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Etiology of inflammatory bowel disease: A unified hypothesis

Thanks for posting Xiaofa ~

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

My worry is that so much money is going to genetic studies and studies trying to unravel the human microbiome, they are super expensive studies that have no direct practical implications.
the genetic studies, i do not think they are a waste. if it had become the case that we identified a true genetic basis for the disease, better treatments would have followed. and it would have been considered a great success. But perhaps you mean in consideration of properly interpreting the existing evidence to determine what strategies might yielded quicker results, then perhaps a more complete investigation to identify some environmental toxin exposure woudl have found a common cause then i suppose it could have turned out differently.
So now we know where the answers arent, so we have eliminated some possibilitys and are certain the answer lies somewhere else, and that is progress, but not success.

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

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

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

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


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

Even the murine model that is used where colitis in KO mice is induced with DDS has very little to do with crohn's disease, the inflammation in crohn's disease is transmural and deep and is nothing like colitis mice at all.
yes,i agree disease models suck. but thats where the microbiome project would come into use i believe, the better defined the disease becomes, the better models we have for it. EDIT- consider this, learning how to eliminate distinct bacterial species so that the flora are identical to the pathological changes in ibd, and seeing if that would be sufficient to create a form of chronic colitis, we cant do that without knowing alot more about the bacteria.
 
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Thanks wildbill_52280 for sharing the thoughts. I think everybody understand and appreciate the great achievements in genetic research since last century. Actually, I had communicated with Dr. James D. Watson, the co-discoverer of the double helix structure of DNA more than two decades ago when I was a postgraduate in China with discussions on his DNA model.

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

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

Do you believe that we are "losing our microbes", perhaps with each successive generation? You're arguing in favor of the hygiene hypothesis, essentially then, right?
 
I think we would have to face the fact that IBD emerged and dramatically increased in modern society along with the improved hygiene. However, the “hygiene hypothesis” and I have a totally different explanation for this increase. The “hygiene hypothesis” proposed that the increases in the autoimmune and allergic diseases in modern society are due to the reduced exposure of the immune system to microbes and thus the lack of education at the early stage, resulting in an "aberrant" immune reaction later. Tremendous efforts (like current research in IBD) have been taking to find out what is going wrong. In contrast, I suspected that the increased immune response as seen in these diseases is just a natural reaction to the increased infiltration of bacterial and dietary components in the gut due to the damage of the gut barrier by factors such as the poorly inactivated digestive proteases, as the result of reduction in gut bacteria (Qin X. What caused the increase of autoimmune and allergic diseases: a decreased or an increased exposure to luminal microbial components? World J Gastroenterol. 2007 Feb 28;13(8):1306-7. http://www.wjgnet.com/1007-9327/full/v13/i8/1306.htm).
 
Xiaofa Qin is of course on the right track I believe. But we must look prior to about 1920 or so for the cause of IBD. MAP,CMV,chlorination,freezing food,canning or a million other things that happened, perhaps something that was protective and we are no longer eating. Even the worm theory. This is all pre antibiotic,pre food additives,many industrial chemicals,Wesson oil 1899,Crisco 1922,who knows. Since I have never eaten saccharin I have to discount that in my case of UC. Chlorination may have started around 1911 but have to do more research on that.
Here is a good IBD history in case you missed it.
We also know that fecal transplant can put some UC people into remission.
It is also interesting to note that prior to about 1920 or so there was little cancer and MI was unheard of,is there a connection.
Old Mike
http://onlinelibrary.wiley.com/doi/10.1002/ibd.3780010103/pdf

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

http://scholar.lib.vt.edu/theses/available/etd-05262005-122146/unrestricted/CivilWarDiet.pdf
 
Thanks Old Mike for sharing the thoughts. Indeed, million things may be changed along with the modernization; each of them may be correlated somehow with the changes in IBD at certain time point and thus presented as a possible connection. So what should we do? Give up or continue? Can we still find those truly responsible? How?

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

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

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

As for saccharin, I also had wondered if and to what extent it would be linked to IBD. This had driven me looking into the history of IBD and saccharin. It is a painstaking process that had taken me more than a decade so far. As shown in the paper, it covered from the earliest of reports of clustered cases of ulcerative colitis in London since 1888 and the earliest marketing and favorite use of the German made saccharin in UK since 1887, through the multiple reports of the leveling off or decrease of IBD during 1980s in many countries and the finding of carcinogenicity and attempted ban on saccharin in later 1970s, with included a brief description of wide spread use of saccharin along with World War I. The more evidence I found, there seems more to support rather against the possible link. Despite that, without a vigorous test, they are just the suspects like the many others. We can definitely bring in more suspects. However, I think we should remove dietary chemicals like saccharin and sucralose from the list of suspects for IBD only after we have found out those with a more perfect and specific match and pinned down as the real criminal.
 
I was informed by the Journal of Crohn’s and Colitis that the manuscript I submitted entitled "Have genome-wide association studies or knockout mice more reflected the true nature of inflammatory bowel disease?", a topic that was discussed in the previous post (#98), has been accepted for publication. It seems a little bit odd that such a crucial issue is brought up by a spare time IBD researcher rather the many those engaged in genetic research of IBD. Hope it may generate some in-depth and insightful thinking that may lead to a more efficient approach toward the solution of IBD.
 
Congrats, I hope it gets published soon. I wish it was not elsevier because that limits the exposure of the paper to people with crohn's disease, but I realise it's not that easy to publish papers.

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

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

Geographic location easily trumps genetic predisposition when you take into account the most common loci like NOD2 and ATG16L1.
 
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Thanks kiny and Mark for the kind congrats.

As for NOD2, many studies have well documented that NOD2 has been the risk gene having the strongest association with Crohn’s disease. Despite that, as pointed by kiny, NOD2 not only failed to show an association with CD in Asian as demonstrated in the multiple studies listed in thread by kiny (http://www.crohnsforum.com/showthread.php?t=45141), it also failed to show a correlation in the western countries, as demonstrated in the study by Hugot JP, et al (Prevalence of CARD15/NOD2 mutations in Caucasian healthy people. Am J Gastroenterol. 2007 Jun;102(6):1259-67. http://www.ncbi.nlm.nih.gov/pubmed/17319929), which had included countries from three continents: Europe (France, Germany, UK, Italy, Belgium, Finland), Northern America (US and Canada) and Australia. Again, this would suggest some factors to be identified make the effect of even the strongest gene minimal, just like its minimization on the effect of smoking and antibiotics as discussed in the previous posts. We need finding out these factors responsible.
 
Just found this study presented at the 2007 Digestive Disease Week (DDW) by Dr. Steven B. Ingle and colleagues at Mayo Clinic, entitled “Increasing Incidence and Prevalence of Inflammatory Bowel Disease in Olmsted County, Minnesota, During 2001-2004” (Gastroenterology 132 (4 suppl): A19-A20, 2007).

