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05-27-2012, 12:50 AM   #1
Mark in Seattle
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Etiology of inflammatory bowel disease: A unified hypothesis

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

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

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


http://www.ncbi.nlm.nih.gov/pmc/arti...4/?tool=pubmed

http://www.ncbi.nlm.nih.gov/pmc/arti...JG-18-1708.pdf


Abstract
Inflammatory bowel disease (IBD), including both ulcerative colitis (UC) and Crohn’s disease (CD), emerged and dramatically increased for about a century. Despite extensive research, its cause remains regarded as unknown. About a decade ago, a series of findings made me suspect that saccharin may be a key causative factor for IBD, through its inhibition on gut bacteria and the resultant impaired inactivation of digestive proteases and over digestion of the mucus layer and gut barrier (the Bacteria-Protease-Mucus-Barrier hypothesis). It explained many puzzles in IBD such as its emergence and temporal changes in last century. Recently I further found evidence suggesting sucralose may be also linked to IBD through a similar mechanism as saccharin and have contributed to the recent worldwide increase of IBD. This new hypothesis suggests that UC and CD are just two symptoms of the same morbidity, rather than two different diseases. They are both caused by a weakening in gut barrier and only differ in that UC is mainly due to increased infiltration of gut bacteria and the resultant recruitment of neutrophils and formation of crypt abscess, while CD is mainly due to increased infiltration of antigens and particles from gut lumen and the resultant recruitment of macrophages and formation of granulomas. It explained the delayed appearance but accelerated increase of CD over UC and many other phenomena. This paper aims to provide a detailed description of a unified hypothesis regarding the etiology of IBD, including the cause and mechanism of IBD, as well as the relationship between UC and CD.
05-27-2012, 02:42 AM   #2
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There are some interesting and well considered ideas in the article. However, there are two important issues that remain unexplained.
The first is that only a very tiny percentage of people who consume saccharin or sucralose actually get I.B.D. And conversely, there are people who never consume those products who get I.B.D. (such as babies.)
The second issue is that removal of the colon cures U.C., even if people continue consumption of saccharin or sucralose.
05-27-2012, 08:38 AM   #3
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Paging Judith.
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05-27-2012, 04:51 PM   #4
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Hi Mark in Seattle,

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

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

Here are a few problems I had with the article:
1. page 1714. The author states,
"...The evidences demonstrated above provided a simple explanation for many puzzles of IBD such as the emergence and temporal changes of IBD in last century. It suggests saccharin might be the key causative factor for IBD, by primarily its inhibition on gut bacteria."
The citation for this statement is the author's previous work but no additional citations that support the statement. This is a bit odd. In addition, I noticed both of these works list the author as the sole author. This is understandable for reviews but for any works requiring experiments it is out of the norm. It is a picky point but considering the author cites themselves alone to back up this statement, I thought I would bring it up.

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

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


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

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

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

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

4. p. 1714
After the emergence of IBD about a century ago, numerous hypotheses had been suggested as the possible mechanism, which included infection, toxicants, psychogenic disturbances, nutritional deficiencies, allergy to pollens or foods, abdominal trauma, impaired vascular or lymphatic circulation, lysozymes and other enzymes or the excessive or deficient immune response due to reduced exposure to bacteria or helminthes. Most of them were invalidated and forgotten.
Uh, Really? I see the literature stating quite the opposite, that all of these mechanisms can have an effect on IBD. They may differ depending on the genetic and environmental background of the patient but I have seen all of these hypotheses validated in the literature to some extent.

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

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

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

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

If artificial sweeteners were the cause of IBD. Should removal of saccharin and sucralose from an IBD patient's diet result in remission of symptoms? I wish it was that simple. Unfortunately, I do not believe this is the case.
05-27-2012, 06:00 PM   #5
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I despise diet sodas, so my exposure to artificial sweeteners has been minimal. But I still have Crohns.
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05-28-2012, 12:52 PM   #6
Mark in Seattle
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You're a gem Judith, thanks for sharing your thoughts!

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

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

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

Thanks again!
05-29-2012, 10:04 PM   #7
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Mark in Seattle,
I think the reason environmental factors are not more well documented in the literature is the result of a couple of factors. First, I believe the genetic components predispose one to IBD but the environmental effects that push one over the edge are probably not due to a single exposure but are probably additive over time and in number. From an epidemeological standpoint, it is very difficult to pinpoint factors under these conditions. If there is an outbreak of say, Salmonella, it is far easier to pinpoint the source and exposure since it is restricted in time and number of persons involved.

