP. How is your son doing now? Hopefully really well. Have you considered seeing Prof. Borody sine you're in AUS. Will have to read some of your recent posts to catch up!

Dr. Qin - I could continue, but I don't think this is productive. I can see we will continue to disagree. I meant no offense to you and your work, and was attempting to have a civil discourse. I know that tone does not come across well on the internet and I see you have taken offense, which I did not intend. I understand you fully believe in your hypothesis, and I look forward to reading your future research on this. I think all CD research is of value to elucidate the puzzle that is sitting there hidden, as you mention. However, as a patient who went from severe CD to a full absence of symptoms in 6 weeks on AMAT (and then histological healing in 6 months), I have become a believer. Especially because I have before and after cultures of my human MAP infection which shows a significant decrease in the pathogen (along with a wealth of other labs, histology and procedure reports) that corresponds to my healing. If one patient can be healed in this way, it only requires figuring out the mechanism to heal others as well.
 

DustyKat

Super Moderator
In that case it was probably a pretty crude test then. :lol: It was also the pathology that said he had no convincing evidence of Crohn’s disease either but that was only because of an absence of granulomas. Yeah, I’m not sure who requested it but it was negative as was TB. I know the doc was doing research at the time, not sure for what though, as he was interested in my son taking part but we lived too far away and frequent, regular testing and annual scoping was required. Since he was not candidate I didn’t delve deeper into what it was all about.

My son did well for 4 years post surgery but flared last year. He was commenced on Humira and that has pulled things back into line and he is doing well. :)

I have two kids and they both have Crohn’s. I do believe in their case it is genetic, both have ileal Crohn’s and until more recently I also thought they had the same phenotype but now I am not so convinced. My daughter had a long undiagnosed period so her disease was left to run rampant with her only receiving her diagnosis on the operating table. That was 10 years ago and she has remained in remission since and has not taken medication for about 6 years I think, her choice. She now lives in Japan.
My son on the other hand was diagnosed very quickly, within 2 weeks, and with next to no symptoms however his disease and complications developed very quickly despite intervention. I now think his phenotype is far more aggressive than his sister’s.

Neither has ever fitted the more common denominators that spring up occasionally as to what may cause Crohn’s or trigger it. Both were normal vaginal births, both were breastfed for at least 12 months, neither had prescribed antibiotics until diagnosed with Crohn’s at 14 years (daughter) and 17 years (son) respectively, we live in a small rural town so limited access to fast food growing up, neither like fizzy drinks, had pets when growing up and access to farm animals and farm life. But had quite significant diversity in what they each liked in a dietary sense and what their interests were that I would question how much a part environment would play.

My kids are now 24 and 23 years old. My son knows about Prof Borody and his research but I don’t know if he will make the move to see him. I know his current GI does not hold the same beliefs about Crohn’s that Prof Borody does and both being in the same state I know they have met at conferences etc.
 
Thanks irishgal, Zim, InstantCoffee for sharing the thoughts and info.

More and more studies showed changes in gut bacteria along with changes in the hygiene condition, or use of antibiotics or some diets may have played critical role in IBD and multiple other diseases. To my knowledge, I know serotonin is mainly produced in in the enterochromaffin cells in the GI, but frankly I have no idea as how serotonin produced by gut bacteria may contribute to inflammation and other functions in the body. Hope studies in the future may shade light on all these issues related to dysbiosis of gut bacteria.
https://www.caltech.edu/news/microbes-help-produce-serotonin-gut-46495

Here is an article on a study done on the bacteria that synthesize serotonin in the gut

The researchers found that the EC cells from germ-free mice produced approximately 60 percent less serotonin than did their peers with conventional bacterial colonies. When these germ-free mice were recolonized with normal gut microbes, the serotonin levels went back up—showing that the deficit in serotonin can be reversed.
I'll see if I can find the source but I believe Crohns usually presents with abnormally high gut serotonin levels.

Here's an article exploring the connection between IBD and gut serotonin http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3977648/
 
https://www.caltech.edu/news/microbes-help-produce-serotonin-gut-46495

Here is an article on a study done on the bacteria that synthesize serotonin in the gut



I'll see if I can find the source but I believe Crohns usually presents with abnormally high gut serotonin levels.

