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Etiology of inflammatory bowel disease: A unified hypothesis

Looking back human history, when had people respected new theory? Are these important?
How do you explain people with diabetes who consume lots of saccharin, having low crohn's disease rates.

The American Diabetic Association has recommended saccharin for years, and yet these people have low rates of crohn's disease.
 
How do you explain people with diabetes who consume lots of saccharin, having low crohn's disease rates.

The American Diabetic Association has recommended saccharin for years, and yet these people have low rates of crohn's disease.
As discussed in my early post (#148), to my knowledge, multiple studies back to 1980s found increased intake of refined sugar in patients with Crohn’s disease (here are some of the studies). However, the enthusiasm receded when some controlled trials failed to show a benefic with the restricted use of sugar (Ritchie JK, et al. Controlled multicentre therapeutic trial of an unrefined carbohydrate, fibre rich diet in Crohn's disease. Br Med J (Clin Res Ed). 1987 Aug 29;295(6597):517-20), especially the poor correlation between the Crohn’s disease and refined sugar consumption (Sonnenberg A. Geographic and temporal variations of sugar and margarine consumption in relation to Crohn's disease. Digestion. 1988;41(3):161-71 ). I suspected that this increased risk in IBD may relate to increased intake of artificial sweeteners rather than refined sugar. As patients with diabetes may have increased intake of sweeteners, I have tried to find if there is a link between diabetes and IBD. I indeed found some studies such as those showing an increased prevalence of diabetes in patients with ulcerative colitis (Kappelman MD, et al. Association of paediatric inflammatory bowel disease with other immune-mediated diseases. Arch Dis Child. 2011 Nov;96(11):1042-6) and a positive association between type 1 diabetes and Crohn’s disease in families (Sipetić S, et al. Family history and risk of type 1 diabetes mellitus. Acta Diabetol. 2002 Sep;39(3):111-5). I have not seen a study showing a reverse relationship between diabetes and CD, and would be happy to see the data you have.
 
So each case becomes a measure of poisons, toxins, diet, ability to absorb, actual bugs or bacteria present, state of the intestines, allergies, immune system, etc
 
Can anyone get the full paper on this so we can figure out exactly what they are saying here,this one is a few days old.
Old Mike






Curr Opin Gastroenterol. 2014 Jan 16. [Epub ahead of print]

Proteases and small intestinal barrier function in health and disease.

Giuffrida P, Biancheri P, Macdonald TT.



Author information



Abstract

PURPOSE OF REVIEW:

To summarize the recent knowledge regarding intestinal proteases and the gut barrier.

RECENT FINDINGS:

It is now well established that intestinal proteases, such as matrix metalloproteinase (MMP)-1, MMP-3, MMP-10 and MMP-12, are key players in the development of ulcers in inflammatory bowel disease, have direct effects on epithelial barrier function and are involved in epithelial restitution. However, more recent work has suggested that the membrane-anchored epithelial cell serine protease matriptase is critical in maintaining the gut barrier, and roles have also been described for elastase, MMP-13, gelatinases, mast cell proteases and proteases derived from parasites and gut bacteria. Interestingly, epithelial proteases often co-localize with epithelial adherens junctions, and nonepithelial-derived proteases have junctional proteins as targets.

SUMMARY:

The role of proteases in controlling normal barrier function in the gut is now becoming very clear, to go alongside their role in intestinal inflammation.
 
As discussed in my early post (#148), to my knowledge, multiple studies back to 1980s found increased intake of refined sugar in patients with Crohn’s disease (here are some of the studies). However, the enthusiasm receded when some controlled trials failed to show a benefic with the restricted use of sugar (Ritchie JK, et al. Controlled multicentre therapeutic trial of an unrefined carbohydrate, fibre rich diet in Crohn's disease. Br Med J (Clin Res Ed). 1987 Aug 29;295(6597):517-20), especially the poor correlation between the Crohn’s disease and refined sugar consumption (Sonnenberg A. Geographic and temporal variations of sugar and margarine consumption in relation to Crohn's disease. Digestion. 1988;41(3):161-71 ). I suspected that this increased risk in IBD may relate to increased intake of artificial sweeteners rather than refined sugar. As patients with diabetes may have increased intake of sweeteners, I have tried to find if there is a link between diabetes and IBD. I indeed found some studies such as those showing an increased prevalence of diabetes in patients with ulcerative colitis (Kappelman MD, et al. Association of paediatric inflammatory bowel disease with other immune-mediated diseases. Arch Dis Child. 2011 Nov;96(11):1042-6) and a positive association between type 1 diabetes and Crohn’s disease in families (Sipetić S, et al. Family history and risk of type 1 diabetes mellitus. Acta Diabetol. 2002 Sep;39(3):111-5). I have not seen a study showing a reverse relationship between diabetes and CD, and would be happy to see the data you have.
Xiaofa Qin, i mentioned this study earlier but perhaps you never got around to looking at it, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1247426/

but it did find a difference between sugar intake and fiber intake and benefits to crohns disease while following patients over the course of 4 years, contrary to the other study. i find that reducing my sugar intake to almost nothing has been one of the main principles that has eliminated diarhea symptoms, but not inflammation. i reduced not only refined sugar, but sugar that is naturally present in foods as well. and whenever i increase the sugar, diarhea can be brought right back, so the connection is irrefutable, many enterobacteria have what is called the lac operon, which enables them to utilize lactose as a food or to create metabolic by products. i have also followed a high fibre diet and have never been to the hospital in 4.5 years since being diagnosed.
 
Can anyone get the full paper on this so we can figure out exactly what they are saying here,this one is a few days old.
Old Mike


Curr Opin Gastroenterol. 2014 Jan 16. [Epub ahead of print]

Proteases and small intestinal barrier function in health and disease.

Giuffrida P, Biancheri P, Macdonald TT.
I would like to help. However, my support as a researcher in the medical school was ended by the end of last year. Now I am staying at home and also cannot get the full text.

This may not be a bad thing. I also lost my job in 2001 that had given me the chance and time to learn more and get involved in IBD. As a spare time IBD researcher during the last decade, I believe I may made more progress toward a better understanding and final solution of IBD than the many studies supported by hundreds of millions or even billions of funding.

Staying at home, I have a vivid feeling of the real world, not just bubble and fantasy.

I can generate hypothesis and express my opinions through the literature. However, test of these hypotheses would need the field work. Before I have to find another job with IBD remaining a spare time hobby, if possible, I would like to use this opportunity to make a transition to become a full time IBD warrior – finding out the principle culprits in IBD that I believe could be just a few factors in the environment, and a cure for IBD that I believe the effective protection and fortification of gut barrier would be essential. Hope I may have the chance to do so. If anybody interested, please join the fight.
 
Xiaofa Qin, i mentioned this study earlier but perhaps you never got around to looking at it, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1247426/

but it did find a difference between sugar intake and fiber intake and benefits to crohns disease while following patients over the course of 4 years, contrary to the other study.
The paper you cited above seems just the one I was cited in my post (#305)(Ritchie JK, et al. Controlled multicentre therapeutic trial of an unrefined carbohydrate, fibre rich diet in Crohn's disease. Br Med J (Clin Res Ed). 1987 Aug 29;295(6597):517-20), with the conclusion that "No clear difference in clinical course was detected among patients who accepted the two different types of dietary advice". Do you mean you have another paper?
 
The paper you cited above seems just the one I was cited in my post (#305)(Ritchie JK, et al. Controlled multicentre therapeutic trial of an unrefined carbohydrate, fibre rich diet in Crohn's disease. Br Med J (Clin Res Ed). 1987 Aug 29;295(6597):517-20), with the conclusion that "No clear difference in clinical course was detected among patients who accepted the two different types of dietary advice". Do you mean you have another paper?
wow, so sorry, i put the wrong link in there. here is the other study i was talking about.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1596427/

There was 32 patients in the control group and 34 in the diet treated group, so its small, but found good results. i wonder if, or why wouldnt their have been larger studies confirming the role of this diet to manage crohns disease in addition to meds. its amazing what information there is out there when you actually look for it, thank god for the internet and free information. to reduce the amount of time spent in the hospital by 75%, that would save alot of money treating this disease, or to the contrary, profiteers from making money off this disease.




Treatment of Crohn's disease with an unrefined-carbohydrate, fibre-rich diet.

Br Med J. 1979 September 29; 2(6193): 764–766.
PMCID: PMC1596427
K W Heaton, J R Thornton, and P M Emmett

Abstract

Thirty-two patients with Crohn's disease were treated with a fibre-rich, unrefined-carbohydrate diet in addition to conventional management and followed for a mean of four years and four months. Their clinical course was compared retrospectively with that of 32 matched patients who had received no dietary instruction. Hospital admissions were significantly fewer and shorter in the diet-treated patients, who spent a total of 111 days in hospital compared with 533 days in the non-diet-treated control group. Whereas five of the controls required intestinal operation, only one diet-treated patient needed surgery. This is in strong contrast to general experience with this disease. Treatment with a fibre-rich, unrefined-carbohydrate diet appears to have a favourable effect on the course of Crohn's disease and does not lead to intestinal obstruction.
 
wow, so sorry, i put the wrong link in there. here is the other study i was talking about.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1596427/

There was 32 patients in the control group and 34 in the diet treated group, so its small, but found good results. i wonder if, or why wouldnt their have been larger studies confirming the role of this diet to manage crohns disease in addition to meds. its amazing what information there is out there when you actually look for it, thank god for the internet and free information. to reduce the amount of time spent in the hospital by 75%, that would save alot of money treating this disease, or to the contrary, profiteers from making money off this disease.
Thanks for sharing the paper. Here again we can see the conflict results among the different studies.

Reading through the full text of these papers, we can found that the paper I cited (Ritchie JK, et al. Controlled multicentre therapeutic trial of an unrefined carbohydrate, fibre rich diet in Crohn's disease. Br Med J (Clin Res Ed). 1987 Aug 29;295(6597):517-20) was in fact just the larger study aimed at confirming the findings in the retrospective study you referred to, through a larger-scale, randomised prospective single blind trial. Unfortunately, it failed to repeat the beneficial effect of the unrefined-carbohydrate diet. Here is the link to the full text.
 
Thanks for sharing the paper. Here again we can see the conflict results among the different studies.