Here are the results:
The age- and sex-adjusted incidence rate for ulcerative colitis in 2001-04 was 12.5 cases per 100,000 person-years (95% confidence interval [CI], 9.4-15.6), compared to an incidence of 10.7 per 100,000 (8.7 - 12.6) in 1991-2000. The age- and sex-adjusted incidence rate for Crohn's disease in 2001-04 was 12.9 per 100,000 (9.7-16.1), compared to an incidence of 9.0 per 100,000 (7.2 - 10.8) in 1991-2000.
Here is the conclusion:
Although incidence rates of Crohn's disease and ulcerative colitis had remained relatively stable in Olmsted County between 1970 and 2000, the incidence of both conditions appears to have increased somewhat over the past 5 years.
As we know, Mayo Clinical had been the place with the earliest reports and treatments of clustered IBD (ulcerative colitis) in the United States, with the reporting of 117 cases of UC treated there during 1915 to 1918 (http://books.google.com/books?hl=en&lr=&id=pIkfAAAAIAAJ&pg=PA180#v=onepage&q&f=false) and 693 cases between 1923-1928 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2183453/). Mayo Clinic has been one of the best-known leading hospitals in the world for the treatment of IBD. So their diagnosis would be highly reliable.

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

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

Abstract

Splenda is comprised of the high-potency artificial sweetener sucralose (1.1%) and the fillers maltodextrin and glucose. Splenda was administered by oral gavage at 100, 300, 500, or 1000 mg/kg to male Sprague-Dawley rats for 12-wk, during which fecal samples were collected weekly for bacterial analysis and measurement of fecal pH. After 12-wk, half of the animals from each treatment group were sacrificed to determine the intestinal expression of the membrane efflux transporter P-glycoprotein (P-gp) and the cytochrome P-450 (CYP) metabolism system by Western blot. The remaining animals were allowed to recover for an additional 12-wk, and further assessments of fecal microflora, fecal pH, and expression of P-gp and CYP were determined. At the end of the 12-wk treatment period, the numbers of total anaerobes, bifidobacteria, lactobacilli, Bacteroides, clostridia, and total aerobic bacteria were significantly decreased; however, there was no significant treatment effect on enterobacteria. Splenda also increased fecal pH and enhanced the expression of P-gp by 2.43-fold, CYP3A4 by 2.51-fold, and CYP2D1 by 3.49-fold. Following the 12-wk recovery period, only the total anaerobes and bifidobacteria remained significantly depressed, whereas pH values, P-gp, and CYP3A4 and CYP2D1 remained elevated. These changes occurred at Splenda dosages that contained sucralose at 1.1-11 mg/kg (the US FDA Acceptable Daily Intake for sucralose is 5 mg/kg). Evidence indicates that a 12-wk administration of Splenda exerted numerous adverse effects, including (1) reduction in beneficial fecal microflora, (2) increased fecal pH, and (3) enhanced expression levels of P-gp, CYP3A4, and CYP2D1, which are known to limit the bioavailability of orally administered drugs.
 
Thanks wildbill for the post. This is just the article I first saw in early last year that led me to suspect the possible link between sucralose and IBD (as described in the previous post #28 in this thread).
 
In my paper (Fig. 4, http://www.ncbi.nlm.nih.gov/pubmed/22553395) and previous posts (#109 and #114 in this thread) I showed some evidence regarding the remarkable increases of IBD shortly after the approval of sucralose in western countries like Canada, the US, Australia, New Zealand, Norway and Ireland. As we know, the heavy use of sucralose in the western countries has made it an increasing environmental concern for its effects on the aquatic organisms in the rivers and lakes (Tollefsen KE, Nizzetto L, Huggett DB. Presence, fate and effects of the intense sweetener sucralose in the aquatic environment. Sci Total Environ. 2012 Nov 1;438:510-6). In fact, sucralose was also approved by Asia countries like Japan, South Korea, and China around 2000. Surprisingly, a recent study found that sucralose has become the top contaminants among the many pharmaceuticals, household chemicals, and pesticides even in China. It would be interesting to know how this has linked to the recent increase of IBD in these countries.

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

Environ Sci Technol. 2012 Aug 21;46(16):8680-8. Epub 2012 Jul 30.

Organic micropollutants in rivers downstream of the megacity Beijing: sources and mass fluxes in a large-scale wastewater irrigation system.

Heeb F, Singer H, Pernet-Coudrier B, Qi W, Liu H, Longrée P, Müller B, Berg M.


Abstract

The Haihe River System (HRS) drains the Chinese megacities Beijing and Tianjin, forming a large-scale irrigation system severely impacted by wastewater-borne pollution. The origin, temporal magnitudes, and annual mass fluxes of a wide range of pharmaceuticals, household chemicals, and pesticides were investigated in the HRS, which drains 70% of the wastewater discharged by 20 million people living in Beijing. Based on Chinese consumption statistics and our initial screening for 268 micropollutants using high-resolution mass spectrometry, 62 compounds were examined in space and time (2009-2010). The median concentrations ranged from 3 ng/L for metolachlor to 1100 ng/L for benzotriazole and sucralose. Concentrations of carbendazim, clarithromycin, diclofenac, and diuron exceed levels of ecotoxicological concern. Mass-flux analyses revealed that pharmaceuticals (5930 kg/year) and most household chemicals (5660 kg/year) originated from urban wastewaters, while the corrosion inhibitor benzotriazole entered the rivers through other pathways. Total pesticide residues amounted to 1550 kg/year. Per capita loads of pharmaceuticals in wastewater were lower than those in Europe, but are expected to increase in the near future. As 95% of the river water is diverted to irrigate agricultural soil, the loads of polar organic micropollutants transported with the water might pose a serious threat to food safety and groundwater quality.
 
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Some people wondered why the inflammation of ulcerative colitis (UC) is limited in the mucosa, while in Crohn’s disease (CD) the inflammation is transmural that can be seen in all layers of the gut. This would be a very basic and yet important question but hardly any textbooks or articles on IBD gave an explanation. In fact, the paper discussed here has actually contained a very simple explanation. I have depicted the overall hypotheses for the cause and mechanism of IBD including both UC and CD in Figure 5 in the paper (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3332284/figure/F5/ ). It suggested that both UC and CD are caused by weakening of gut barrier. However, the large amounts of bacteria in the colon made the recruitment of neutrophils and formation of crypt abscess as the main manifestation of UC, while the infiltration of antigens and dietary particles in the small and large intestine has mainly caused the recruitment of macrophages that led to the formation of granulomas as the main manifestations in CD. With a life span of just a couple of days, neutrophils are the fast reaction army of the body and will be dispatched to the very front and fight vigorously there with the enemy until die. However, macrophages are the cleaner and order keeper inside the body, with a basic duty to cleared up debris like the dead cells. They have a life span of months and can fulfill their job by eating the debris, digesting them, moving around, and picking up again for quite a while. However, things like dietary particles and multiple species of bacteria such as Mycobacterium, Salmonella, Listeria and Shigella are beyond the ability of macrophage to digest. But the macrophages may have carried and moved them quite inside before they caused the cells to die. Then the particles or bacteria will be released and picked up by other macrophages and moved further inside. Eventually, the macrophages will realize that they just cannot get rid of the intruder and call in more macrophages and lymphocytes to quarantine them. This is how the granulomas were formed (http://en.wikipedia.org/wiki/Granuloma ). In my opinion, UC is more like the bacterial pneumonia ( http://en.wikipedia.org/wiki/Bacterial_pneumonia ) with the involvement of mainly neutriphils and the inflammation mainly inside the alveoli, while CD is more like some pneumoconiosis (caused by inhalation of dusts) such as silicosis or berylliosis ( http://radiographics.rsna.org/content/26/1/59.full) or tuberculosis of the lung with the involvement of mainly macrophages and manifested as glanulomatous inflammation, destruction of the tissue, extensive proliferation of fibroblasts and formation of fibrosis, etc. I think this may also attributed to the genetic, epidemiological and other aspects of the similarities and discrepancies between UC and CD as discussed in the paper (in page 1716-1717, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3332284/pdf/WJG-18-1708.pdf)
 