Here's an article exploring the connection between IBD and gut serotonin http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3977648/
Thanks for sharing these info. From these materials we can learn that more than 90% of the serotonin in the body is located in gut tissue and mainly produced by the EC cells in the mucosa, with the materials generated within the body rather than exogenous sources like diet. Gut bacteria may significantly affect serotonin level, but still by impact on EC cells. Production of serotonin by gut bacteria in the lumen is likely minimal, which would be even lower along with the use of antibiotics and the resultant decrease in gut bacteria. Serotonin is pro-inflammation. Therefore, we may expect to see decreased risk of IBD by antibiotics if the production of serotonin in the lumen by gut bacteria may play important role, but this seems in contrary to the increased risk of IBD by antibiotics as reported in multiple studies. It may need more studies to elucidate the relationship among gut bacteria, diet, serotonin, and IBD.
 
Dr. Qin - I could continue, but I don't think this is productive. I can see we will continue to disagree. I meant no offense to you and your work, and was attempting to have a civil discourse. I know that tone does not come across well on the internet and I see you have taken offense, which I did not intend. I understand you fully believe in your hypothesis, and I look forward to reading your future research on this. I think all CD research is of value to elucidate the puzzle that is sitting there hidden, as you mention. However, as a patient who went from severe CD to a full absence of symptoms in 6 weeks on AMAT (and then histological healing in 6 months), I have become a believer. Especially because I have before and after cultures of my human MAP infection which shows a significant decrease in the pathogen (along with a wealth of other labs, histology and procedure reports) that corresponds to my healing. If one patient can be healed in this way, it only requires figuring out the mechanism to heal others as well.
I think we all share the same goal of ending the suffering of disease imposed on human being.

I know even some minor personal experiences may greatly affect the belief of an individual on something. However, this kind of belief is also the most unreliable. You have mentioned in other post that you was on Remicade just prior to AMAT. Frankly, I do not know why you have such a deep belief that your remission was due to AMAT rather than the well-known currently most effective CD drug Remicade?

Not only the personal experience of an individual, even the many of the open-label clinical trials in this days become so unreliable. One example would be the attempt to use Trichuris suis ova (TSO) to treat CD and other diseases. The miracle effect of the worm eggs has been shown in so many studies publish in many of most prestigious scientific journals and discussed in the many major social media, but it turn out complete fail when tested by the stringent double-blinded clinical trials ( See: Coronado crashes as Crohn’s disease trial fails and Coronado Biosciences (CNDO) No Longer Pursuing Trichuris Suis Ova Program, resulting in heavy costs for both the company to develop the product as well as the public.

As for Dr. Selby’s study you mentioned, the doses for those antibiotics would be selected with a thorough understanding and review of the multiple studies before that. Although the 50 mg/day of clofazamine used in the first 10 months may not be fully released due to some defects in the capsule as you mentioned, there are still other two antibiotics, Clarithromycin 750mg/day and Rifabutin 450mg/day, would be fully functional and all these three antibiotics would have worked well for the remaining 14 months in the two year study. In fact, multiple clinical trials had claimed wonderful efficacy with fewer and even lower dose of these antibiotics and shorter treatment time. For instance:

500 mg/day Clarithromycin alone for 4 – 12 weeks
Leiper K, Morris AI, Rhodes JM. Open label trial of oral clarithromycin in active Crohn's disease. Aliment Pharmacol Ther. 2000 Jun;14(6):801-6.

Clarithromycin 500mg/d + rifabutin 300mg/d for 4 – 17 months
Shafran I, Kugler L, El-Zaatari FA, Naser SA, Sandoval J. Open clinical trial of rifabutin and clarithromycin therapy in Crohn's disease. Dig Liver Dis. 2002 Jan;34(1):22-8.

As discussed in my paper, MAP is actually much sensitive to the antibiotics such as clarithromycin than M. tuberculosis. However, as we know, most of the patients with TB (and also leprosy) can be effective cured by antibiotics but nothing else. Why MAP in CD is so difficult to be killed? Real or tale? The new clinical trials in future may eventually bring us the answer. Let’s see.