Reading through the full text of these papers, we can found that the paper I cited (Ritchie JK, et al. Controlled multicentre therapeutic trial of an unrefined carbohydrate, fibre rich diet in Crohn's disease. Br Med J (Clin Res Ed). 1987 Aug 29;295(6597):517-20) was in fact just the larger study aimed at confirming the findings in the retrospective study you referred to, through a larger-scale, randomised prospective single blind trial. Unfortunately, it failed to repeat the beneficial effect of the unrefined-carbohydrate diet. Here is the link to the full text.

very interesting indeed. the second study was 2 years and the first was 4 years? didnt seem like the exact replication then, but im not really refuting their findings too much here though. I'll stick with the specificity of how my disease works, rather then enumerative induction(if 20 crohn's patients react the same way, then all must react this way), WHICH is unfortunatly how science is done. its possible some patients are more sensitive to these dietary factors then others which might explain the differences in findings.
 
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I would like to help. However, my support as a researcher in the medical school was ended by the end of last year. Now I am staying at home and also cannot get the full text.

This may not be a bad thing. I also lost my job in 2001 that had given me the chance and time to learn more and get involved in IBD. As a spare time IBD researcher during the last decade, I believe I may made more progress toward a better understanding and final solution of IBD than the many studies supported by hundreds of millions or even billions of funding.

Staying at home, I have a vivid feeling of the real world, not just bubble and fantasy.

I can generate hypothesis and express my opinions through the literature. However, test of these hypotheses would need the field work. Before I have to find another job with IBD remaining a spare time hobby, if possible, I would like to use this opportunity to make a transition to become a full time IBD warrior – finding out the principle culprits in IBD that I believe could be just a few factors in the environment, and a cure for IBD that I believe the effective protection and fortification of gut barrier would be essential. Hope I may have the chance to do so. If anybody interested, please join the fight.
of course my opinoin isnt very well developed yet, but take another look at soy products. i have some interesting studies ill send your way. this is based on using myself, my own testimony/experiance of having IBD a as source of clues. in 2006-7 i stopped drinking milk and switched entirely to drinking silk soy milk which has carageenen and trypsin inhibitors, i learned weeks ago of the possibility that trypsin is a requirement for the production of defensins, which vitamin d is also a requirement to make defensins, possibly bringing the information we have on north south gradient of ibd incidence and how low vitamin d may protect from dysbiosis, soy products may have a similar damaging effect increasing risk of ibd. The main variable i believe caused crohn's was amoxicillin, but the soy milk may have put me at greater risk. i believe i developed it in feb 2008 after antibiotics, diagnosed april 2009.

the presence of active trypsin is needed for maximum production of defensins in the lining of the gut, or at least maybe. it may take alot of soy mlik to depress enough defensins to create ibd though, some things to look into.
 
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of course my opinoin isnt very well developed yet, but take another look at soy products. i have some interesting studies ill send your way. this is based on using myself, my own testimony/experiance of having IBD a as source of clues. in 2006-7 i stopped drinking milk and switched entirely to drinking silk soy milk which has carageenen and trypsin inhibitors, i learned weeks ago of the possibility that trypsin is a requirement for the production of defensins, which vitamin d is also a requirement to make defensins, possibly bringing the information we have on north south gradient of ibd incidence and how low vitamin d may protect from dysbiosis, soy products may have a similar damaging effect increasing risk of ibd. The main variable i believe caused crohn's was amoxicillin, but the soy milk may have put me at greater risk. i believe i developed it in feb 2008 after antibiotics, diagnosed april 2009.

the presence of active trypsin is needed for maximum production of defensins in the lining of the gut, or at least maybe. it may take alot of soy mlik to depress enough defensins to create ibd though, some things to look into.
The body is complex. The world is complex. Trypsin may indeed stimulate the production of defensins that are regarded as important protective molecules for the gut. However, it has been well documented that treatment with antibiotics will result in a dramatic increase of digestive proteases like trypsin in the lower gut due to impaired inactivation, thus, according to your info, this may lead to great increase in the production of defensins. However, antibiotics increased but not decreased the risk of IBD. So, is increased trypsin really beneficial or actually detrimental? Is the inhibition of trypsin by some components in the soy milk more likely increased or decreased the risk of IBD? We may have to make a comprehensive analysis of the different evidences, most times being conflicting, rather than a piece of evidence, to get a likely right judgment.
 
The body is complex. The world is complex. Trypsin may indeed stimulate the production of defensins that are regarded as important protective molecules for the gut. However, it has been well documented that treatment with antibiotics will result in a dramatic increase of digestive proteases like trypsin in the lower gut due to impaired inactivation, thus, according to your info, this may lead to great increase in the production of defensins. However, antibiotics increased but not decreased the risk of IBD. So, is increased trypsin really beneficial or actually detrimental? Is the inhibition of trypsin by some components in the soy milk more likely increased or decreased the risk of IBD? We may have to make a comprehensive analysis of the different evidences, most times being conflicting, rather than a piece of evidence, to get a likely right judgment.
good points, i agree, the impact of trypsin inhibitors from soy milk, may be so miniscule. ill send some links anyway, its interesting stuff either way.


Trypsin Mediates Growth Phase-Dependent Transcriptional Regulation of Genes Involved in Biosynthesis of Ruminococcin A, a Lantibiotic Produced by a Ruminococcus gnavus Strain from a Human Intestinal Microbiota

ABSTRACT
Ruminococcin A (RumA) is a trypsin-dependent l antibiotic produced byRuminococcus gnavus E1, a gram-positive strict anaerobic strain isolated from a human intestinal microbiota. A 12.8-kb region from R. gnavus E1 chromosome, containing the biosynthetic gene cluster of RumA, has been cloned and sequenced. It consisted of 13 open reading frames, organized in three operons with predicted functions in lantibiotic biosynthesis, signal transduction regulation, and immunity. One unusual feature of the locus is the presence of three almost identical structural genes, all of them encoding the RumA precursor. In order to determine the role of trypsin in RumA production, the transcription of the rum genes has been investigated under inducing and noninducing conditions. Trypsin activity is needed for the growth phase-dependent transcriptional activation of RumA operons. Our results suggest that bacteriocin production by R. gnavus E1 is controlled through a complex signaling mechanism involving the proteolytic processing of a putative extracellular inducer-peptide by trypsin, a specific environmental cue of the digestive ecosystem.

link: http://jb.asm.org/content/184/1/18.full




Biologically-active defensins are released upon the proteolytic processing of their proforms by certain enzymes[4], including trypsin for DEFA5 and DEFA6 in humans[5] and matrilysin for cryptdins in mice[6]. This suggests that appropriate control of homeostatic quantities of both defensins and defensin-activating proteases may ultimately dictate the outcome of the gut immunological response to intruding pathogens and to commensal microorganisms that are permanently present.
source: http://www.wjgnet.com/1007-9327/full/v17/i5/567.htm
 
Thank you wildbill for sharing the paper. Here is a study showing that trypsin in fecal extracts may increase 100 times after the treatment by antibiotics.

-----------------

Digestion. 1983;27(1):8-15.

Determination of immunoreactive trypsin, pancreatic elastase and chymotrypsin in extracts of human feces and ileostomy drainage.

Bohe M, Borgström A, Genell S, Ohlsson K.

Abstract

The total daily amount of extractable cationic trypsin, chymotrypsin, and pancreatic elastase 2 in feces and ileostomy fluids has been studied in normal individuals and healthy colectomized subjects. Quantitation was performed using immunological assays with polyethylene glycol as a fecal marker. The extractable amount of each of these enzymes in the feces of normal individuals was less than 1 mg/24 h. However, in fecal extracts from antibiotic-treated normal individuals a 100-fold increase in immunoreactive cationic trypsin was observed, while chymotrypsin and elastase 2 were only 2- to 3-fold higher. In extracts from ileostomy fluids cationic trypsin, elastase, and chymotrypsin all showed mean values in the order of 50-200 mg/24 h. The characterization of the immunoreactivity of pancreatic proteases showed no qualitative differences when measured in duodenal juice or fecal and ileostomy extracts.


PMID: 6554206 [PubMed - indexed for MEDLINE]
 
Thank you wildbill for sharing the paper. Here is a study showing that trypsin in fecal extracts may increase 100 times after the treatment by antibiotics.

-----------------

Digestion. 1983;27(1):8-15.

Determination of immunoreactive trypsin, pancreatic elastase and chymotrypsin in extracts of human feces and ileostomy drainage.

Bohe M, Borgström A, Genell S, Ohlsson K.

Abstract

The total daily amount of extractable cationic trypsin, chymotrypsin, and pancreatic elastase 2 in feces and ileostomy fluids has been studied in normal individuals and healthy colectomized subjects. Quantitation was performed using immunological assays with polyethylene glycol as a fecal marker. The extractable amount of each of these enzymes in the feces of normal individuals was less than 1 mg/24 h. However, in fecal extracts from antibiotic-treated normal individuals a 100-fold increase in immunoreactive cationic trypsin was observed, while chymotrypsin and elastase 2 were only 2- to 3-fold higher. In extracts from ileostomy fluids cationic trypsin, elastase, and chymotrypsin all showed mean values in the order of 50-200 mg/24 h. The characterization of the immunoreactivity of pancreatic proteases showed no qualitative differences when measured in duodenal juice or fecal and ileostomy extracts.


PMID: 6554206 [PubMed - indexed for MEDLINE]

thanks. maybe this slightly suggests trypsin inhibition would not be enough to deplete defensins and affect dysbiosis leading to IBD. but it could also suggest increases in trypsin production are a compensatory defense mechanism to also increase defensin to counteract the dysbiosis induced by antibiotics.

i'm still not sure that is enough to prove that trypsin inhibitors do not affect defensin production.

the question remains:
do trypsin inhibitors from soy products specifically in soy milk, in any quantity, affect defensin production. i suppose then that is my question.
 
here is some info on the production of soy milk and trypsin inhibitor content:

J Agric Food Chem. 2008 Sep 10;56(17):7957-63. doi: 10.1021/jf801039h. Epub 2008 Aug 9.

Elimination of trypsin inhibitor activity and beany flavor in soy milk by consecutive blanching and ultrahigh-temperature (UHT) processing.