Xiaofa: I am still up in the air about your theory, I read that B glucuronidase
is related to increased colon cancer risk. Can you explain the problem as to inhibition reducing cancer and inhibition causing IBD.
http://www.homeopathicdoctor.ca/GSD...sessments/CDSA_2/CDSA2_SuppGd/CDSA2_BetaG.pdf

There are of course many more references to the above.

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

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

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

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

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

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

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

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

sialic acid degrading enzymes from bacteria
http://www-05.all-portland.net/cs/074/0071/0740071.pdf
Thanks
Old Mike
 
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Thanks Old Mike for sharing the thoughts and info. The core of my hypothesis is that the primary cause of IBD is the over digestion of gut barrier by the poorly inactivated proteases (most may from the pancreas, but some may be from the bacteria) due to the inhibition of gut bacteria by dietary chemicals along with the improved hygiene. This is initiated by the finding that digestive proteases are inactivated by unconjugated but not conjugated bilirubin. It is well known that bilirubin secreted from the bile into the lumen is mainly in the conjugated form, which can be deconjugated by beta-glucuronidase enriched in gut bacteria. Yes, this enzyme may have also involved in the formation of some carcinogens. This would just reflect the many complicated interactions of the body and environment, just like smoking is protective for ulcerative colitis but a risk for many other diseases including Crohn’s disease. Yes, many patients with ulcerative colitis have the antineutrophil antibodies (ANCA), with a large portion being the antibody against beta-glucuronidase. As this enzyme has been one of the main enzymes released by neutrophils at the site of inflammation, I personally suspected that this enzyme may be beneficial and its inactivation by the antibodies may have somehow contributed to the pathogenesis of the disease.

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

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

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

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




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

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

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

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

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

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

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

Thanks again for sharing the paper.

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

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

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

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

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

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

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

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

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

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

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

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




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

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

I indeed learnt before BBIC is a potent protease inhibitor that also showed inhibition on the development of multiple cancers. Here is a clinical trial regarding the effect of BBIC on ulcerative colitis, showing some benefits (Lichtenstein GR, et al. Bowman-Birk inhibitor concentrate: a novel therapeutic agent for patients with active ulcerative colitis. Dig Dis Sci. 2008 Jan;53(1):175-80). But as you say, it seems that taking large amount of soy products may not be a good way of inactivating digestive proteases in the large intestine, as it may also impair the digestion of proteins from the diet (in addition to gassy). Therefore, targeted delivery of some small molecule inhibitors to the lower intestine would be a more ideal way for this purpose. I have to point out that the increased activities of digestive proteases and over digestion of the mucus layer may probably have played a more important role in the initiation of the disease. Once the weakening of gut barrier allowed the infiltration of significant amounts of gut bacteria and its products, the infection would become the main driving force for the persistent inflammation, just like the infection of a wound after a cut. The increased existence of adhesive and invasive E. coli (AIEC) and other bacteria in Crohn’s disease and the crypt abscess in ulcerative colitis would suggest antibiotics should have some effect. I suspected that the impaired inactivation of digestive proteases may have confounded the efficacy of antibiotics (Qin X. Impaired inactivation of digestive proteases: a factor that may have confounded the efficacy of antibiotics aimed at reducing the exposure to luminal bacteria and their components. Am J Gastroenterol. 2008 Nov;103(11):2955-6. http://www.ncbi.nlm.nih.gov/pubmed/19032485 ). Right now, the treatment of IBD still mainly focuses on suppression of the inflammation, which seems mainly alleviated the symptoms rather than gets out the roots of the diseases. The prolonged inflammation has caused a reduction or depletion of goblet cells. I believe the restoration of the number and full function of goblet cells should be added as a big marker and goal for the treatment of IBD. After the gut barrier function restored to normal, I think then the commensal flora rather than the protease inhibitor should be used to keep the gut normal. I am just an amateur IBD researcher and this is just my personal opinion.
 
Xiaofa:Thank you for your thoughts.
I have gotten through about 200 medline abstracts on BBI so far.
It seems to be safe,about 50% is absorbed into the circulation from ingested amounts,which might lead to other systemic benefits.

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

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

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

this approach may not be safe,seems to cause problems in rats
http://link.springer.com/article/10.1007/BF01092012#page-1
 
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Old Mike: thank you for the great effort you take and sharing the info.

Yes, there are many studies and publications on BBI before. By the end of the paper published in 2008 regarding the clinical trial of BBIC on ulcerative colitis (Lichtenstein GR, et al. Bowman-Birk inhibitor concentrate: a novel therapeutic agent for patients with active ulcerative colitis. Dig Dis Sci. 2008 Jan;53(1):175-80), it mentioned that a larger clinical trial was underway. Do not know the trial is still ongoing or stopped by some reason.
 
Xiaofa:Sorry I can not find anything on other BBI UC trials,perhaps they found a problem
as in the rat study of potato protease inhibitors above. A question might be how much non fermented soybean is in the asian diet,and is long term low level BBI consumption
protective. We know IBD incidence in asia is low but increasing,perhaps due to westernization of diet.
Another interesting thought is what is going on in Sweden with UC.
http://www.ncbi.nlm.nih.gov/pubmed/23491313
Old Mike
this paper seems to indicter soy BBI is safe
http://ajcn.nutrition.org/content/68/6/1406S.full.pdf
looks like 35-55 mg bbi/100g soymilk,looks like 30mg enough to start to prevent cancer. From above paper.
http://cebp.aacrjournals.org/content/9/7/741.full

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

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

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

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

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

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

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

Taken together this might be enough information to at least infer that
saccharin is to some extent in drinking water,and I would guess that back around 1920 there was perhaps more,due to lack of sewage/water treatment
plants. It is in my toothpaste,have to find a brand without,but trying to find toothpaste without any artificial sweetener is difficult. In the past I have switched to just baking soda,but for some reason my teeth become sensitive.
Old Mike
 
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Thanks Old Mike for checking out and sharing the info. I added a little more discussion and info in the previous post (#130). Although IBD may be caused by many factors, a true contribution of each factor may depends on the extent of consumption, the strength of their toxic effects on the target, and how much can really reach the target (like the bacteria in the lower gut). I suspect that the artificial sweeteners may be capable of causing a big impact on the population due to the wide use. However, I think the small amount of saccharin in the toothpaste, if not swallowed, probably would not be enough to cause a big problem on gut bacteria.
 