The accidental findings of the possible cause and mechanism of IBD fifteen years ago led me a great interest in IBD. I tried to exchange thoughts and views with others that I believe this would benefit for all. The recent two papers on MAP/CD among the much more of others (http://www.ncbi.nlm.nih.gov/pubmed/?term=xiaofa+qin) just reflected such an effort. Hope people may work together to bring an end to the disease.
 
Haven't gone through the whole threat but just want to remind of something:

Correlation is not the same as causality. *nerd-mode off lol*

So even if a study or 10 studies can determine one factor that seems to correlate with the outcome it does not mean that there are 10 other factors that would correlate with the outcome as well but have just not been investigated for that.

Don't ever trust statistics that you haven't falsified yourself. ;-)
 
Hi Dr. Qin - thank you for your thoughts. I certainly agree that the RedHill study will determine if AMAT is beneficial in CD, and that is the type of rigorous, long term study that is necessary. As for my case and Remicade, I failed Remicade prior to starting AMAT. It worked for about 6 months to alleviate symptoms (though I had little healing) and it wore off quicker and quicker after each dose. Then I would flare even worse until I could get my next dose. The blood test showed I had built significant antibodies and I didn't have a clinical level in my body. This was all prior to AMAT, and I had fully stopped Remicade prior to AMAT, so there is no way my healing could have come from Remicade. Trust me - I was so sick at that point that I was bitterly disappointed that Remicade failed, which was my last treatment. I was terrified of going on something experimental. Reading the research and having it make sense in an intellectual way and actually making the leap to take heavy duty antibiotics which you know your GI is against was amazingly frightening. But I had no other viable options (and I considered helminths, SSI and FMT as well). Everything was experimental for me! And then to have AMAT work in only 6 weeks was emotionally disorienting. Then I found others like me, and wondered how many more were out there who had been told by their doc that they were out of treatments. Even if it worked in some, those patients would have their life back!

And I agree - single patient experiences are terribly unreliable in the scientific context. I shared my person story to provide some background as to why I thought AMAT may be a viable treatment for some CD patients. Certainly continued research needs to be done to find out why some experience healing like I did solely on antibiotics. I'm hoping the advent of a reliable diagnositic will answer some of these questions.

I will look forward to reading the future research on your hypothesis.
 
Hi, irishgal – Thank you for the explanation. Wish you keep on this wonderful good health all the time. Admire your great enthusiasm for helping others. Hope we may find out the root cause and mechanism of this dreadful disease sooner, no matter what it would be, and provide not only a cure but also effective prevention of it, and eventually make the world IBD free.
 
.And then to have AMAT work in only 6 weeks was emotionally disorienting. Then I found others like me, and wondered how many more were out there who had been told by their doc that they were out of treatments. Even if it worked in some, those patients would have their life back!
From what I've read on RHB-104 recently, a couple of the ABX in AMAT also have anti-inflammatory and immunomodulatory effects. Clarithromycin, a macrolide, is known to have anti-inflammatory properties by suppressing various inflammatory IL-x cytokines and TNF-alpha. And clofazamine modifies macrophage aptosis.

These are some of the rationale Redhill is using to expand their research on RHB-104 into MS and RA.

It'd be interesting if they can show conclusively whether RHB-104 works by killing MAP, or if it works due to these other immune modifying properties. If it's the latter, in my mind at least, it sort of explains why David in this Prof. Borody Interview video has stayed on AMAT for 12 years.
 
xeridea - that would be really interesting, and so confusing if the antibiotics were working not only on a MAP killing theory but also on an anti-inflammatory model. I guess the only way to sort that out would to be with reliable before and after MAP load testing. I think RedHill is doing that - or attempting it. Or at least collecting the before and after samples, then will test them eventually when they have a reliable diagnostic. I'll have to look into it more to see what they say, but I did see they just pushed back their timelines, which I know happens in these large trials. But interestingly, their press release said they are still blinded as to effectiveness, so it can't be because it either works/doesn't.

I seen that interview with David too, and I think now he's been on for nearly 20 years! If it's the same guy, I saw an old news story about how his bones were destroyed by pred, so he's sticking with AMAT as long as he's allowed. Probably not a bad theory if it's working that well for him! I can only hope it works that long for me.
 