Abstract

Soy foods contain significant health-promoting components but also may contain beany flavor and trypsin inhibitor activity (TIA), which can cause pancreatic disease if present at a high level. Thermal processing can inactivate TIA and lipoxygenase. Ultrahigh-temperature (UHT) processing is relatively new for manufacturing soy milk. Simultaneous elimination of TIA and soy odor by UHT processing for enhancing soy milk quality has not been reported. The objective was to determine TIA in soy milk processed by traditional, steam injection, blanching, and UHT methods and to compare the products with commercial soy milk products. Soybean was soaked and blanched at 70-85 degrees C for 30 s-7.5 min. The blanched beans were made into base soy milk. The hexanal content of the base soy milk was determined by gas chromatography to determine the best conditions for further thermal processing by indirect and direct UHT methods at 135-150 degrees C for 10-50 s using the Microthermics processor. Soy milk was also made from soaked soybeans by traditional batch cooking and steaming methods. Eighteen commercial products were selected from the supermarket. Residual TIA in soy milk processed by the traditional and steam injection to 100 degrees C for 20 min was approximately 13%. Blanching could inactivate 25-50% of TIAs of the raw soy milk. The blanch conditions of 80 degrees C and 2 min were selected for UHT processing because these conditions produced blanched soy milk without hexanal, indicating a complete heat inactivation of lipoxygenases. The TIA decreased with increased temperature and time of UHT heating. The maximal trypsin inhibitor inactivation was achieved by UHT direct and indirect methods with residual activities of approximately 10%. Some commercial soy milk products contained high TIAs (trypsin inhibitor activity). The results are important to the food industry and consumers. Kinetic analysis showed that heat inactivation (denaturation) of TIA, under the continuous processing conditions of the Microthermics processor, followed first-order reaction kinetics, and the activation energy of the inactivation was 34 kJ/mol.
 
Could it be that these parasites are killing off the competition before they perish? Not that the immune system is "BOOSTED" or "CORRECTED"
 
The boost comes when the body is no longer fighting? And that the lack of ability to produce proper pancreatic balance is the root cause?
 
that seems to be the problem with most trials, they need to look at ALL the variables, I.e did the people that showed response have certain characteristics, i.e granuloma formation, or no granuloma, disease location etc, atm I think everything is too broadly looked at. I don't have the link to the results of the trials but they're somewhere on here, I remember it not being any higher than the placebo control though...
 
The goal would be a cure, which could end up being genetic reprogramming. I have also heard of healthy family members donating healthy intestinal flora for an infusion into the afflicted's bowels.
 
The goal would be a cure, which could end up being genetic reprogramming.
IBD only started to emerge and became epidemic in last century, which would be caused by changes of the environment but not the gene. There would be more easy solutions than genetic reprogramming.
 
I am of the opinion that we started paying attention in the last century. And that dietary issues like preservatives and chemicals have increased the number of afflicted.
 
Perhaps eating "dirtier" food was a better human condition? Perhaps we are degrading as human beings because we have the technology to keep pregnancies going and keep sick people alive longer?
 
Fistula treatment can be seen in Ancient Egypt, using camel hair to seton the fistula. So that is proof enough for me that issues have always been here
 
Fistula treatment can be seen in Ancient Egypt, using camel hair to seton the fistula. So that is proof enough for me that issues have always been here
We may never have the chance to check out if those ancient reports were indeed cases of IBD. However, as discussed early (see post #236), the recent dramatic increase of IBD such as the increase of Crohn's patients in a Saudi clinic from 0 or 1 during 1993 to 2000, to 3 or 4 cases during 2001 to 2003, then jumping to 174 cases in 2009, should indeed raise some big concern (here is the figure). This would definitely not caused by the failure of evolutionary selection.
 
Probably directly in relation to processed foods, or letting another population in, or it could be that a doctor finally just started documenting it? Without proper controls, it's not an epidemic
 
I would love as much as anyone to figure this out. But the common tendency at the GI is to throw drugs first, check for actual cause after that doesn't work or if the symptoms expand.
 
The problem I think, is that it then gets registered as Crohn's or IBD, when it isn't. Then the facts never get adjusted to what the real culprit was. So, like my case, you get treated with medicine that makes you sicker. Only after running to the RIGHT doctor do you get tests that prove they are trying to kill you by using the wrong medicine.
 
In my case I simply have a genetic immune problem. Boosting my immune system fixes the problem. So I was on a Crohn's diagnosis. How many others are falsely being mistreated by GI doctors?
 
I bet nobody went back and said, hey.. case number 16790 was not Crohn's, let's fix the data before we kill another few by suppressing an already damaged immune system
 
Diagnostics is very, very important, and the signs for Crohn's does not make it Crohn's, this is a huge problem. The results are an end product, not the cause.
 
Probably directly in relation to processed foods, or letting another population in, or it could be that a doctor finally just started documenting it? Without proper controls, it's not an epidemic
From the figure in the paper published in the Saudi Journal of Gastroenterology, we can see a much more dramatic increase of Crohn’s disease (from 0 -1 during 1993 to 2000 to 174 in 2009) than ulcerative colitis (from 7-14 during 1993 to 2000 to 21 in 2009). This seems unlikely to be explained by increased awareness or referral, or a better diagnose and documentation, or a change in population.

This dramatic increase in CD since early 2000s not only occurred in Saudi, but also reported in Singapore (Chu HP, Logarajah V, Tan N, Phua KB. Paediatric inflammatory bowel disease in a multiracial Asian country. Singapore Med J. 2013 Apr;54(4):201-5) and Ireland (Hope B, et al. Rapid rise in incidence of Irish paediatric inflammatory bowel disease. Arch Dis Child. 2012 Jul;97(7):590-4).

Interestingly, these increases occurred shortly after the approval of sucralose in these countries, which were also showed in studies from other countries like Canada, Australia, United States, Norway, etc, as demonstrated in Figure 4 of my paper discussed here. Therefore, I have written to these journals advocating checking out this possibility. The papers have been published regarding the increase of IBD in Singapore (Qin X. Comment on: Paediatric inflammatory bowel disease in a multiracial Asian country. Singapore Med J. 2013 Dec;54(12):716) and Ireland (Qin X. The possible cause for the rapid rise in incidence of Irish paediatric inflammatory bowel disease). The paper regarding Saudi has also been accepted for publication by The Saudi Journal of Gastroenterology, and hopefully people may see it soon.

The paper published in Singapore Medical Journal has free access. For the convenience of the reader, I post it here.

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

Comment on: Paediatric inflammatory bowel disease in a multiracial Asian Country

Singapore Med J 2013; 54(12): 716 doi:10.11622/smedj.2013256

I read with great interest the study by Chu et al regarding the remarkable increase of paediatric inflammatory bowel disease (IBD) in Singapore since the beginning of the new millennium (1).

In the last decade, a series of findings have made me suspect that dietary chemicals like saccharin and sucralose may play an important causative role in IBD, through their inhibition on gut bacteria, and the resultant damage of the mucus layer and underlying gut tissue by poorly inactivated digestive protease. This eventually led me to publish a paper last year with a unified hypothesis on the aetiology of IBD. In this paper, I included some evidence ollected at that time, such as the remarkable increase of IBD in Alberta, Canada since the early 1990s, in Brisbane, Australia since the middle of the 1990s, in northern California, United States of America since the end of the 1990s, and in south-eastern Norway since the middle of the 2000s. These aforementioned increases in IBD occurred shortly after the approval of sucralose in Canada in 1991, in Australia in 1993, in the United States in 1998, and by the European Union in 2004. After the publication of my paper, another study was released, showing a remarkable increase in paediatric IBD in Ireland since the middle of the 2000s, which, again, occurred shortly after the approval of sucralose in Ireland in 2003 (2). Similarly, this remarkable increase in paediatric IBD in Singapore since the beginning of the new millennium, as pointed out by Chu et al (3) happened shortly after the approval of sucralose in Singapore in 1998. Therefore, I recommend further investigation of the possible link between sucrolose and IBD.

Xiaofa Qin

References:

1. Chu HP, Logarajah V, Tan N, Phua KB. Paediatric inflammatory bowel disease in a multiracial Asian country. Singapore Med J 2013; 54:201-5.
2. Qin X. Etiology of inflammatory bowel disease: a unified hypothesis. World J Gastroenterol 2012; 18:1708-22.
3. Qin X. The possible cause for the rapid rise in incidence of Irish paediatric inflammatory bowel disease. Response to: Hope B, Shahdadpuri R, Dunne C, et al. Rapid rise in incidence of Irish paediatric inflammatory bowel disease. Arch Dis Child. 2012; 97:590- 4.
 
There is a book called

Origins and Directions of Inflammatory Bowel Disease: Early Studies of the "Nonspecific" Inflammatory Bowel Diseases that has the history of first cases of non-TB inflammation of the intestines.
 
Diagnostics is very, very important, and the signs for Crohn's does not make it Crohn's, this is a huge problem. The results are an end product, not the cause.
Crohn's disease is probably not one disease. People classify it all nicely in papers, they mention granuloma, how crypts look, ASCA tests, CRP, yada yada yada.

Often times they can't even see if there is granuloma or not because the tissue is for lack of a better word...a mess...half the time doctors have no idea what they're looking at.

Crohn's disease is a nice umbrella term for something that can be clinically very different from person to person.
 
Speaking of sweeteners... what about the benzoates? Those are just as bad, different issues.
Here is a study (Cong D, Fong AK, Lee R, Pang KS. Absorption of benzoic acid in segmental regions of the vascularly perfused rat small intestine preparation. Drug Metab Dispos. 2001 Dec;29(12):1539-47) showing that benzoic acid injected into closed segments of shorter lengths (12 or 20 cm) can be effectively absorbed (92-96% dose). This would suggest benzoates people take along the food may probably be effective absorbed by the upper small intestine, without the chance to exert a big impact on the bacteria in the lower gut. Do not know if any body can find more studies on this.
 
Xiaofa in your opinion, how would one overcome this protease problem? Do you believe there is there a way to restore normal function?
 
Xiaofa in your opinion, how would one overcome this protease problem?
I think one of the easy ways could be a targeted delivery of protease inhibitors to the lower intestine.