Thanks Old Mike for sharing the article. The results are amazing but not surprising. It would be just what may (should) happen according to the hypothesis discussed here. Unfortunately, it is just case report. It would be worthwhile to conduct some randomized, double-blind, placebo-controlled clinical trial for a more accurate assessment.
 
Xiaofa: This should be enough to prove at least that inhibiting proteases in the colon will induce remission,the case report and the BBIC trial.
At any rate here might be why there are no more BBIC trials.
The company who made the BBIC was taken over and the new management is not interested in BBIC.
Go to the insert and read the last paragraph.
Never the less I am excited to have found the Camostat report,hopefully natural protease inhibitors also work as well,and that the synthetic drug is not many times more effective/powerfull than the natural compounds.
Old Mike
http://link.springer.com/chapter/10.1007/978-94-007-6214-5_11#

here is an article on trypsin inhibitors in the colon UC included
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1869860/pdf/amjpathol00050-0024.pdf
 
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Thanks Old Mike for checking out and sharing the info. Hope new clinical trials will be conducted and new drugs (treatments) may develop that may get rid of the root of the disease and lead to a real cure of IBD without the need of lifelong medication.
 
I found a thread in this forum started by D Bergy entitled “Most medical research false?”. I think it would be not accurate to say most of medical research false. However, in my opinion, there are some fundamental problems in medical research that is far beyond just the bias caused by the funding from some private companies and a declaration of Conflict of Interest in the publication can solve.

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

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

WOW.

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




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

after thinking about traditional medicine systems i realized that there was this vast amount of knowledge gained about plants and their medicinal properties for disease, observations over periods of thousands of years by chinese and ayruvedic medicine that were all conducted in vivo, there is likely many promising herbs from these systems for the human body for treating diseases, of course others have realized the same thing, not trying to claim this as originally mine or anything like that, like realizing/understanding this in my own mind.
 
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So Xiaofa, do you.have an alternate research funding system in mind?
Not yet. I indeed feel we have some big problem in the current funding system. For instance, I believe I have more thorough and deep thinking on IBD than many IBD professionals and that is how I can construct this unified hypothesis on the etiology of IBD. However, due to the lack of direct research on IBD, I was scored by the reviewers very low as the investigator that would be enough to fail any application.

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

after thinking about traditional medicine systems i realized that there was this vast amount of knowledge gained about plants and their medicinal properties for disease, observations over periods of thousands of years by chinese and ayruvedic medicine that were all conducted in vivo, there is likely many promising herbs from these systems for the human body for treating diseases, of course others have realized the same thing, not trying to claim this as originally mine or anything like that, like realizing/understanding this in my own mind.
Thanks wildbill_52280 for sharing your thought and story. Although I grew up in China, frankly, I was not very confident in traditional medicine at beginning. But this was changed after I found the inhibition of digestive protease by the unconjugated bilirubin and pursed further.

The gallstone of the ox (also called Calculus Bovis in academic, or Niuhuang in Chinese) was described in “Shennong Bencao Jing” (Divine Farmer’s Materia Medica Classic, the first book of Chinese herbal medicine written two thousand years ago) as a superior medicine and has been one of most precious medicine in China. For instance, Angong Niuhuang Wan (Calm the Palace Pill with Cattle Gallstone) can be more than $100 per pill. It is reported having life-saving effects for critically ill patients. Here is a story regarding a Hong Kong TV hostess who was hit by a train and declared brain dead in London but got a full recovery after being brought back and treated in China. In fact, the main component of cattle gallstone is unconjugated bilirubin, formed due to the infection of the biliary system and precipitation of deconjugated bilirubin in the bile by beta-glucuronidase from the bacteria. I believe bilirubin would be the indispensable component of cattle gallstone (Qin XF. Bilirubin would be the indispensable component for some of the most important therapeutic effects of Calculus Bovis (Niuhuang). Chin Med J (Engl). 2008 Mar 5;121(5):480), through mechanisms such as the inhibition of digestive proteases. Definitely, there would be many valuable staff in the traditional medicine we may explore.
 
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Xiaofa:Here is another possible mechanism.
H0-1
http://www.ncbi.nlm.nih.gov/pubmed/15803024


HO-1 induction,will make CO and bilirubin

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

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

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

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

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

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

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

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

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

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

lipoic acid also induces

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

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

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

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

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

Seems we are caught in some form of biochemical trap.
Just suppose we bleed then become anemic,and then we cannot induce H0-1 because we are anemic,we continue to bleed and become more anemic,and induce less and less H0-1.
I know I am anemic,and many with UC are also anemic. I hate to take iron pills they seem to make me wose,but will now force myself to take iron,will also take lipoic acid
which induces HO-1. Will see where this goes.
Hope I was somewhat clear with the mechansim of what is taking place.
Old Mike
 
Thanks Old Mike for checking out and sharing these articles. Multiple studies showed that HO-1 is induced at the site of inflammation or injury, with beneficial effects to the body.

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

Just my few cents.
 
Grungle: Thanks for the input,I have have UC since 1980,tried SCD 3 times,also no dairy,no nightshade,no sugar,and many other alternative approaches. Still have UC.
Old Mike
 