Here is at least one paper on this topic:

3. Immunoregulation and Anti-Inflammatory Action of Macrolides

In recent years, it has been shown that macrolides beyond the bacteriostatic and bactericidal effect have also anti-inflammatory effect, which was used in chronic inflammatory diseases such as atopic dermatitis, nonspecific inflammatory bowel disease, psoriasis, and arthritis. The effect of macrolides on the inflammatory cell activity by influencing the production and release of proinflammatory cytokines has been demonstrated in many studies. Cytokines and chemokines play a key role in regulating both the proinflammatory immune response—tumour necrosis factor (TNF-), granulocyte—macrophage colony-stimulating factor (GM-CSF), interleukin-L IL-1, IL-6, IL-8, and interferon gamma (IFN-) and anti-inflammatory (e.g., IL-10).

It was shown that macrolides inhibit the production and secretion of IL-1SS and TNF-. in monocytes [5] and IL-1SS, IL-6, TNF-., and GM-CSF in mast cells [6], and IL-8 protein epithelial neutrophil-activating (ENA-78) macrophage inflammatory protein (MIP-1) in macrophages and leukocytes [7]. It was also shown that clarithromycin suppresses the production of IL-6 and IL-1SS by fibroblast-like cells of the synovial membrane [8]. Therapeutic concentrations of erythromycin and clarithromycin reduce the expression of IL-8 mRNA level in bronchial epithelial cells of patients with chronic inflammatory airway disease [9].​
 
And this, another writeup looking at use of another macrolide, rapamycin, in pediatric refractory IBD. It's a small cohort, but they demonstrated 67% mucosal healing. Not bad for a compound produced by a species of Streptomyces bacteria you find in soil.


The records of 14 patients were analyzed. Eleven of them had ulcerative colitis (UC) and 3 Crohn's disease (CD); mean age at diagnosis was 9.1 years (standard deviation 3.8). Of UC patients, 5 (45%) achieved clinical remission and 2 (18%) showed clinical response. All CD patients went into clinical remission. Mucosal healing was achieved by 5 children (45%) with UC and 2 (67%) with CD patients. One child with ulcerative colitis was weaned off adalimumab, while 2 children with CD were weaned off prednisolone and methotrexate successfully.

For what it's worth, rapamycin, and more generally, a class of 100 or so analogs of this compound, are having a renaissance of sorts in areas of cancer and longevity research. I'm kind of fascinated by this compound at the moment. Yay macrolides?
 
And this, another writeup looking at use of another macrolide, rapamycin, in pediatric refractory IBD. It's a small cohort, but they demonstrated 67% mucosal healing. Not bad for a compound produced by a species of Streptomyces bacteria you find in soil.


The records of 14 patients were analyzed. Eleven of them had ulcerative colitis (UC) and 3 Crohn's disease (CD); mean age at diagnosis was 9.1 years (standard deviation 3.8). Of UC patients, 5 (45%) achieved clinical remission and 2 (18%) showed clinical response. All CD patients went into clinical remission. Mucosal healing was achieved by 5 children (45%) with UC and 2 (67%) with CD patients. One child with ulcerative colitis was weaned off adalimumab, while 2 children with CD were weaned off prednisolone and methotrexate successfully.

For what it's worth, rapamycin, and more generally, a class of 100 or so analogs of this compound, are having a renaissance of sorts in areas of cancer and longevity research. I'm kind of fascinated by this compound at the moment. Yay macrolides?
I vaguely recall one report of a women who used either rapamycin or something like that and achieved remission, I thought it was the only case that existed until i read this link. I use autophagy stimulators lithium and resveratrol to reduce some of my symptoms, they are similar to rapamycin at least in regards to their ability to stimulate autophagy. Stimulating autophagy as you may already know, can help eliminate intercellular bacteria like MAP or AEIC, something that crohn's patients seem to have a problem with.
 