Do you believe there is there a way to restore normal function?
I think if the damage of the gut is not too severe that make the crypt stem cells still capable of differentiating into different epithelial cells (absorptive cells, goblet cells, etc) and reconstruct a relative normal structure on the remaining tissue, a normal function probably can be gradually restored after the inflammation was stopped.
 
If you believe all these diseases are "similar"...you're welcome to point out to us how etanercept that works for all these diseases does not work for crohn's disease.
There are actually some difference between etanercept and anti-TNF α antibodies like infliximab: according the description, etanercept is a fusion protein produced by fusing the TNF receptor to the constant end of the IgG1 antibody, while infliximab is an antibody to TNF α. One explanation I think of regarding the difference of efficacy between these two would be that each infliximab molecule would be capable of binding and inactivated one TNF α, while the efficacy of etanercept to trap and inactivate TNF α would depand on the ratio of etanercept (the introduced exogenous TNF α receptors) to the amounts of endogenous TNF α receptor inside the body. If the exogenous and endogenous receptors are equal, only half of the administrated etanercept may bind a TNF α. If the endogenous receptors are 10 times in number of the injected etanercept, only about 1/10 of administrated etanercept may bind a TNF α. The gut has a large number of immune cells and the inflammation of gut may have caused a huge increase in endogenous TNF α receptor, thus a big variation and low efficacy of etanercept. This is just a speculation for a tentative explanation.
kiny, do you think the explanation above reasonable or nonsensical. Yes, both etanercept and anti TNF α antibodies bind TNF α. What is your explanation for the different efficacy of these two on Crohn's disease?
 
I think one of the easy ways could be a targeted delivery of protease inhibitors to the lower intestine.




I think if the damage of the gut is not too severe that make the crypt stem cells still capable of differentiating into different epithelial cells (absorptive cells, goblet cells, etc) and reconstruct a relative normal structure on the remaining tissue, a normal function probably can be gradually restored after the inflammation was stopped.
Sorry I'm not very educated with this, do protease inhibitors exist? Whats an example of one and how would one get it to the colon?
 
kiny, do you think the explanation above reasonable or nonsensical. Yes, both etanercept and anti TNF α antibodies bind TNF α. What is your explanation for the different efficacy of these two on Crohn's disease?
Infliximab binds to lamina propria and submucosa immune cells, etanercept doesn't.

My point is that all these diseases are different.

Vedoluzimab for example works for UC and is completely ineffective for crohn's disease.

Infliximab doesn't even work for all crohn's disease, it works for like 50%, my guess is that within crohn's disease there are multiple separate diseases.

"IBD" is a really unfortunate term. I never use it because it perpetuates the idea that these diseases are similar or that treatment is similar. It's really bad for the progress for both patients to be put under an umbrella term.

If something works for UC does not in any shape or form mean it works for crohn's disease, and most of the time it doesn't. Because the diseases are very different.
 
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Sorry I'm not very educated with this, do protease inhibitors exist?
Yes, there are many kinds, such as Bowman-Birk inhibitor (BBI) (see post #128) and Camostat Mesilate (see post #133) discussed early in this thread.



Whats an example of one and how would one get it to the colon?
Below are some reviews with discussions on targeted drug delivery to the colon:

Jain SK, Jain A. Target-specific drug release to the colon. Expert Opin Drug Deliv. 2008 May;5(5):483-98

Chourasia MK, Jain SK. Pharmaceutical approaches to colon targeted drug delivery systems. J Pharm Pharm Sci. 2003 Jan-Apr;6(1):33-66

Kumar P, Mishra B. Colon targeted drug delivery systems--an overview. Curr Drug Deliv. 2008 Jul;5(3):186-98
 
Infliximab binds to lamina propria and submucosa immune cells, etanercept doesn't.
You are trying to solve a small puzzle with a bigger puzzle, trying to clean something with a thing even dirtier.

Infliximab is effective not only for Crohn's disease in the gut, but also arthritis of the joint, and psoriasis of the skin, suggesting the similar action of TNF-α over the body for inflammation. Do you have evidence that immune cells and, more specifically, TNF-α in lamina propria and submucosa are different from the other parts of the body? How?




Infliximab doesn't even work for all crohn's disease, it works for like 50%, my guess is that within crohn's disease there are multiple separate diseases.
As mentioned above infliximab is also effective for autoimmune diseases like psoriasis and rheumatoid arthritis, but may be less effective for ulcerative colitis. However, according to your early post, you believe ulcerative colitis but not Crohn's disease being autoimmune disease. How do you explain this discrepancy?
 
Not going to restart the same argument, I explained for 4 pages why UC and crohn's disease are vastly different.

Autophagy deficiencies, macrophage deficiencies, slow recruitment of immune cells, transmural disease, skip lesions, bacterial involvement, antibiotics use, differences in indices, lymphopenia in CD, granuloma, fistula, disease clustering.

None of the above is seen in UC. None of these things are seen in any autoimmune disease either. Crohn's disease is a very complex disease.

You think UC and crohn's disease are similar, well fine, I disagree, I don't pretend the genetics data and pathology differences aren't there just to fit them in the same bracket like you do. It's the only way your study would make any sense.

UC and crohn's disease are vastly different diseases, they actually have very little in common.

I can't even think of anything they have in common right now. Inflammation or dysbiosis of the intestine? Well there's many diseases that cause that, it doesn't mean they are similar, and we don't group those diseases either, the word "IBD" actually hurts both people with UC and CD.
 
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It's the only way your study would make any sense.
Ironically, only a clumsy theory from a spare time researcher without any funding explained and predicted what happened in the real world, from the emerging of clustered cases in 1888 to the recent worldwide increase of IBD, but it is utterly ridiculed by the patient. Yes, I just found there is no way to make sense out of everything, everybody.
 
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Xiaofa Qin,

you have had more then your fair share of great points to make, and contributions to the research. your track record is pretty good in my eyes.
 
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Xiaofa Qin,

you have had more then your fair share of great points to make, and contributions to the research. your track record is pretty good in my eyes.
Thanks for the warm words and inspiration.



Xiaofa Qin, were you aware of this study? it seems to support the theory that sucralose could be associated with ibd as it was supposedly approved in 1998.

http://www.sciencedaily.com/releases/2013/06/130625141208.htm
http://www.ncbi.nlm.nih.gov/pubmed/23797749
As I mentioned in an early post (#221), I wrote a paper regarding the possible link between the marketing of sucralose and the new round of increase of IBD in the United States, which was accepted and got published online recently by the Journal of Clinical Gastroenterology (Qin X. When and How Was the New Round of Increase in Inflammatory Bowel Disease in the United States Started? J Clin Gastroenterol. 2013 Nov 13. [Epub ahead of print]). I included several papers I found at that time such as:

Debruyn JC, Soon IS, Hubbard J, Wrobel I, Panaccione R, Kaplan GG. Nationwide Temporal Trends in Incidence of Hospitalization and Surgical Intestinal Resection in Pediatric Inflammatory Bowel Diseases in the United States from 1997 to 2009. Inflamm Bowel Dis 2013.

Nguyen GC, Tuskey A, Dassopoulos T, Harris ML, Brant SR. Rising hospitalization rates for inflammatory bowel disease in the United States between 1998 and 2004. Inflamm Bowel Dis 2007;13:1529-35.

Ananthakrishnan AN, McGinley EL, Binion DG, Saeian K. A nationwide analysis of changes in severity and outcomes of inflammatory bowel disease hospitalizations. J Gastrointest Surg 2011;15:267-76.

Bewtra M, Su C, Lewis JD. Trends in hospitalization rates for inflammatory bowel disease in the United States. Clin Gastroenterol Hepatol 2007;5:597-601

Sewell JL, Yee HF, Jr., Inadomi JM. Hospitalizations are increasing among minority patients with Crohn's disease and ulcerative colitis. Inflamm Bowel Dis 2010;16:204-7.

Ingle SB, Loftus EV, Tremaine WJ, Harmsen WS, Zinsmeister AR, Melton Lj, et al. Increasing Incidence and Prevalence of Inflammatory Bowel Disease in Olmsted County, Minnesota, During 2001-2004 (Abstract). Gastroenterology 2007;132:A19-A20.



However, the paper you listed here was out of my radar. Otherwise I would have included it as well. Any way, thanks for sharing the paper.
 
However, the paper you listed here was out of my radar. Otherwise I would have included it as well. Any way, thanks for sharing the paper.
I guess that's a good thing and a bad thing. Its good that you are now aware, and bad because it could have helped your paper a bit.

just to be clear i'm not here to poke holes for the sake of making you look foolish, that's impossible because of your reputation, as it is firmly established. we are on the same side and hopefully none of us forget that. so it makes me happy to make my own contributions as well, such as, bringing something like this that escaped your awareness, for me that's a very cool moment. especially when we are so used to generating millions of hypothesis that seem to go nowhere, ha. until we get one that seems to fit, and thats such an awesome feeling.
 