IBD, on the other hand, is found worldwide. There are so many factors that feed into a patient's disease (or not) that I believe we will find that it is extremely complex. I agree with you that IBD is likely exacerbated by industrialized living. I do feel that in the unindustrialized world IBD is probably underreported. The epidemeology of IBD is a very interesting topic.
05-29-2012, 11:09 PM   #8
yeldarb49
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Disagree with This study,

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

PS: I never used diet products ever before I got sick with Crohn's, did take Accutane though...
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05-30-2012, 08:43 AM   #9
wildbill_52280
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alternate theory- antibiotics also came out in 1930's, so that could alternately explain the data. fast forward to today-with new ways of detecting bacterial species in the intestine via dna methods that have been recently applied finding reduced diversity in butyrate producing microbes in crohn's disease, i believe a combination of excessive hygiene, antibiotics, low fiber diet from highly processed foods, formula fed infants with poorly established gut integrity all these variables of industrialized society combine in unfortunate ways to lead to certain gi diseases. im sure the sacharrin theory has some contributions, but so do all other factors, antibiotics being the strongest. i also believe it could explain the geographic distribution of ibd, but related to vitamin d deficit where people are more likely to develop lung, sinus and middle ear infections and therefore turn to antibiotics for a treatment, thereby increasing exposure to gut bacteria altering treatments.

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

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

Last edited by wildbill_52280; 06-01-2012 at 09:44 AM.
05-30-2012, 08:54 AM   #10
yeldarb49
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I can also believe that the correct gut flora of bacteria is critical in Crohns. MY first GI Dr. Kept me on antibiotics, clavulin, for more then two years after my initial near death flare, I often wonder if the clavulin did something, kept the bacteria I needed there and killed others...and if my remission is related to that 2 plus years...
06-01-2012, 05:42 AM   #11
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Agreed. Appropriate gut flora are an extremely important barrier to minimize mucosal invasion by pathogenic microbes.
06-01-2012, 02:42 PM   #12
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My children likely had exposure to artificial sweeteners via foodstuffs but neither is a fan of soft drinks. In fact my daughter may have had a soft drink once or twice in 20 years, she hates them (it's the fizzy sensation that she can't abide) and my son's love of them isn't much more than hers.

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

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06-01-2012, 06:22 PM   #13
wildbill_52280
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My children likely had exposure to artificial sweeteners via foodstuffs but neither is a fan of soft drinks. In fact my daughter may have had a soft drink once or twice in 20 years, she hates them (it's the fizzy sensation that she can't abide) and my son's love of them isn't much more than hers.

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

Dusty.

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

also, did the mother have antibiotics before giving birth, if her flora was damaged before giving birth, that could have put your children at risk as the mothers flora is transferred to the children. also, being born c section may have put them at risk.
06-01-2012, 06:39 PM   #14
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They were both breast fed.

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

Dusty.
06-02-2012, 07:59 AM   #15
mf15
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Hi everyone,new hear usually on the healingwell boards for UC but found your
discussion by accident using google. UC since 1980,been researching it for
many years. Anyhow I have also been researching this particular subject for a few days. Here are some thoughts I have,mostly copied from my post
on healingwell.




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

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

Forget the saccharin at least for now.

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

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

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

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

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

was more restrictive on certain veggies it would work better.

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

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

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


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


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


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

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

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

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

Last edited by mf15; 06-03-2012 at 03:58 PM.
06-02-2012, 08:17 AM   #16
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Thanks old mike.this makes more sense to me.
07-08-2012, 03:06 PM   #17
Xiaofa Qin
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Hello, everyone,

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

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

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

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

Last edited by Xiaofa Qin; 07-09-2012 at 09:28 AM.
07-08-2012, 03:29 PM   #18
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Actually, pursuit on this has caused me a lot of trouble and suffering, and this paper is just the result of tremendous efforts when I was out of work and the countless nights and weekends in the last decade. In fact, I paid more than $300 publish fee for the paper published in Medical Hypothesis in 2002 and more than $1800 publish fee for this paper by my own. I am very grateful for the understanding and support of my wife.
People are taking action against the fees. http://thecostofknowledge.com/

Thanks for posting on the forum.
07-08-2012, 10:37 PM   #19
Xiaofa Qin
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Thanks, Kiny. I also feel the restriction by most of the journals has greatly limited the free access to the knowledge and sharing of information. I am glad that this paper was eventually published in an open access journal. Although I have to pay much higher publish fee, everybody in the world can access it for free that may help generating more new thoughts.