Hello there

You may also consider this paper (search the title for full-text):

A randomized controlled trial on the effect of vitamin D3 on inflammation and cathelicidin gene expression in ulcerative colitis patients

Background: Inflammatory bowel disease (IBD) is an intestinal chronic inflammatory condition and includes Crohn's disease (CD) and ulcerative colitis (UC). It has been proposed that Vitamin D supplementation may have a beneficial role in IBD. Aim: To characterize the effects of Vitamin D on cathelicidin (hCAP/LL37) gene expression, ESR, and serum hs-CRP levels. Materials and Methods: Ninety UC patients on remission were randomized to receive 300,000 IU intramuscular Vitamin D or 1 mL normal saline as placebo, respectively. Before and 90 days after intervention, serum levels of 25 (OH)-Vitamin D3, PTH, Calcium, ESR, and hs-CRP were measured. Cathelicidin gene expression was also quantified using qRT-PCR. Results: Baseline serum 25-OH-Vitamin D3 levels were not different between the two groups and after intervention, increased only in Vitamin D group (P < 0.001). Hs-CRP levels were lower in Vitamin D group after intervention (Before: 3.43 ± 3.47 vs 3.86 ± 3.55 mg/L, P = 0.56; after: 2.31 ± 2.25 vs 3.90 ± 3.97 mg/L, P= 0.023). ESR decreased significantly in Vitamin D group (Before: 12.4 ± 6.1 vs 12.1 ± 5.3 mm/h, P= 0.77; after: 6.7 ± 4.5 vs 11.4 ± 5.5 mm/h, P< 0.001). The mean fold change in hCAP18 gene expression in Vitamin D group was significantly higher than placebo group. (Mean ± SD: 3.13 ± 2.56 vs 1.09 ± 0.56; median ± interquartile range: 2.17 ± 3.81 vs 0.87 ± 0.53, P<,; 0.001).
Conclusion: Decreases in ESR and hs-CRP levels and increase in LL37 gene expression support the hypothesis that Vitamin D supplementation may have a beneficial role in UC patients.
 
Here is a link with the introduction to vaccine: https://en.wikipedia.org/wiki/Vaccine

As stated, "a vaccine is a biological preparation that provides active acquired immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing micro-organism and is often made from weakened or killed forms of the microbe, its toxins or one of its surface proteins".
Obviously, I know what a vaccine is and how it works...

Vaccine is not the original pathogen. It may reduce the susceptibility to the original pathogen,
It "may" reduce susceptibility because we have differences in own immune systems. It is not usually the original pathogen in its entirety, but from your link:

"A vaccine typically contains an agent that resembles a disease-causing micro-organism and is often made from weakened or killed forms of the microbe, its toxins or one of its surface proteins

but still the more the exposure to the virulent pathogen, the more the disease
It isn't that simple. Exposure does not imply infection. Infection does not imply disease. You are drawing the wrong conclusions because of over-simplistic and wrong assumptions.
 
It isn't that simple. Exposure does not imply infection. Infection does not imply disease. You are drawing the wrong conclusions because of over-simplistic and wrong assumptions.
It seems you still disparate over the papers I wrote regarding the inverse relationship between milk consumption and the risk of IBD negated the causative role of MAP in CD (Qin X. Increased Milk Consumption but Decreased Risk of Crohn's Disease (CD): Critical Evidence Negated Causative Role of Mycobacterium avium Subspecies paratuberculosis (MAP) in CD. Inflamm Bowel Dis. 2016 Sep;22(9):E37-8.) and my view that the evidence against the causative role of MAP in CD greatly over-weigh those support it (Qin X. Can Crohn's Disease Really be Caused by Mycobacterium avium Subspecies Paratuberculosis?-With My Alternative Theory that Reduction in Commensal Gut Bacteria and Resultant Impaired Inactivation of Digestive Proteases as the Primary Cause. Int J Clin Med Microbiol, 1: IJCMM-109). Frankly, I do not have the interest to argue. Again, if you feel you have a thought that is of a value to express, I suggest you write a rebuttal to the journal. Or if you feel difficult to do so due to the lack of background and training in medicine, I suggest you advocating those eminent MAP/CD proponent scholars you highly admired and were familiar with to do it together. So we may have formal professional discussions there that can be judged by the world and future, and may also possibly draw more attention and studies in this area that may help to bring an end to this controversy early.
 