I want to put this idea to you all. Check available data on milk consumption per capita for different countries, for example in Europe, and number of IBD cases. It gives some idea. There seem to be a very good correlation between theese numbers. Why make this so hard? I took away milk and sugar from my diet 8 years ago, after fighting Crohn's for two years. I actually followed SCD diet for two years after, with not a single cheat, not a single time i ate something out of the diet. Im a very disciplined guy.. ;) I have been well ever since, no medicines whatsoever. Thats why i even had the idea. For me it seems kind of obvious that problems in bowel are caused by what you put into it. Nightshades might play a role as well during the leaking from an oversensitive bowel, at least.
Thank Grungel for sharing the thoughts and experience. To my knowledge, multiple studies back to 1980s found increased intake of refined sugar in patients with Crohn’s disease (here are some of the studies). However, the enthusiasm receded when some controlled trials failed to show a benefic with the restricted use of sugar (Ritchie JK, et al. Controlled multicentre therapeutic trial of an unrefined carbohydrate, fibre rich diet in Crohn's disease. Br Med J (Clin Res Ed). 1987 Aug 29;295(6597):517-20), especially the poor correlation between the Crohn’s disease and refined sugar consumption (Sonnenberg A. Geographic and temporal variations of sugar and margarine consumption in relation to Crohn's disease. Digestion. 1988;41(3):161-71). However, I have not noticed any vigorous research between the milk consumption and IBD. Your post interested me to have a look on this and found out a ranking list of countries by milk consumption per capita). However, I cannot perceive a good correlation between the milk consumption per capita and the incidence of IBD. For instance, according to a study on the incidence of IBD across Europe (Shivananda S, et al. Incidence of inflammatory bowel disease across Europe: is there a difference between north and south? Results of the European Collaborative Study on Inflammatory Bowel Disease (EC-IBD). Gut. 1996 Nov;39(5):690-7), Ioannina in Greece has the lowest incidence of Crohn's disease. However, according to the list, Greece is among the countries with the highest milk consumption per capita. On the other hand, although countries like Canada and New Zealand have the highest incidence of IBD, their milk consumption are much lower than countries with very low incidence of IBD such as Lithuania (Kiudelis G, et al. Incidence of inflammatory bowel disease in Kaunas region, Lithuania. Medicina (Kaunas). 2012;48(8):431-5) or Romania (Gheorghe C, et al. Epidemiology of inflammatory bowel disease in adults who refer to gastroenterology care in Romania: a multicentre study. Eur J Gastroenterol Hepatol. 2004 Nov;16(11):1153-9). It would be great if you would share your evidence and analysis for the good correlation between milk consumption per capita and incidence of IBD. Anyway, glad to know you have been in long remission without any medication, which would suggest IBD patients may indeed recover to full health.
 
I want to put this idea to you all. Check available data on milk consumption per capita for different countries, for example in Europe, and number of IBD cases. It gives some idea. There seem to be a very good correlation between theese numbers. Why make this so hard? I took away milk and sugar from my diet 8 years ago, after fighting Crohn's for two years. I actually followed SCD diet for two years after, with not a single cheat, not a single time i ate something out of the diet. Im a very disciplined guy.. ;) I have been well ever since, no medicines whatsoever. Thats why i even had the idea. For me it seems kind of obvious that problems in bowel are caused by what you put into it. Nightshades might play a role as well during the leaking from an oversensitive bowel, at least.

Just my few cents.
you likely have a mild to moderate case of ibd, which can be easily controlled by removing lactose and sucrose and following the SCD. the guidelines to the SCD are to remove/reduce lactose and sucrose to starve bacteria, as well as some select starches/complex carbs. it is also possible that by avoiding milk, you avoid coming in contact with MAP bacteria, which can sometimes survive pasteurization according to some studies. but this may not be the only intracellular bacteria that may be involved in crohn's disease, there may be others. IBD seems to generally be defined as, a lowered ability to eradicate pathogenic bacteria, likely due to some degree of preceding dysbiosis. the severity of dysbiosis from damaged intestinal flora, and the type of bacteria you may come in contact with, will generally explain the differences in ibd cases, in my opinion.
 
There are several studies published recently that may be of some interest. One study showed that the incidence of IBD in the children in Shanghai, China increased 12-folds from 2001-2010 (Wang XQ, et al. Inflammatory bowel disease in Chinese children: a multicenter analysis over a decade from Shanghai. Inflamm Bowel Dis. 2013 Feb;19(2):423-8. http://www.ncbi.nlm.nih.gov/pubmed/23340680 ). It seems this recent increase in IBD in Asian cannot be simply explained by the development in the economy. For instance, in another retrospective hospital study on the pediatric IBD in the already highly developed Singapore (Chu HP, Logarajah V, Tan N, Phua KB. Paediatric inflammatory bowel disease in a multiracial Asian country. Singapore Med J. 2013 Apr;54(4):201-5. http://www.sma.org.sg/UploadedImg/files/SMJ/5404/5404a1.pdf ) , there was either zero or only one case of IBD during 1996 –2001, but multiple cases started to emerge since 2002, with 8 cases in 2008. Interestingly, this increase occurred again shortly after the approval of sucralose in Singapore in 1999 and the opening of the $198 million sucralose plant in 2007 (http://www.chemweek.com/regions/sou.../Tate-and-Lyle-Opens-Singapore-Unit_6383.html ). I do not want to explain everything by the hypothesis I proposed and exclude the many other possibilities, but the co-incidences kept on popping up. Does anyone have any better explanations we can share? Hope people may find out the reason.
 
Xiaofa Qin,
The last article you posted a link to, I am not sure I understand... I thought the genetic variants associated with crohn's facilitated bacterial infection, so is this study suggesting that the opposite may be true? it seems there is still a very long way to go before they figure out what causes IBD. :(
 
There's nothing beneficial about having autophagy defects (NOD2 / ATG16L1 / IRGM / VDR). Defects in xenophagy result in severely decreased ability to deal with both bacteria and viruses.

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

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

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

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

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

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

Autophagy is a major major part of dealing correctly with infections.
 
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It showed that mutation or deficiency of the Crohn’s disease - core autophagy gene ATG16L1 conferred protection from bacterial invasion and infection.
By saying that, to me it seems like you're casually suggesting that impaired autophagy is somehow beneficial, which it isn't, especially not in relationship to crohn's disease.

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

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

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

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

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

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

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

Impaired cytokine response to Viral infections related to ATG16L1:

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

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

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

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

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

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

(I posted the full study some time ago)

Infliximab is detrimental to the survival of MAP for example.

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


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

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


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

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

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

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

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


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

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

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


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


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

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

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




 
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723crossroads

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

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

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

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

multiple factors involved in developing this disease. diet alone may even be enough to cause dysbiosis leading to IBD. that's the least likely route i believe though.
 
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Did anyone ever think possibly it could be from chemicals in our water? To me that makes more sense. Way back, there was very little pollution to the water and thus no chemicals added. Then along came factories and the water is full of crap. Then we add tons of chlorine and other harmful chemicals to kill the crap and we are all getting sick with cancer ,IBD's etc.... Any thoughts along these lines besides mine?
Maybe the broad street pump story interests you if you haven't read it yet.

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

Also a number of studies that show crohn's disease clustering in families with unrelated bloodlines.
 
Thanks all for the posts, and thanks kiny for sharing the thoughts and info.

I agree and disagree.

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

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

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

(I posted the full study some time ago)

Infliximab is detrimental to the survival of MAP for example.

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


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

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


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

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

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

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

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

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

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

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

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

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

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

Two things can do this, an autoantigen...which has never been found with any consistency in crohn's disease (you'd also have indiscriminate inflammation all over the organ, which isn't the case in crohn's disease)...or you need an antigen in the form of a bacteria or virus.
As illustrated in my paper, I believe that the weakening of gut barrier and increased infiltration of toxic components like lipopolysaccharides (LPS) and the Muramyl dipeptide (MDP) containing peptidoglycan of bacteria might be the primary trigger of the inflammation. As we know, the gut contains large amounts of LPS (also called endotoxin) that can kill the host thousands of times over, and the long evolution has equipped the body with an innate immune system with defense cells like macrophages being able to launch promptly a vigorous instinct response to low doses of LPS. Thus the inflammation of the gut can be started and continued without any antigen.