Ironically, only a clumsy theory from a spare time researcher without any funding explained and predicted what happened in the real world
sucralose use matches crohn's disease indices, and so do 1000 of other things

you're not the "only" person who has made up a theory and managed to match crohn's disease up with something inherent to a Western lifestyle

it matches many things, ppl don't do it because you can keep generating hypothesis like that until you're blue in your face

I've learned quickly not to partake in that, because you can explain crohn's disease a million and one ways, I base myself on what is out there and can be verified, genetic predisposition and clinical symptoms



crohn's disease is a perfect inverse map of TB infections, in fact it is far more accurate a match than your sucralose, countries with high TB have low CD, countries with low TB have high CD, it matches perfectly, not only that, when TB goes down in countries, CD goes up

obviously you should drop your sucralose theory for the inverse TB relationship, it is more accurate, many people have noted this inverse relationship, no one has written a paper on it, you could be the first one

the reason people don't do it, is because you can do that with a million and one things, you end up nowhere



it matches helminths contact:



sunlight exposure:



industrialisation:



micronutrient deficiency:




internet usage:



and 1000 other things
 
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just to be clear i'm not here to poke holes for the sake of making you look foolish, that's impossible because of your reputation, as it is firmly established. we are on the same side and hopefully none of us forget that. so it makes me happy to make my own contributions as well, such as, bringing something like this that escaped your awareness, for me that's a very cool moment. especially when we are so used to generating millions of hypothesis that seem to go nowhere, ha. until we get one that seems to fit, and thats such an awesome feeling.
The theory I proposed is indeed just a hypothesis with holes. As stated in my early post (see # 126), without a more vigorous test, even myself do not know how much this hypothesis would be correct. I am just an ordinary person, and foolish – spend so much time and energy on something that will predictably bring in a lot of criticism and radicle. Yes, as you stated in your post, it still makes us happy when we make our own contribution to something meaningful, which may have helped us to overcome the hardship we encountered. I think this may also be the innate force that has driven human civilization forward.
 
sucralose use matches crohn's disease indices, and so do 1000 of other things

you're not the "only" person who has made up a theory and managed to match crohn's disease up with something inherent to a Western lifestyle

it matches many things, ppl don't do it because you can keep generating hypothesis like that until you're blue in your face

I've learned quickly not to partake in that, because you can explain crohn's disease a million and one ways, I base myself on what is out there and can be verified, genetic predisposition and clinical symptoms



crohn's disease is a perfect inverse map of TB infections, in fact it is far more accurate a match than your sucralose, countries with high TB have low CD, countries with low TB have high CD, it matches perfectly, not only that, when TB goes down in countries, CD goes up

obviously you should drop your sucralose theory for the inverse TB relationship, it is more accurate, many people have noted this inverse relationship, no one has written a paper on it, you could be the first one

the reason people don't do it, is because you can do that with a million and one things, you end up nowhere
You feel acting like an angel, but you accused it a sin for tips that may track down the devil, just because you perceived many are capable of doing this bad thing. I have made about half of dozen of comments last year on most, if not all, newly published epidemiological findings with incidence data on IBD that encompass not only the increases of IBD in Ireland, Singapore, Saudi Arabia, and United States, but also the decrease of CD and increase of UC in Sweden, and the even higher incidence of IBD in Guangzhou, China than the adjacent more developed Hong Kong and Macau (here are some of these publications). Yes, I am the only person doing this. Do you find any other person providing explanations on these? If you or anybody indeed have a better explanation than I do and really interested in solving the mystery of IBD, you should bring it up. These new findings may provide us a rare chance to find out the cause and thus the possible root mechanism of IBD. Yes, there are many possibilities. Should we give up because, as you suggested, it will end up nowhere? Or try our best to find the cause? I had a post (see post # 109) about one year ago with some discussions on the same issue. I would like to re-post it here.


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

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

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

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

As for saccharin, I also had wondered if and to what extent it would be linked to IBD. This had driven me looking into the history of IBD and saccharin. It is a painstaking process that had taken me more than a decade so far. As shown in the paper, it covered from the earliest of reports of clustered cases of ulcerative colitis in London since 1888 and the earliest marketing and favorite use of the German made saccharin in UK since 1887, through the multiple reports of the leveling off or decrease of IBD during 1980s in many countries and the finding of carcinogenicity and attempted ban on saccharin in later 1970s, with included a brief description of wide spread use of saccharin along with World War I. The more evidence I found, there seems more to support rather against the possible link. Despite that, without a vigorous test, they are just the suspects like the many others. We can definitely bring in more suspects. However, I think we should remove dietary chemicals like saccharin and sucralose from the list of suspects for IBD only after we have found out those with a more perfect and specific match and pinned down as the real criminal.”
 
Xiaofa: I don't know whether you are right or wrong on the artificial sweeteners,I never
ate any,except in toothpaste. I have now eliminated saccharin from my toothpaste.

But we do know at least in UC there is excess protease in the colon,this does cause a problem.
We also know from very small trials of BBI,that UC is put into remission, also the
two people who were given Camostat went into remission.

So if nothing else I have learned that excess protease is part of the disease process,
whether casual,not sure.


Keep up the good work.
Old Mike
 
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Yes, I am the only person doing this.

Do you find any other person providing explanations on these? If you or anybody indeed have a better explanation than I do and really interested in solving the mystery of IBD, you should bring it up.
There have been many hypothesis.

-refrigeration of foods, which leads to an increase in psychotropic food borne bacteria, the rise of refrigeration accurately matches the rise in crohn's disease, it's the "cold chain hypothesis", and yes listeria and yersinia have both been found in people with crohn's disease, you can't dismisss this hypothesis easily

-exposure to sunlight, or rather lack thereof, it "fairly" accurately matches crohn's disease indices, low vitamin D status is linked to higher incidence of crohn's disease, vitamin D helps restore macrophage function through autophagy stimulation

-increase in types of domesticated pets in industrialised nations, which can carry invasive E Coli

-hygiene hypothesis, Th expansion bias

-inverse relationship with TB, mycobacteria live in competitive environments

-western diet that promotes the expansion of invasive E Coli, I linked the study not too long ago

-MAP, pretty sure I don't need to explain that one, milk consumption is far more common in western society because of lactose tolerance

I disagree that you're the only person who suggested an explanation for the rise in crohn's disease.
 
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There have been many hypothesis.
Yes, I certainly know there are many hypotheses. Many have been discussed in my paper.

However, my original post is as following:

Ironically, only a clumsy theory from a spare time researcher without any funding explained and predicted what happened in the real world, from the emerging of clustered cases in 1888 to the recent worldwide increase of IBD, but it is utterly ridiculed by the patient. Yes, I just found there is no way to make sense out of everything, everybody.
Do you find anyone explained and predicted what happened in the real world, from the emerging of clustered cases in 1888 to the recent worldwide increase of IBD?
 
Xiaofa: I don't know where you are right or wrong on the artificial sweeteners,I never
ate any,except in toothpaste. I have now eliminated saccharin from my toothpaste.

But we do know at least in UC there is excess protease in the colon,this does cause a problem.
We also know from very small trials of BBI,that UC is put into remission, also the
two people who were given Camostat went into remission.

So if nothing else I have learned that excess protease is part of the disease process,
whether casual,not sure.


Keep up the good work.
Old Mike
Thanks Old Mike for sharing your thoughts. As I mentioned in my early post (see #132), I think the small amount of saccharin in the toothpaste, if not swallowed, probably would not be enough to cause a big problem on gut bacteria. Without more rigorous study, nobody can be sure if and to what extent these artificial sweeteners may be linked to IBD. Definitely, there would be some other agents, such as antibiotics, that may cause IBD. Hope the recent worldwide increase of IBD may bring people more interest and effort to find out the causative agent(s) in the environment.
 
Do you find anyone explained and predicted what happened in the real world, from the emerging of clustered cases in 1888 to the recent worldwide increase of IBD?
I don't put UC and Crohn's disease in one group. Regarding crohn's disease, there's a paper from dalziel I linked once.

http://www.crohnsforum.com/showthread.php?t=39658



I've written down the name of a book a few pages ago that has the history of all intestinal diseases that could potentially have been crohn's disease. The earliest I am convinced of is the one from 1913...he tested for intestinal TB, he saw both inflammation of the small and large intestine, the ages of his patients match the ages most people tend to be diagnosed with crohn's disease today, often children and young adults. He named it chronic interstitial enteritis, my guess is, he's describing crohn's disease.

The Cold-chain hypothesis was described here:

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2803%2915024-6/abstract

It matches Dalziel's study, industrial large scale refrigeration started around the beginning of the 1900s. But so did many other things.

ATG16L1 and NOD2 variants are extremely common in the West, much more common than in Asia, a study showed considerable underreporting of CD cases in Asia too since it still to this day gets confused with intestinal TB, I don't think you can easily weigh in all those factors and claim one hypothesis is more likely than the next.
 
There is a book called

Origins and Directions of Inflammatory Bowel Disease: Early Studies of the "Nonspecific" Inflammatory Bowel Diseases that has the history of first cases of non-TB inflammation of the intestines.
A very good book by Dr. Joseph B. Kirsner, a professor at University of Chicago Medical Center and one of the most renowned IBD researcher in the world. I read this book more than a decade ago and learn a lot from it. In fact, I emailed him a copy of the draft of the manuscript that was eventually published in Medical Hypotheses in 2002 (Qin XF. Impaired inactivation of digestive proteases by deconjugated bilirubin: the possible mechanism for inflammatory bowel disease. Med Hypotheses. 2002 Aug;59(2):159-63) to seek his opinion, but failed to get a response.
 
I don't put UC and Crohn's disease in one group.
If you read through my paper discussed here, you will find I not only provided explanation for the connections between UC and CD, such as why UC emerged first, followed by CD, then CD tends to exceed UC, but also provided some explanation for their difference such as the characteristic feature of crypt abscess in UC and inflammatory granulomas in CD. People have to face the fact that UC and CD have both differences and similarities.
 
ATG16L1 and NOD2 variants are extremely common in the West, much more common than in Asia.
I wrote a paper that gave a new explanation for the relationship among NOD2, autophagy and gut bacteria (Qin X. How NOD2 and autophagy may be related to Crohn's disease? A viewshifted from live microbes to luminal bacterial debris. J Crohns Colitis. 2014 Jan 1;8(1):88). You are welcome to read it, think over it, then bring in some analytic critiques, but not just arguments with some extreme words.
 
I don't agree that immunosupressant use that makes people with CD better in the short terms somehow then indicates that there is no infection present. Inflammation is in large part responsible for the tissue damage in infectious disease, and a large part of patients who die from an infection, die from that tissue damage. Sepsis is a good example how destructive the inflammation to antigen form bacterial origin can be.

But I don't completely disagree with what you write either, autophagy is involved in a lot more than bacterial clearance and is a general housekeeper, I don't agree that people keep recommending us probiotics like we're some sort of group of people you can sell your wares to, and we're supposed to just accept this unregulated industry is good for us. Million of those bacteria will die, they will release considerable amounts of toxins and cytokine.
 
All these different hypothesis are important, even if they do not lead one one solid answer just yet. variables like diet and vitamin d levels exposure to antibiotics, sucralose, low fiber are all things that seem to enhance the risk of developing crohn's disease, what we need is that one universal explanation that connects them all, because all are valid and explain parts of the puzzle. I do believe eradication of indigenous bacteria would at least for now, be the universal cause. i believe in the end, the slight differences in disease state will be a combination of genetic variation among patients, variations among specific indigenous flora that are extinct, and variations in pathogens that colonize the gut after healthy flora have been damaged. These different combinations will likely explain variations in symptoms between UC and Crohn's.
 