I would also like to thank Judith for taking time to read through this paper, raising the questions, and found out the data of the Monroe county population. I agree that the population could be potentially a big confounding factor for this kind of analysis. It would be ideal to compare the incidence (rather the new cases) of IBD with the per capita (rather total) saccharin consumption, either both of them being from the Monroe county or from the Unites States. Unfortunately, we cannot get this kind of data. As the result, the analysis used in this paper could be overestimated but also could be more likely underestimated the real correlation. It seems that a correction by population would only have minor effects on the analysis. For instance, compared to that of 1960, the population in Monroe County increased 1.21-fold in 1970 and 1.20 fold in 1980. However, during the same period, both the new cases of IBD in Monroe County and the saccharin consumption in US increased about 5 to 6 folds. Nevertheless, we should also notice the remarkable decrease in IBD in the middle 1980s, which would likely contain more valuable information. It cannot be explained by the change of population and opposites the increased awareness and improved diagnosis, but it paralleled the reduced saccharin consumption after the finding of its carcinogenicity in animals and the attempt ban in 1977 and the launching and marketing of aspartame afterwards. Certainly, more study would be needed for a more solid conclusion. Thanks Judith again for the critiques. Sparkling of conflicting thoughts may help clearing our vision. Hope we may have more chance to exchange our views.
07-09-2012, 10:43 AM   #20
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For what it's worth, I checked the toothpasteswhile I was shopping, many of them have sodium saccharin in them. The most commonly used is Fluocaril , that toothpaste and all of it's derivatives with flavors use saccharin. Then I went looking at the boxes of sweets and the soda brands, many many of them have saccharin in them like coca-cola etc, so at least here it's everywhere in foods and toothpaste. If you want saccharin free toothpaste, the only big brand I could find making it is OralB (and you need to buy the one called "saccharin free", their normal toothpaste has saccharin). Colgate uses saccharin.

Last edited by kiny; 01-12-2013 at 07:13 PM.
07-09-2012, 10:37 PM   #21
Xiaofa Qin
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Thanks kiny for the posts and information.

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

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

Last edited by Xiaofa Qin; 07-10-2012 at 06:02 AM.
07-10-2012, 11:11 PM   #22
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I came across this research report on pubmed, in which the author outlines a hypothesis that artificial sweeteners saccharin and sucralose are responsible for IBD.
One thing I DO know is that consuming soribitol (or even just having it in my mouth - ie: most modern toothpastes, sugar free gum - immediately makes my gut start to feel bad. I have switched to a "natural" Olive Leaf based toothpaste which seem to be OK in this regard.

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07-17-2012, 01:45 PM   #23
Mark in Seattle
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Xiaofa,

I was just noticing on my elemental diet drink that it says it is sweetened with acesulfame-potassium, and when I read about this on the internet, it mentions that it is about as sweet as saccharin or sucralose. I don't know how many artificial sweeteners are in use today, but would you tend to lump them all in together in terms of their effect on conjugation/deconjucation etc. of the digestive proteases?
07-17-2012, 02:50 PM   #24
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Though there has been a steady rise of cases of IBD, not only must we question the cause of the disease, but also whether or not the surge of numbers is due to better medicine per say. Just like with other diseases, such as cancer, Autisim, there have been surges of disease, and higher prevalence as time goes in. The first documented case of cancer was seen in 1500 bc, in Egypt. Playing devil's advocate, Crohns/UC are both diseases that are extremely hard to diagnosis without expensive, modern tests. Whether it be blood tests or colonoscopys/biopsies to verify the disease, even going back 20-30 years it would be very hard to diagnosis this disease, not to mention two hundred years ago.

From an epidemiological back round(masters in public health, Epi, and working on my phd) I just try to keep all sides in mind.
__________________
Original Dx: April 2011


Crohn's, Traumatic Brain Injury, Autoimmune Hepatitis (May 2014)


Current meds:Bactrim DS, Azathioprine, Entyvio, levbid
Past meds: Pentasa, Lialda, Prednisone, Entocort, Asacol HD, Prilosec, Lomotil, Lotronex, Nexium, Myfortic, Humira




http://lifeinthetimeofuncertainty.blogspot.com
07-17-2012, 10:51 PM   #25
Xiaofa Qin
Senior Member
 