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

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

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

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

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

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

The above is just my personal opinion.
 
I need to go over your paper again because I truly don't understand everything you're saying, I lack the knowledge to understand everything.

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

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

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

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



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

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

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

Random coincidence? Fat chance.

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

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

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





Ignoring the bacterial and infectious component in crohn's disease, considering the moutain of evidence, genetic, clinical, limited response to antibiotics, is really hard to justify at this point.
 
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As we discussed in some early posts, I also believe that infection by bacteria may have contributed significantly to the pathogenesis of the disease, especially when the prolonged inflammation has caused such a damage that allowed the luminal bacteria easily get in. However, I suspected that the sustained inflammation is mainly caused by the continuous infiltration of toxic luminal components, not only the live bacteria (probably multiple strains in nature) but also their debris like LPS and peptidoglycan, rather than UNCONTROLLABLE tenacious infection of certain species of bacteria.

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

I admired the great passion and enthusiasm you and many others in this forum put trying to find the root of this disease. Hope our efforts will eventually get some meaningful results.
 
really hate to interrupt your discussion, but the issues in crohn's goes far beyond inflammation trigger by lps through a leaky gut. leaky gut is controlled through butyrate via its influenced in intestinal tight junction proteins.

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

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

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

as always, im intrigued.

quickly tho,the study states,
However, 4.6% of microbes found in controls were lacking in CD patients.

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

I will consider this new information more completly tomorrow.

thank you.
 
I just submitted a paper to the Journal of Crohn’s and Colitis entitled “Does the association with NOD2, autophagy and some pathogens really mean Crohn’s disease is caused by uncontrolled infection?”, and I was informed the paper has been accepted for publication. Apparently, the journal comprehends the notion that Crohn’s disease is more likely caused by escalated immune reaction to the increased infiltration of luminal bacteria and their debris rather than deficiency of the immune system and uncontrolled infection being reasonable, not ridiculous.
 
I just submitted a paper to the Journal of Crohn’s and Colitis entitled “Does the association with NOD2, autophagy and some pathogens really mean Crohn’s disease is caused by uncontrolled infection?”, and I was informed the paper has been accepted for publication.
Apparently, the journal comprehends the notion that Crohn’s disease is more likely caused by escalated immune reaction to the increased infiltration of luminal bacteria and their debris rather than deficiency of the immune system and uncontrolled infection being reasonable, not ridiculous.
That's a lot of assumptions, it goes completely against current evidence, and you run into a host of issues by blaming the gut flora and ignoring autophagy:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The reason I don't believe in the idea that our own body is somehow attacking our indigenous flora, and that luminal content is somehow infiltrating so deep into tissue that it's causing transmural inflammation and fistulas is because it makes no sense and it's not based on any evidence.
 
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I just submitted a paper to the Journal of Crohn’s and Colitis entitled “Does the association with NOD2, autophagy and some pathogens really mean Crohn’s disease is caused by uncontrolled infection?”, and I was informed the paper has been accepted for publication. Apparently, the journal comprehends the notion that Crohn’s disease is more likely caused by escalated immune reaction to the increased infiltration of luminal bacteria and their debris rather than deficiency of the immune system and uncontrolled infection being reasonable, not ridiculous.

what a wonderful question that needs to be properly addressed.

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



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

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

All this seems to point in the direction of the flora being disrupted. Which would explain the remarkable results from fecal microbiota transplants. We still need to explain this data as well, why does a fecal transplant seem to eliminate all disease in patients without any drugs? there is a very good question. perhaps the answer is because correcting dysbiosis reverses the disease.
 
I just submitted a paper to the Journal of Crohn’s and Colitis. Apparently, the journal comprehends the notion that Crohn’s disease is more likely caused by escalated immune reaction to the increased infiltration of luminal bacteria and their debris rather than deficiency of the immune system and uncontrolled infection being reasonable, not ridiculous.
Have you wondered why this journal is biased though?

Have you wondered why this journal is against biosimilars?

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

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

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



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

I feel the same way Kuenstner does.

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

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

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

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

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

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

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

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


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

The evidence that autophagy, immune deficiency and an intracellular pathogen are involved: thousands of papers. And this includes concrete genetic evidence, which supports that autophagy is a major component in this disease.
 
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kiny posted several long posts. Frankly, I would like to discuss with people with reasoning, but have no interest to argue with people over arbitrary allegations. You raised a lot of questions. In fact, you can find my answers to most of these questions in my paper or my previous posts.

That's a lot of assumptions, it goes completely against current evidence, and you run into a host of issues by blaming the gut flora and ignoring autophagy:
You should realize that the paper is in fact dealing with the possible relationship among NOD2, autophagy, pathogens and Crohn’s disease with up to date evidences. How can I ignore autophagy?

-you'd have to explain why the first signs of crohn's disease is inflammation of the peyer's patches, peyer's patches sip pathogens with their M cell, not the indingenous luminal bacteria
As stated in post 168” As we know, the Peyer’s patch has less goblet cells and thinner mucus layer (http://www.ncbi.nlm.nih.gov/pubmed/7054025 ) and enriched with inflammatory cells, thus would be more vulnerable and sensitive. It would be no surprising that the inflammation started at these sites.” The inflammation would be started once the mucus layer became thinner enough to let just the debris rather the whole bacteria get in, at a stage the surface seems still intact as shown in the area of red ring in your post #167.

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

-you're ignoring the fact that people with those mutated autophagy genes actually have a worse disease than those who do not
As shown in the title in the paper as well as the post 166, I am not ignoring autophagy and NOD2, but provided some new explanation to the massive conflicting evidences.

-you'd have to explain how indigenous luminal bacteria "infiltrate"...they don't, indigenous luminal bacteria don't infiltrate into the submucosa
In fact, the indigenous bacteria in gut lumen can get into the mucosa, into the lymph, into blood and many organs under many situations like the alcoholic and non-alcoholic liver disease, cirrhosis, pancreatitis, shock, burn, etc, even without the apparent damage of the gut like in IBD. Here is a paper: Berg RD. Bacterial translocation from the gastrointestinal tract. J Med. 1992;23(3-4):217-44.

-you'd have to explain why the immune reaction is transmural, the indigenous flora isn't capable of doing that
Read my post #118, I have a detailed description there. I have also submitted a manuscript entitled “Why damage is limited to the mucosa in ulcerative colitis while transmural in Crohn’s disease?” to World Journal of Gastrointestinal Pathophysiology and it has been accepted for publication (another journal of conspiracy?). This is an open assess journal and hopefully people can see it soon.

-you'd have to explain why people get fistulas, the indigenous flora isn't capable of doing that
Fistula would be just a further development of the tranmural damage, read my post #118.