I think the reason environmental factors are not more well documented in the literature is the result of a couple of factors. First, I believe the genetic components predispose one to IBD but the environmental effects that push one over the edge are probably not due to a single exposure but are probably additive over time and in number. From an epidemeological standpoint, it is very difficult to pinpoint factors under these conditions. If there is an outbreak of say, Salmonella, it is far easier to pinpoint the source and exposure since it is restricted in time and number of persons involved.
So let's assume that Crohn's is a result of genetic predisposition, plus some external environmental factor. If it was a single external environmental factor, then it would probably have been identified by now, which probably means there are multiple factors as you suggest above.

Now, historically, this makes it very hard to identify the key factors as the human brain has a very finite capacity for retaining and processing data. Essentially though, this is just a data mining problem and with the internet and computing power now available we have the capability to:
a) collect a huge amount of data from relevant patients from all over the world
b) search that data for patterns very quickly and easily

Capturing all of the environmental factors you have been exposed to is probably still not simple, but I see no reason why this problem cannot be tackled with a brute force, big data approach and as far as I know, no one is doing this.
 
I have been trying to do this for years,but lots of multiple factors that perhaps change with time.
Early on 1890's, early 1900's-1920 ish.
MAP new in 1895,new viruse,aluminum in baking powder,artifical lights,office work/indoor,cities,central heating,shift work,chlorination,lead pipes,lecitin,pollution water and air,mercury fillings,root canals,
new fruits and veggies in diet,industrial chemicals,saccharin,improved sanitation,refrigeration, canning, pasteurization,wesson oil 1899,crisco 1911,
cooking methods high heat,less fermented foods,nitrate fertilizers,toothpaste,
possible,some synthetic detergents.
All this before antibiotics,and many industrial chemicals.
Plus I guess a zillion other things.
I try to concentrate on these early timelines,since from the history of IBD
the increase started in this time frame.
Lest I forget increased sugar and salt consumption.
The switch from whole grains,to industrial flour, the switch from
sourdough to industrial bakers yeast. They also have to look carefully at twins,
and clusters.
Old Mike
 
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Capturing all of the environmental factors you have been exposed to is probably still not simple, but I see no reason why this problem cannot be tackled with a brute force, big data approach and as far as I know, no one is doing this.
How does it matter.

Are people drinking less milk because milk contain MAP? No.

Are people going more in the sun because crohn's disease has been linked to low vitamin D status? No.

Do people stop getting pets because they can carry invasive E Coli? No.


I don't want money invested in that because,
A..it probably doesn't matter...
B...many diseases are effectively cured long before causality is found.

Find out what is driving in the inflammatory process so we get better and safer treatment and hopefully a cure one day. YES

Find out how this whole process initially started. NO. They wasted enough money on things that got us nowhere.

It's really interesting to discuss, but it would be money wasted trying to find out why country A has 2% more crohn's disease than country B.

We have a disease that is severely lacking in safe treatment.
 
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I don't agree that immunosupressant use that makes people with CD better in the short terms somehow then indicates that there is no infection present. Inflammation is in large part responsible for the tissue damage in infectious disease, and a large part of patients who die from an infection, die from that tissue damage. Sepsis is a good example how destructive the inflammation to antigen form bacterial origin can be.
Yes, inflammation is in large part responsible for the tissue damage during infection. Have you thought over what inflammation is and how it cause tissue damage? Inflammation is largely just the phenomenon of fighting between the immune system against the perceived enemy, and the damage of the tissue is largely caused by the bombing and firing mainly from the immune cells of the body. The enemy could be real, like pathogens invaded into the tissue, or false such as self-antigens in autoimmune diseases. Immune suppression is by nature an action to disarm the immune system. This would indeed lead to a radical solution for autoimmune disease, as the self-antigen they attacked is not the real enemy but itself. However, it would be a totally different scenario when there is existence of real enemy. Yes, the ceasefire order to the defending force fighting fiercely with the enemy also result in temporary peace. As you suggested, immunosupressant use that makes people with CD better in the short terms somehow cannot rule out that there is no infection present. However, a long term disarmament of defense would definitely result in losing but not winning of battle. This is why the long term use of immune suppression agents like TNF-alpha blocks result in the escape of TB prisoned by the immune system after a dormant infection and become flourishing inside the body. These immune suppression agents also result in invasion and rampage of some opportunistic pathogens that otherwise would never have the chance to do so with a normal immune system. However, largely by virtue of the great finding of some genes like NOD2 and autophagy that related to both Crohn’s disease and bacteria, it become a popular notion that immune suppression agents like TNF-alpha blocks exerted their effect by killing and clearance of the invincible bacteria that are unconquerable even by the most powerful antibiotics and the uncompromised immune system. Is there any explanation how this is possible? Frankly, that is beyond my ability of imagination and thus I brought in an alternative explanation: NOD2 is related to bacteria not through its binding to live bacteria but rather binding to the infiltrated luminal bacterial debris containing Muramyl dipeptide (MDP, the NOD2 binding motif in peptidoglycan that has a molecular weight of only 500) that penetrated the weakened gut barrier. Autophagy is associated with CD not through the killing and clearance of live bacteria but rather the degradation of NOD2/MDP complex, as described in the published paper (Qin X. How NOD2 and autophagy may be related to Crohn's disease? A view shifted from live microbes to luminal bacterial debris. J Crohns Colitis. 2014 Jan 1;8(1):88)
 
How does it matter.
How can you solve a problem without information? Guess work? What happened to the scientific process?

I don't want money invested in that because,
A..it probably doesn't matter...
Why?

B...many diseases are effectively cured long before causality is found.
How? Give me examples.

Find out what is driving in the inflammatory process so we get better and safer treatment and hopefully a cure one day. YES
That is one way. Should it be the only approach. No.

What you seem not to have grasped is that the world has changed significantly over the last 20 years and our ability to collect and process data has grown exponentially. The cost of doing this has collapsed, yet medical research, from my exposure to it from having Crohns and constantly asking my doctor "tell me about progress with treating this disease" seems to be stuck in the dark ages.

Curing Crohns is a data processing and pattern matching problem. We have radically more ability to do that now than we did in the past, I think this deserves more focus.
 
NOD2 is related to bacteria not through its binding to live bacteria but rather binding to the infiltrated luminal bacterial debris

Autophagy is associated with CD not through the killing and clearance of live bacteria
That is completely false, where are you getting these ideas from.

NOD2 and autophagy signaling of ATG16L1 is directly involved in control of live LF82, which is consistently being isolated from crohn's disease patients, has been shown in studies.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3743084/

NOD2 and autophagy is crucial for controlling intracellular infections.

http://www.ncbi.nlm.nih.gov/pubmed/19802566

Our Forum Wiki explanation:

http://www.crohnsforum.com/wiki/Nod2-Card15-Gene

Subverting autophagy is actually how AIEC manages to survive in people with crohn's disease. If you stimulate autophagy, or optimise vitamin D status or deprive cells of nutrients, AIEC actually dies so do mycobacteria, because it stimulates autophagy.

NOD2 KO mice have a very hard time controlling bacterial infections. Autophagy is involved in neutrophil phagocytosis which is essential for control of intracellular bacteria.

Plenty of studies both in vivo and vitro that have shown this. That's something I'm not going to even discuss, people have linked plenty, there's a laundry list of studies on this forum about it.

You consistently manipulate data and twist facts around to further your own ideas, it's not objective. Don't write papers if you can not be objective. Not bothering anymore.
 
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That is completely false, where are you getting these ideas from.

Can you learn to get the true meaning and key points from the whole context, rather than just jump to conclusions with your extreme words? Of course, I know there are a lot of studies on NOD2 and autophagy. That is how I can make comments on this and get published. The big question we have to answer is, as discussed in my early post (#385), is really possible that immune suppression agents like TNF-alpha blockers exerted their effect by killing and clearance of invaded bacteria that have been regarded by some people as unconquerable even by the most powerful antibiotics and the uncompromised immune system, while this disarmament of the immune system has greatly increased the risk of infection by TB and many other weaker opportunistic pathogens. I proposed an alternative explanation for this. If you think you have a better, cohesive explanation on this, share it with us. That would be a more reasonable and constructive approach.

Looking back human history, we may find that the truth usually hide behind small pieces of bizarre phenomenon, rather than the vast evidences people take for granted as true. For so long, people deeply believed the earth is the center of the universe, with the sun, the moon and all stars turning around it. A doubt on this started from the back-and-forth movements of some planets that were only observed at very rare occasions. We all feel time is absolute and the space is straight. But from the constancy of speed of light, Einstein postulated that the time is relative and the space is curved. People started to believe this because it predicted the bending of light observed during eclipse and many other things in the universe. These taught us that we need think it over and over before jumping to a conclusion from our intuition and it is not easy to find the piece of evidence that bares the clues of the truth.
 
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You consistently manipulate data and twist facts around to further your own ideas, it's not objective. Don't write papers if you can not be objective. Not bothering anymore.

since you are giving advice about getting papers published in scientific journals, i was wondering if you could provide some links to the papers you have written and successfully published, so we can see what experience you have?

thanks.
 
You consistently manipulate data and twist facts around to further your own ideas, it's not objective. Don't write papers if you can not be objective. Not bothering anymore.
You should realize that many of epidemiological studies such as the increases of IBD in Ireland, Singapore, Saudi Arabia, and United States, the decrease of CD and increase of UC in Sweden, and the even higher incidence of IBD in Guangzhou, China than the adjacent more developed Hong Kong and Macau were published after I published this paper discussed here, but can be easily explained by the already published hypothesis. Are you suggesting I have the power to manipulate what will happen in the future. Is it a sin to provide evidence for the possible cause of IBD? As stated in my early post, if you indeed have better explanations than I do and really interested in solving the mystery of IBD, you should bring it up, as these new findings may provide us a rare chance to find out the cause and thus the possible root mechanism of IBD.

You are the victim of the devil, but you denounce the efforts to track down the devil. Why?
 
Now this is interesting,in China they say tap water is protective for UC.
The first time I have ever seen that one.
Meaning it is untreated, as opposed to boiled,and that none pathogenic
bacteria in the tap water is having an immune modulating effect.
Chlorination in the USA started around 1908.