Join Date: Jul 2012
Location: New Jersey
Thanks a lot for Mark in Seattle for the interest in my article and started this thread. The hypothesis proposed here lumped up those that can make a significant inhibition on gut bacteria rather than just artificial sweeteners. For instance, aspartame dominated the artificial sweetener market for many years after saccharin but before sucralose having played this role. However, aspartame is a compound composed of two natural amino acids that can easily be breakdown in the upper intestine and get absorbed into the body. Although some people have worried about the possible toxic effect of its metabolic products such as formaldehyde and formic acid, the rapid clearance of aspartame from the upper intestine made it unlikely to cause a big effect on gut bacteria that are enriched in the lower small intestine and colon. As for acesulfame potassium (Ace K), I indeed suspected that it could have a similar impact as saccharin and sucralose. Here is a study showing that acesulfame K, cyclamate and saccharin all can inhibit gut bacteria (Pfeffer M, et al. Acesulfame K, cyclamate and saccharin inhibit the anaerobic fermentation of glucose by intestinal bacteria. Z Ernahrungswiss. 1985 Dec;24(4):231-5). Acesulfame K, cyclamate, saccharin and sucralose shared many similar properties, such as being very stable to heat and other conditions, hardly metabolized by the body, and inhibition on gut bacteria. I did not bring up the potential risk of Ace K and cyclamate as the paper is already pretty long, with overwhelmingly large amounts of new concepts, and I tried not to make it super complex. Ace K had been one of the major artificial sweeteners in some European countries. Although its use in US increased in recent years, Ace K remained a small fraction in the artificial sweetener market. In fact, there was more interesting stories on cyclamate. It has been banned in US since 1970s but allowed to be used in Canada even after the ban on saccharin since 1977, which may make cyclamate a possible important factor after the saccharin ban but before the approval and wide use of sucralose in Canada since 1991.

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

Last edited by Xiaofa Qin; 07-18-2012 at 02:43 AM.
07-21-2012, 09:59 PM   #26
Xiaofa Qin
Senior Member
 
Join Date: Jul 2012
Location: New Jersey
Here is how I got to sucralose and this unified hypothesis on the etiology of IBD.

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

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

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

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

I also believe that there would be multiple factors that may cause or affect the development of IBD one way or another. However, this would also be true for lung cancer. Despite that, according to CDC, we know now that about 90% of lung cancer are caused by smoking, 10% by radon, 1% by air pollution, and even less by many other factors. We would also need quantitative assessment like this on IBD. Antibiotics would have more strong effect on gut bacteria than saccharin and sucralose. But saccharin and sucralose may have a much big impact on the general population because of their wide and sustained use. The century-long great efforts have produced enormous amounts of information on IBD, but many of them may be superficial, confusing, or even erroneous and misleading. I agree with Mark in Seattle that, to identify and make a rational (ideally quantitative) assessment of environmental variables, we would need to be more thoughtful and thorough enough. A big breaking through in the effective treatment and prevention of IBD would largely depend on finding out the main cause and thus the root mechanism. Hope that day would not be too far.
07-22-2012, 07:17 AM   #27
mf15
Senior Member
 
Join Date: Jun 2012
Location: Pennsylvania
Xiaofa Qin:Hi,This is Mike we corresponded by email about a month back.
Anyhow have you also looked into Johne's disease and its correlation with IBD,the countries with high IBD rates also have high Johne's cattle disease rates. Also what is most
interesting is Crohn's/UC clustering. I cannot post links yet but search google for
the broad street pump revisited.
The paper discusses a most recent cluster in Forest Virginia.
I moved into my current house in 1979,which is about two blocks from a working dairy farm, I got UC 1980. I also quit smoking in 1977.
Also search Johne's disease history read the first hit.
Johne's first described in the USA 1908.
MAP may cause both Crohn's and UC.
Mike/Old Mike
07-23-2012, 01:45 PM   #28
wildbill_52280
Senior Member
 
Join Date: Sep 2009
Here is how I got to sucralose and this unified hypothesis on the etiology of IBD.