-you'd have to explain why the disease is patchy, if it was the indigenous flora causing an immune reaction you'd have inflammation everywhere
The inflammations usually occurred at places where the feces stayed longer ( https://en.wikipedia.org/wiki/Crohn's_disease ), and the inflammation became greatly alleviated after diversion of the luminal content. This would suggest the inflammation are largely caused by the toxic components in gut lumen, rather than an uncontrolled growth of AIEC, MAP, etc, in the macrophages and mucosa.

-you'd have to explain the granuloma, not caused by the indigenous flora
As illustrated in my paper, increased infiltration of bacteria, their debris, or even dietary particles all can cause granuloma.

-you have to explain why classic crohn's disease is regional in the terminal ileum, a pathogen explains this, luminal bacteria do not
How does a pathogen explain this? Because the mucosa at terminal ileum is different from the other sites? Again, it would be the prolonged stay of the feces and high pressure here due to the existence of the ileocecal valve that gave bacteria the chance to penetrate into the mucosa and became flourished there.

-you have to explain why the disease would be in the ileum instead of the colon, the colon has a way higher bacterial load...but there's no inflammation there for many people with crohn's disease
As illustrated in my paper (Fig. 5), I believe the largely macrophage mediated Crohn’s disease occurred when relative sterile. Otherwise, large amounts of neutrophils will be recruited and manifested as ulcerative colitis. You should realize that Crohn’s Disease just at the colon has become the dominant type in multiple recent studies. For instance, in Stockholm County, Sweden, colonic CD increased from 15% during 1959-1964 to 32% during 1980-1989, and further to 52% during 1990-2001. My paper provided some explanation.

-you're simply ignoring evidence at this point, you're ignoring NOD2 and autophagy
This is the third time of the same accusal. I am tired to reply.

-you're ignoring the fact crohn's disease doesn't look like an immune response against the indigenous flora, it looks like.....intestinal TB, in fact it looks a whole lot like intestinal TB, from the transmural inflammation, to the patchy lesions, to the granuloma, what it doesn't look like at all, is UC
As stated in my post 118 and the paper to be published, I actually felt CD would be more like tuberculosis and pneumoconiosis in that they mainly involve macrophages and formation of glanulomas.

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

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

-and the most important one, never has there been an immune response found against the indigenous flora, you actually need to find the immune response against the flora, not just guess that's it's there. You keep wondering if an infection is involved or not, you ignore the fact there is an immune response found against AIEC and MAP, and you're going with a theory that lacks any evidence of an immune response.
As stated in my post #166, “the gut contains large amounts of LPS (also called endotoxin) that can kill the host thousands of times over, and the long evolution has equipped the body with an innate immune system with defense cells like macrophages being able to launch promptly a vigorous instinct response to low doses of LPS. Thus the inflammation of the gut can be started and continued without any antigen.”

The reason I don't believe in the idea that our own body is somehow attacking our indigenous flora, and that luminal content is somehow infiltrating so deep into tissue that it's causing transmural inflammation and fistulas is because it makes no sense and it's not based on any evidence.
In fact, even under normal condition, the body secretes large amounts (3 - 5 g/day) of antibodies (Ig A) into the lumen of the gut. This may make no sense to you but is a critical mechanism of front-line defense of the body (Fagarasan S, Honjo T. Intestinal IgA synthesis: regulation of front-line body
defences. Nat Rev Immunol. 2003 Jan;3(1):63-72
). As stated above, the indigenous gut bacteria can be translocated deep into the mucosa and other organs under many situations even with less damage of the gut. There are a lot of evidences.

As you stated, the notion of infection is not new. In fact, from the very beginning, infectious agents had been suspected as the cause and extensively studied. Most people finally gave up this notion due to the failure of the anti-infection treatment. Apparently, a cure would largely depend on finding out the real cause and root mechanism of the disease, which would in turn depends on careful analysis and insightful reasoning of all the evidences.
 
As stated in post 168” As we know, the Peyer’s patch has less goblet cells and thinner mucus layer (http://www.ncbi.nlm.nih.gov/pubmed/7054025 ) and enriched with inflammatory cells, thus would be more vulnerable and sensitive. It would be no surprising that the inflammation started at these sites.” The inflammation would be started once the mucus layer became thinner enough to let just the debris rather the whole bacteria get in, at a stage the surface seems still intact as shown in the area of red ring in your post #167.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3049390/

I think this is what is going on. The PP are mini lymph nodes, they aren't just inflamed, they are activated, they would be the APC trigger that's need to cause an inflammatory cascade, and AIEC has been shown to invade them.
 
How does a pathogen explain this? Because the mucosa at terminal ileum is different from the other sites?
Pathogens all have a niche in the body. When a cow gets infected with MAP, it goes straight to the terminal ileum. Why? Because, that's why, pathogens are site specific, they find a niche that allows them to prosper.

Why is H pylori in the stomach? Because.

Why is C diff in the colon? Because.

Why the terminal ileum in crohn's disease? Because it has peyer's patches I'm thinking.
 
Thanks sir.clausin and many others for the interest. Here I would like to share another personal story.

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

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

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


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

Although clustering cases of a disease can be caused by both genetic and environmental factors, for the clustered cases in a family like above, I think more tests should be done on other genes like MUC2, etc, rather than just the glamorous ones like NOD2 and those related to autophagy.
 
I don't think the clustering is a coincidence. There might be undiscovered genetic predispostions...but really...we're talking an epidemic at this point.

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

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

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

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

Another interesting thing about Canada and Western Europe, immigrants from regions with low crohn's disease rates, get it at rates higher than the local population once they immigrated.
 
Ok, so I can not shut up, because I was thinking this last night. This is what makes me Believe it´s an infection of some sort, because a friend of mine moved from Iran to Sweden a couple of years ago, and only one year after living here *BAM* Crohns disease in the ileum.

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

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

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

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

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

Another interesting thing about Canada and Western Europe, immigrants from regions with low crohn's disease rates, get it at rates higher than the local population once they immigrated.
My early post (#185) was actually talking about the occurrence of Crohn’s disease in the father and his 4 of the 8 children as referred by your early post (#183) that fits into the pattern of some inherited genetic diseases. As for the epidemic of IBD since last century, I think we share the same feeling that some environmental factors would have played the predominant role. I believe a really reduction in IBD would largely depend on finding out these causative factors in the environment (Qin X. How can we really reduce the morbidity of inflammatory bowel disease - Research on genes and cytokines, or find out the causative factors in the environment? J Crohns Colitis. 2009 Dec;3(4):315). It would be indeed worrisome for the rapid increase of IBD in Asia. Appallingly, as shown by a recent study by the Asia-Pacific Crohn's and Colitis Epidemiology Study, Guangzhou, China has an even higher incidence of IBD than the more developed neighboring Hong Kong and Macau; Sri Lanka, Malaysia, and Indonesia also showed a similar, or even higher incidence of IBD compared to the much more developed Singapore. It would suggest the causative agents are spreading into the developing countries. I submitted a paper to Gastroenterology entitled “Is the gap between the developed and developing countries in the incidence of inflammatory bowel disease disappearing?” to raise this alarm, and this paper has been accepted for publication.
 