Would be interesting to see how much of the tap water in China is chlorinated,
or treated in some other manner.
Well well well.
http://www.travelchinaguide.com/essential/water.htm

http://www.nytimes.com/2013/11/08/opinion/if-you-think-chinas-air-is-bad.html

Also would be interesting to find out when chlorination started in England
to see in timelines match up with the increase in IBD, in the span from
say 1890 to 1920.
Ask and you shall receive,interesting 1890 for England.
While correlation is not causation,I have to now start to become
much more interested in what might be going on here.
This is why I spend a lot of time on historical timelines.
http://humboldt.edu/arcatamarsh/chlorination.html

Here is a good history of IBD,best I have ran across.
http://onlinelibrary.wiley.com/doi/10.1002/ibd.3780010103/pdf



This a link to the cached version,cant pull up the live version,where it
talks about tap water.
Wow chlorination has probably saved many millions of people from infection,yet it might be killing us.
Old Mike

http://webcache.googleusercontent.c...df/v19/i11/1827.pdf+&cd=9&hl=en&ct=clnk&gl=us
 
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Now this is interesting,in China they say tap water is protective for UC.
The first time I have ever seen that one.
Meaning it is untreated, as opposed to boiled,and that none pathogenic
bacteria in the tap water is having an immune modulating effect.
Chlorination in the USA started around 1908.

Would be interesting to see how much of the tap water in China is chlorinated,
or treated in some other manner.
Well well well.
http://www.travelchinaguide.com/essential/water.htm

http://www.nytimes.com/2013/11/08/opinion/if-you-think-chinas-air-is-bad.html

Also would be interesting to find out when chlorination started in England
to see in timelines match up with the increase in IBD, in the span from
say 1890 to 1920.
Ask and you shall receive,interesting 1890 for England.
While correlation is not causation,I have to now start to become
much more interested in what might be going on here.
This is why I spend a lot of time on historical timelines.
http://humboldt.edu/arcatamarsh/chlorination.html

Here is a good history of IBD,best I have ran across.
http://onlinelibrary.wiley.com/doi/10.1002/ibd.3780010103/pdf



This a link to the cached version,cant pull up the live version,where it
talks about tap water.
Wow chlorination has probably saved many millions of people from infection,yet it might be killing us.
Old Mike

http://webcache.googleusercontent.c...df/v19/i11/1827.pdf+&cd=9&hl=en&ct=clnk&gl=us
Thanks Old Mike for sharing the info. Below is the link to the live version of the paper above:

Wang YF, et al. Multicenter case-control study of the risk factors for ulcerative colitis in China. World J Gastroenterol. 2013 Mar 21;19(11):1827-33.

This is a paper out of my radar. It is interesting to find that sugar and spice food have been the main risk factors for UC.

In China, drinking hot water is a general habit. Here is a link with several pictures showing how the students line up to get hot water from the hot water facility of the school.. Regular tap waters are usually not that sterile and contain some bacteria, which may be the reason for its protective effect on UC.
 
Thanks Xiaofa:
We have known about the sugar connection for many years.
What I have never seen, or no one will admit is that untreated water is protective for UC.
Perhaps the connection is only possible in China or few other places.
In the USA and England the connection is buried in time.
We also know that at least in the West , UC is associated with urban living, which in the USA would imply water chlorination,also the hygiene hypothesis
perhaps a hidden not talked about consequence is mostly sterile water,which
improves the health of the general population,but is of course perhaps not good for our colons or small intestines.


Old Mike
 
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I am surprised that the study did not find any difference between urban and rural areas, as there is usually a big difference regarding their sanitary condition. Probably, the poor hygiene condition in the rural area has led more people there drinking boiled water and avoided tap water.

Another thing that interested me is sugar versus spicy food. In another recent study (Ng SC, et al. Asia–Pacific Crohn's and Colitis Epidemiologic Study (ACCESS) Study Group. Incidence and phenotype of inflammatory bowel disease based on results from the Asia-pacific Crohn's and colitis epidemiology study. Gastroenterology. 2013 Jul;145(1):158-165), it is showed that Guangzhou, the capital of Guangdong Province and a city near Hong Kong with sugar usually an important gradient in their dishes (see Guangdong, also known by foreigners as Cantonese cuisine) has the IBD incidence of 3.44 (CD 1.09, UC 2.05), while Chengdu, the capital of Sichuan Province with a fame for hot and spicy food (see Sichuan, also known by foreigners as Szechuan cuisine) has an IBD incidence of only 0.58 (CD 0.15, UC 0.42), (here is the table), suggesting sugar may probably have a more tight link than spicy food for IBD.
 
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Xiaofa: I ran across that study on my searching on China.
I believe the research doc's are missing a big opportunity to solve the cause of IBD if
they do not concentrate efforts on countries such as China with emerging/increasing IBD incidence.
Old Mike
 
Old Mike: I agree with you.

This study found the increased sugar consumption as one of the most important risk factors for UC. In fact I have sent email years ago to quite a few of the top IBD researchers in China (some of them being in the author list in the published paper: Wang YF, et al. Multicenter case-control study of the risk factors for ulcerative colitis in China. World J Gastroenterol. 2013 Mar 21;19(11):1827-33) suggesting them checking out the possible link between artificial sweeteners and IBD. Apparently, it failed to raise any action. Thus, we still do not know if artificial sweetener may be involved in the observed increased risk, as suggested in the paper discussed here. Anyway, I think people should put more effort to find out the cause of recent dramatic increase of IBD, but not just repeat again and again on factors we already know that are positive but not essential, rather we should check out the other suspected agents that may have played more significant causative role.
 
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Capturing all of the environmental factors you have been exposed to is probably still not simple, but I see no reason why this problem cannot be tackled with a brute force, big data approach and as far as I know, no one is doing this.
I personally feel IBD could be much simple than people currently perceived. The dramatic increase of Crohn's patients in the Saudi clinic from 0 or 1 case during 1993 to 2000 to 174 cases in 2009 (here is the figure) would be more likely due to a sudden introduction of one risk agent rather than a changed balance of complex interactions between numerous risk versus protective factors.
 
Can't we work on getting a real study funded to figure out the real causes, differences in diseases, treatments and cures? Where is the help to be found? Who can write up the request among you? Design proper controls?
 
I personally feel IBD could be much simple than people currently perceived. The dramatic increase of Crohn's patients in the Saudi clinic from 0 or 1 case during 1993 to 2000 to 174 cases in 2009 (here is the figure) would be more likely due to a sudden introduction of one risk agent rather than a changed balance of complex interactions between numerous risk versus protective factors.
I tend to agree. I expect the cause to be something relatively simple as it was with peptic ulcers and Coeliac disease. We just need the key insight to unlock the problem and I think we are in a much better position now than we were 20 years ago, simply because it is much easier to get in contact with ten of thousands of people with the disease and analyse the data.
 
I tend to agree. I expect the cause to be something relatively simple as it was with peptic ulcers and Coeliac disease. We just need the key insight to unlock the problem and I think we are in a much better position now than we were 20 years ago, simply because it is much easier to get in contact with ten of thousands of people with the disease and analyse the data.
As mentioned in my early post (see #294), the existence of H. Pylori (the spiral-shaped bacteria) in the lining of the human stomach had been found by German scientists back to 1875. As early as 1899, Professor Walery Jaworski of the Jagiellonian University in Kraków had suggested that these spiral shape bacteria, which he called Vibrio rugula, may have played a possible role in the pathogenesis of gastric diseases (http://en.wikipedia.org/wiki/Helicobacter_pylori). However, time and again, these findings and suggestions were soon forgotten. It took nearly a century that Barry Marshall and Robin Warren rediscovered these bacteria in the stomach and proved they are actually even more detrimental to the mucosa than the strong acids and have been the primary cause of peptic ulcer. Probably one day when we look back we may find that the cause of IBD is also just this simple.
 
Can't we work on getting a real study funded to figure out the real causes, differences in diseases, treatments and cures? Where is the help to be found? Who can write up the request among you? Design proper controls?
Sorry for the delayed response. Frankly, I have hesitated but now I feel it would be necessary to share what I experienced during the more than a decade pursuit in IBD, so we may have a more clear vision of the situation and problems in current IBD research and where could be the likely simple solution for IBD.

Regarding funding, as mentioned in the paper discussed here (Qin X. Etiology of inflammatory bowel disease: a unified hypothesis. World J Gastroenterol. 2012 Apr 21;18(15):1708-22) I have tried many times to apply grants from different agencies such as NIH, Crohn's and Colitis Foundation of America (CCFA), Broad Foundation, and Rainin Foundation, etc. However, all the submitted applications were triaged, meaning the applications were so bad that they were even not worthy to be brought up for a formal discussion at the study sections, or the Letter of Interest was turned down, meaning the idea is so bad that there is no need to submit a formal application. Right now the annual funding in IBD research by National Institute of Health (NIH) of the United States alone is about 120 million (Here is the link). It is not a lot, but still can do a lot of things. As discussed in multiple of my early posts (see posts on 08-19-2012, on 01-12-2013, on 03-29-2013, on 03-31-2013, and on 08-24-2013), I feel the big problem is not the resource but rather the attitude. As discussed in my early post on 08-19-2012, I found the possible link between saccharin and IBD in 2001, about the same time of finding the first IBD gene, NOD2/Card15, also called IBD1, associated with Crohn’s disease. During the last decade, people conducted genome wide analysis of 75,000 patients and controls with the cost of hundreds or even thousands of US dollars at early times for each and thus hundreds of millions for the whole study. However, nobody have interest to spend a little effort to check out if dietary chemicals like saccharin could be indeed a risk factor for IBD as I demonstrated in the paper published in 2002, by just collecting the urine or feces from some patients and controls and conducting an analysis with the well-established methods that are sensitive enough for an accurate assay for these chemicals even in the contaminated rivers and lakes (here is a recent paper from Canada: Spoelstra J, Schiff SL, Brown SJ. Artificial sweeteners in a large Canadian river reflect human consumption in the watershed. PLoS One. 2013 Dec 11;8(12):e82706). As the result, although we still do not know how NOD2 related to IBD, we found about 200 more risk genes (Jostins L, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012 Nov 1;491(7422):119-24). It generated a lot hypotheses and theories, but they can hardly explain anything happened in the real world. NOD2, the gene with the strongest association with Crohn’s disease, not only failed to show an association with CD in Asian, but also failed to show a correlation with the incidence of CD in the western countries that encompass three continents: Europe (France, Germany, UK, Italy, Belgium, Finland), Northern America (US and Canada) and Australia (Hugot JP, et al. Prevalence of CARD15/NOD2 mutations in Caucasian healthy people. Am J Gastroenterol. 2007 Jun;102(6):1259-67). This would have simply reflected the fact that the dramatic increase of IBD since last century is caused by factors in the environment rather than the gene. Nobody can catch the moon appeared in the water, because the moon is not there, but it still can generate a lot of hypothesis such as the water is too deep, the rope is not long enough, etc. Similarly, as discussed in my early post on 01-12-2013, despite of the low explaining ability, these genetic studies were presented as great achievements and explained as extra complexity of IBD that can only be deciphered by finding out the much more risk genes and the interactions among these genes, the gut microbiota with genes being 100 times of human genome, and many other epigenetic and other factors. In contrast, I believe the hypothesis I proposed a decade ago without any funding provided much better explanation and prediction for what happened in the real world, as demonstrated by the multiple papers I wrote. In my opinion, a simple breakthrough more likely lays in finding out the principal causative factors in the environment and thus the root mechanism of IBD. Probably, several hundreds of thousands may make even bigger progress than the hundreds of millions or even billions spent in the last decades. But we need finding the people who would like to do so.