I found the study by Hviid A et al being with very high quality, as it is a nationwide cohort study that included all Danish singleton children born from 1995 to 2003 (N=577,627). However, I was greatly puzzled by the fact that use of antibiotics was more related to Crohn’s disease rather than ulcerative colitis. As large amount of bacteria are in the colon rather than the small intestine, we would expect that use of antibiotics should have more impact on ulcerative colitis rather than Crohn’s disease. I pondered over this discrepancy for a long time and could not get an answer. This led me to eventually shift some of my attentions from epidemiological studies of IBD to the classification of ulcerative colitis and Crohn’s disease. To my surprise, I found multiple studies showing a shift of Crohn’s disease from the small intestine to the colon over time. Some recent studies have found the Crohn’s disease with only the involvement of colon (Crohn’s colitis) has been the main form. This made me to realize that the relative increase in Crohn’s disease versus ulcerative colitis along with the continuous improvement in hygiene condition or the use of antibiotics would largely due to a shift from ulcerative colitis to Crohn’s colitis. This would be again in accordance with my hypothesis that both ulcerative colitis and Crohn’s disease are due to a weakening in gut barrier, they only differ in that ulcerative colitis are mainly due to the increased infiltration of gut bacteria, but Crohn’s disease are mainly as the result of increased infiltration of particles or antigens from gut lumen. This notion also provided explanations for many more puzzles in IBD, such as the high incidence of Crohn’s colitis in young children, etc, as described in the paper. The shift from ulcerative to Crohn’s colitis along with the reduction of gut bacteria would suggest ulcerative colitis and Crohn’s disease are virtually two symptoms of the same disease rather than two diseases.
i currently agree that there is likely some unifying explanation to crohns and U.C., and that the extinction of certain bacterial species important for gut barrier function in combination with various pathogens may explain the differences. What is also interesting is that both diagnosis can be either mixed falling into both categories or indetermined and uncharacterizable falling into neither category. reading some personal testimonys on c. difficile infection a man described his disease and it sound precisely like crohns, yet he was officially diagnosed with C. difficile, but this is a very casual observation.

some support for missing bacteria linking cases of "colitis"
Low counts of Faecalibacterium prausnitzii in colitis microbiota
http://onlinelibrary.wiley.com/doi/1...ibd.20903/full

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


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

also, it has been reported that rates among women had increased after the antibiotic usage in 1945, i wonder if that could be explained by differences in antibiotic usage for urinary tract infections.
07-26-2012, 10:21 PM   #29
Xiaofa Qin
Senior Member
 
Join Date: Jul 2012
Location: New Jersey
Hi, Old Mike, sorry for the delay. I am in a vacation with my family with busy schedules and limited access to Internet. It had been a pleasure to have exchanged thoughts, ideas and information over the email, and thanks for your interest in my opinion on the possible link between Mycobacterium avium subsp. paratuberculosis (MAP) and IBD, especially Crohn’s disease (CD).

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

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

At beginning people were suspected a similar origin for both Johne’s disease in cattle and CD in humans as they both showed the obstructive damage near the end of the ileum. However, as shown in some of the recent studies, there was a shift of CD from the small intestine to large intestine over time and the involvement of only large intestine has become the main form for CD (the Crohn’s colitis). I suspected that IBD now would be more mimic the commonly seen IBD in pet dogs and cats rather than the Johne’s disease in cattle (Qin X. What is human inflammatory bowel disease (IBD) more like: Johne's disease in cattle or IBD in dogs and cats? Inflamm Bowel Dis. 2008 Jan;14(1):138). There were also many other fundamental differences between Johne’s disease and CD. For instance, large amounts of MAP can be found in the mucosa or feces of cattle with Johne’s disease, which can be transmitted to healthy herds; in contrast, the bacteria are hardly seen in the tissues and feces of patients with CD, and IBD in general is regarded as noncontiguous. Although studies showed higher rates of existence of MAP in gut tissue of CD patients by the high sensitive methods such as the PCR detection of the IS900 DNA segments, there are also increase in other bacteria such as Helicobacter spp., Listeria monocytogenes and Escherichia coli, suggesting this could be just reflected the weakening of gut barrier and increased gut permeability (Tiveljung A, et al. Presence of eubacteria in biopsies from Crohn's disease inflammatory lesions as determined by 16S rRNA gene-based PCR. J Med Microbiol 1999;48:263-8). Finding of viable MAP in patients with CD would be important evidence for the possible link. However, the more rigorous test organized by NIH failed to repeat and confirm these findings (Van Kruiningen HJ. Where are the weapons of mass destruction - the Mycobacterium paratuberculosis in Crohn's disease? J Crohns Colitis 2011;5:638-44). Therefore, it would be no surprising that there are many deep believers on both sides. Both sides think they hold enough scientific evidences. However, one thing would be true: one side must be wrong, along with the many “solid scientific facts”.
07-27-2012, 09:26 AM   #30
mf15
Senior Member
 
Join Date: Jun 2012
Location: Pennsylvania
Xiaofa: Thank you for your insight.
I guess my main point for my post is the clustering of IBD,in Forrest Vir,it would seem highly
unusual.
Old Mike
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