Last edited:
I see this thread is still going.
I posted this info back in 2013 or so.
Seems overlooked by the GI community.
Old Mike

yes only 2 people but it worked
https://www.jstage.jst.go.jp/article/internalmedicine1992/32/4/32_4_350/_pdf

BBI
http://www.ncbi.nlm.nih.gov/pubmed/17551835

potato juice
what I find interesting is that

Faecal protease activity in faeces from patients with intestinal resections and healthy infants was found to be significantly higher than in healthy adults.

Brings up the question as to why infants don't get colitis, generally.
Perhaps mucosal anti trypsin activity is quite effective, in infants.

http://www.ncbi.nlm.nih.gov/pubmed/15086363

just to cover another base
Disease associations in alpha-1-antitrypsin deficiency
http://www.ncbi.nlm.nih.gov/pubmed/24176989

another
http://www.ncbi.nlm.nih.gov/pubmed/10807072
 
I searched this one does not seem to be in the thread.
Induction of Intestinal Inflammation in Mouse by Activation of Proteinase-Activated Receptor-2
From 2002
Old Mike
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1850779/

What we have going on here is PAR-2 activation by trypsin and mast cell tryptase which are elevated
in UC. While our alpha-1 antitrypsin is low.

Quercetin is both a mast cell stabilizer/trypsin/tryptase inhibitor.

The problem is you cant get quercetin to the colon unless you I guess overload dosage
with like 50/mg/kg or about 3 grams for a 60 kg person.

But if you take quercitrin it will pass into the colon and breakdown into quercetin.
But you cant get quercitrin as a supplement, except perhaps as dried apple peel will look
at that more. But you can get Rutin which will do the same thing.

Here is the explanation of what is going on,with guercetin,which works in a test tube,but not
in UC models unless you over load to get it to the colon.
http://hera.ugr.es/doi/15772342.pdf

What else is going on of which I will have to track down again if I can find it is that the trypsin
is auto digesting our colon cells,some of the trypsin is also from bacteria .

Will fill out more as I get organized with this info.
Auto digestion.
/www.ncbi.nlm.nih.gov/pmc/articles/PMC3288241/

Protective effect of quercetin not seen at lower doses than 50mg/kg in mice.
www.omicsonline.org/proceedings/pro...ogical-and-biochemical-alterations-13963.html

Rutin
/www.ncbi.nlm.nih.gov/pubmed/15652231

might also need high does rutin
/www.ncbi.nlm.nih.gov/pubmed/25281414

Just another thought many of the quercetin supplements now have bromalein, don't think this
is a good idea, you want to get the quercetin into the lower gut, not perhaps into the blood stream.

rutin give extended exposure of quercetin in the gut even may help ileitis
www.sciencedirect.com/science/article/pii/S1756464614004204

rutin metabolism
/www.drrathresearch.org/images/attachments/education/Phytobiology/Rutin_2015.pdf

I see Briggs beat me to it, but he mentions it as an antioxidant
thepowerofpoop.com/wp/wp-content/uploads/2015/07/IBD-Briggs-July-21-2015-1-1.pdf

My angle is down regulation of protease activity.
Old Mike
 
Last edited:
This is interesting. I wonder what other types of artificial sweeteners are guilty of this?

Regardless, I personally know I'm going to really look into this. Perhaps it's the cause of my issues. Anything new to explore is better than a dead end.
 
Several years past since the last post. More studies emerge. I have also had more publications that can be found at: https://pubmed.ncbi.nlm.nih.gov/?term=Xiaofa+Qin

Recently, I also put a video on YouTube with my simple explanation as how changes of gut microbiota in modern society may associated with IBD and other diseases. The video can be found at:

Welcome critiques, comments and discussion.


The company, GI Biopharma Inc, finally put on market its first product, GI001 Probiotics, which can be purchased online at following website:

Company website: https://GI-Biopharma.com/our-products

Amazon: https://www.amazon.com/GI-GI001-Probiotics/dp/B08NFKTF3G/

EBay: https://www.ebay.com/itm/GI001-Probiotics/353295485431?

If interest, please contact me, I may give some discounts.
 
Top