Regarding the help, when I found the possible link between saccharin and IBD, I thought I may get some help from government or international agencies in charge of food safety, and foundations or professionals related to IBD research, but it turned out that none of these seemed really helped. Following is a list of some of my efforts:

- National Institute of Health (NIH) of US: I contacted in December 2001 the Director of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) responsive for studies in diseases of digestive system like IBD. The director responded through a person at the Office of Communications and Public Liaison, suggested me to apply grants from NIH or Crohn's and Colitis Foundation of America (CCFA). At that time, I had no way to do so, as I was ousted from my job since July 2001 largely due to my pursuit in the possible role of digestive proteases in diseases like IBD, then the immigration agency messed up my record and I had to stay at home for more than one year waiting for the correction and new process of hiring. After I went back to research and became a faculty I indeed tried very hard to apply some grants from NIH and CCFA, but all these applications were triaged as stated above.

- Food and Drug Administration (FDA) of US: I contacted in December 2001 the Director of the FDA’s Center for Food Safety and Applied Nutrition (CFSAN), but failed to get any response.

- Crohn's and Colitis Foundation of America (CCFA): I contacted in December 2001 the Chair of CCFA's National Scientific Advisory Committee and I was suggested to apply grant. I did try multiple times, but all triaged. During the last decade, I have also contact quite a number of the annually rotating Chairs of CCFA's National Scientific Advisory Committee suggesting a discussion on the evidence I gathered regarding the possible link between dietary chemicals and IBD, but I got no positive response.

- Center of Disease Control (CDC) of US: In February 2008, I learnt from CDC web site that some scientists/epidemiologists there were conducting an epidemiological study on IBD. I contacted the people there. The medical officer of CDC participated in this study told me that they were working as collaborating scientists with CCFA. Then she introduced me to the top officer in CCFA in charge of research and this officer then introduced me to a well-known IBD researcher. The professor told me he would like discuss with me after reading the material I sent him, but I failed getting any response.

- Joint Food and Agriculture Organization(FAO)/World Health Organization (WHO) Expert Committee on Food Additives (JECFA): I contacted in December 2001 the Secretary of JECFA and I was told in the response that they do not have sufficient resources to undertake work in this area.

- The European Union: I contacted in January 2002 the office of Scientific Committee for Food of European Union, but failed to get any response.

- Health Canada: I contacted in January 2002 the top officer in Canadian Food Inspection Agency. I got a response by the end of April telling me that my email was forwarded to Chemical Health Hazard Assessment Division in Health Canada. Then I got the opinion that saccharin was unlikely an important causative factor as Canada restricted its use after finding its carcinogenicity in animals in 1977. I felt this opinion reasonable and started to believe that even there is a link between artificial sweeteners and IBD, the link may not be strong. However, this notion changed after I found a paper in 2011 that sucralose inhibited gut bacteria and further leant that this new artificial sweetener was first approved by Canada in 1991. I immediately realized that sucralose may have played an important role in the high incidence of IBD observed in Canada in recent years. More evidences I collected seemed to support this notion. I wrote a paper on this that was published in Canadian Journal of Gastroenterology (Qin X. What made Canada become a country with the highest incidence of inflammatory bowel disease: could sucralose be the culprit? Can J Gastroenterol. 2011 Sep;25(9):511). Meanwhile, I contacted Health Canada again and tried to reach those I communicated about a decade ago, but failed to get any response.

- Food Standard Agency of UK: I contacted in March 2002 people in the Chemical Safety and Toxicology Branch of Food Standard Agency. They told me that they would be most interested to see new published data in my possession that casted doubt over the safety of saccharin. I sent them a draft of the manuscript that was eventually published in Medical Hypotheses (Qin XF. Impaired inactivation of digestive proteases by deconjugated bilirubin: the possible mechanism for inflammatory bowel disease. Med Hypotheses. 2002 Aug;59(2):159-63), but I never got any further response.

- IBD professional: As mentioned in my previous post on 01-30-2014, shortly after I found the possible link between saccharin and IBD, I contacted and would like to get an opinion from Dr. Joseph B. Kirsner, Professor at University of Chicago Medical Center and one of the most renowned IBD researcher in the world, but failed to get any response. During the 2003 Digestive Disease Week (DDW) conference, I also handed a copy of my paper published In Medical Hypotheses in 2002 as mentioned above to Dr. Stephen B. Hanauer, also a professor at University of Chicago Medical Center and one of the most renowned IBD researcher, and the multiple year co-Chairman for the yearly Advances in Inflammatory Bowel Diseases, Crohn’s & Colitis Foundation’s Clinical & Research Conference, asking for his opinion, but failed to get a response. As stated in my early post on 01-12-2013, I also started a discussion at several IBD-related LinkedIn groups including the European Crohn's and Colitis Organisation (ECCO), CCFA (Crohn's & Colitis Foundation of America), IBD - Crohn's disease & Ulcerative Colitis – CCF, and IBD Research Foundation, entitled “We should put a little bit more effort to find out the cause of inflammatory bowel disease”, in hoping to generate some in-depth discussion on the cause and etiology of IBD among the IBD professionals, but none of the IBD professionals responded. I had also submitted an abstract to the 2012 Advances in Inflammatory Bowel Diseases: Crohn's and Colitis Foundation's Clinical and Research Conference and the 8th European Crohn's and Colitis Organisation Congress of Inflammatory Bowel Diseases 2013, in hoping to have the chance exchanging information, evidences and views with IBD professions regarding the etiology of IBD, but the abstract was rejected by both of the conferences. As stated in my early post on 03-17-2013, shortly after the publication of this paper discussed here, I have emailed a copy of this paper to each member of the Epidemiology and Natural History Task Force of the International Organization of Inflammatory Bowel Disease (IOIBD) advocating them checking out this possibility. Apparently it failed to raise any attention, which is reflected by the fact that this group later published a paper regarding the environmental risk factors in IBD (Ng SC, et al. Geographical variability and environmental risk factors in inflammatory bowel disease. Gut. 2013 Apr;62(4):630-49) without mentioning the existence of such a hypothesis. I submitted a manuscript as a letter to the editor entitled “Dietary chemicals like saccharin and sucralose should not be omitted by epidemiologists as the possible important causative factors for inflammatory bowel disease”, but was rejected (see the post on 03-17-2013 for the rejected paper).

From my experience, and time and again demonstrated in human history, the only thing that can ultimately help to differentiate truth versus false is time, despite that the behavior of human may greatly affect how long it will take to achieve this. It took nearly 2000 years from someone proposed the earth turning around the sun to people really accepted it, and It took nearly a century from someone proposed the spiral-shaped bacteria may have played a role in the pathogenesis of gastric diseases to the finding of H. Pylori as the primary cause of peptic ulcer. We still do not know how long it will take for a final solution of IBD. However, as stated in my previous post on 08-24-2013, “I and the mainstream presented two totally different scenarios: I feel I, as a spare time IBD researcher and without any funding on IBD, may have virtually solved the mystery of IBD more than a decade ago, while the mainstream presented an extremely complex IBD that may need billions, if not trillions, and decades, if not centuries, to decipher it”. Which one is right? Some very easy tests can tell. As described above, I have tried so hard in the last decade to get this test down, either by myself through a grant or others capable of doing so. However, none would like to provide the tiny bit of resource or spent a little bit efforts. With time passing by, more and more evidences suggest my concern on the possible link between dietary chemicals and IBD is likely real rather than lunatic illusion, as demonstrated by the multiple recent epidemiological findings in IBD that I have commented on (here included some of these papers I wrote). As an individual, I often feel so helpless in front of the mainstream. The mainstream is so powerful. They can get and spend billions and asking for trillions under the glories claim to seek a solution of the disease, but put any evidence of the possible easy solution into the abyss of shadow and make the suggestion for this easy solution as heresy and ridiculous. Luckily, time and nature is even more powerful and always teach us, little by little, what is true, although time and again we just take too long to comprehend it. Looking back into what happened during the last decade, now I feel more confident to say there seems simple cause and easy solution for IBD. However, to reach this goal, we may need not only the efforts of the whole society but also, more importantly, the right approach that leads towards to but not away from the solution.
 
Xiaofa: Part of the problem is the not invented here syndrome with American doctors.
What really baffles me is that since say around the 1930's some of the best medical minds
have been working on IBD,with no solution. There last chance perhaps for a cause is emerging countries like China,I believe they missed their chance in Japan.
As we see in one of the above papers, unsterilized tap water may be a key,at least for protection. An implication from this is chlorination/boiling possibly as a cause.
Resulting in loss/lack of renewal of protective bacteria,which perhaps are killed off by certain foodstuffs.

Old Mike
 
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