Ok, so I can not shut up, because I was thinking this last night. This is what makes me Believe it´s an infection of some sort, because a friend of mine moved from Iran to Sweden a couple of years ago, and only one year after living here *BAM* Crohns disease in the ileum.

And what really scares me is, that I read somewhere in a local Swedish Magazine that Sweden have the largest numbers of Crohns patient (newly diagnosed) IN THE WORLD! So what makes Sweden unique?! The only obvious reason I can Think of is....milk. Milk consumption in Sweden is very high, second only to Finland. But that might not be the whole truth, but anyways...I can´t be that hard to figure out what makes people get it here so easily...I wish we knew. I don´t Believe in the genes-thingy, too many is getting this shitty disease.
It would be very interesting for the MILK theory in Sweden, as all the link between milk and Crohn’s disease has pointed to the contamination of the milk by Mycobacterium avium subsp. paratuberculosis (MAP) from the cattle with Johne’s disease. However, as discussed in the early post (see post #31), according to document by some government agency, Sweden had hardly any uncontrolled MAP infection in the herds (see Sternberg Lewerin S et al. Control of paratuberculosis in Sweden). Are you suggesting the poor accuracy of these documents or some new pathogens in the milk other than MAP? Anyway, thanks for sharing the thoughts and story.
 
Xiaofa Qin, tell me what you think about this.

http://www.ncbi.nlm.nih.gov/pubmed/23850724
Sorry for the delayed response. I have some other things to do. I read this paper. To my understanding, the so called allelic imbalance refers to a difference in the expression of a risk gene versus the normal gene, thus may somehow reflected the intensity of the risk, but not the mechanism and nature of the risk. Therefore, the increased NOD2 expression by the Newcastle Disease Virus seems more related to the pathogenesis or etiology of IBD. However, increased NOD2 expression can be caused not only by some infectious agents like bacteria or virus, but also some non-infectious agents like organic dusts (Poole JA, et al. Organic dust augments nucleotide-binding oligomerization domain expression via an NF-{kappa}B pathway to negatively regulate inflammatory responses. Am J Physiol Lung Cell Mol Physiol. 2011 Sep;301(3):L296-306). NOD2 knockout mice demonstrated increased expression of some pro-inflammatory cytokines like IL-6, along with higher degree of airway inflammation induced by the dust. This is in accordance with my notion that Crohn's disease and pneumoconiosis may share some similarities in pathogenesis as discussed in my early posts (see post 118). It is the highly effective treatments of CD by the immune suppression agents but significantly increased risk of infection to bacteria, fungi, and virus that made me suspected that NOD2 and autophagy may be related to CD through the tolerance and degradation of the increasingly infiltrated luminal bacterial debris like LPS and peptidoglycan by inflammatory cells like macrophages, more than the killing and clearance of the live microbes. I submitted a paper entitled “How NOD2 and autophagy may be related to Crohn’s disease? A view shifted from live microbes to luminal bacterial debris” to Journal of Crohns and Colitis to express my view, and it was accepted for publication. This is just my personal opinion.
 
My early post (#185) was actually talking about the occurrence of Crohn’s disease in the father and his 4 of the 8 children as referred by your early post (#183) that fits into the pattern of some inherited genetic diseases. As for the epidemic of IBD since last century, I think we share the same feeling that some environmental factors would have played the predominant role. I believe a really reduction in IBD would largely depend on finding out these causative factors in the environment (Qin X. How can we really reduce the morbidity of inflammatory bowel disease - Research on genes and cytokines, or find out the causative factors in the environment? J Crohns Colitis. 2009 Dec;3(4):315). It would be indeed worrisome for the rapid increase of IBD in Asia. Appallingly, as shown by a recent study by the Asia-Pacific Crohn's and Colitis Epidemiology Study, Guangzhou, China has an even higher incidence of IBD than the more developed neighboring Hong Kong and Macau; Sri Lanka, Malaysia, and Indonesia also showed a similar, or even higher incidence of IBD compared to the much more developed Singapore. It would suggest the causative agents are spreading into the developing countries. I submitted a paper to Gastroenterology entitled “Is the gap between the developed and developing countries in the incidence of inflammatory bowel disease disappearing?” to raise this alarm, and this paper has been accepted for publication.
although i do not agree with everything stated here, i see the possibility of perhaps some bacteria which might travel around or something which could find a susceptible host. i'm wondering if it could originate from a more developed country or something, i do recall them finding strange bacteria in ibd patients, sorry i'm lacking the sharpness today on the terminology, but i believe it was bacteria that are termed superbugs/antibiotic resistant or something like that.

sorry, really bad theory/hypothesis on my part here, but just thought id say something related.
 
It would be very interesting for the MILK theory in Sweden, as all the link between milk and Crohn’s disease has pointed to the contamination of the milk by Mycobacterium avium subsp. paratuberculosis (MAP) from the cattle with Johne’s disease. However, as discussed in the early post (see post #31), according to document by some government agency, Sweden had hardly any uncontrolled MAP infection in the herds (see Sternberg Lewerin S et al. Control of paratuberculosis in Sweden). Are you suggesting the poor accuracy of these documents or some new pathogens in the milk other than MAP? Anyway, thanks for sharing the thoughts and story.
i would like to say about this idea is that before i was officially diagnosed with crohns disease, for about 1.5 years prior i had been almost entirely dairy free on some fad diet related to helping my acne, therefore i only ate cheese that had been cooked @ 500 something degrees, as i only ate pizza on occasion.

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

sorry about all the details but i tried my damnest over the years to recall every event prior to getting crohns so i could understand this disease. hopefully my testimony helps a bit.
 
I don't know where they got the 1 in 250 people in Europe with IBD.

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

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

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

1 in 100 have IBD there I read.
 
the more and more people getting crohns I think is due to different causes, after all, what is the tell tale diagnostic tool, chronic inflammation of a biopsy underneath a microscope? this inflammation is bound to have multiple causes, whether micro bacterium to disbiosis related, who knows.
 
Thanks all for the posts.

Thanks Old Mike for referring me the EU-funded project IPODD ('IBD: proteases offer new targets for drug discovery'). It is an interesting study. They looked into the matrix metalloproteases (MMPs) within the tissue as well as the proteases from gut bacteria, but, unfortunately, not the digestive proteases like trypsin and chymotrypsin. In my opinion, impaired inactivation of these pancreatic proteases probably played a more important, primary causative role, as proposed in the paper I published more than a decade ago (Qin XF. Impaired inactivation of digestive proteases by deconjugated bilirubin: the possible mechanism for inflammatory bowel disease. Med Hypotheses. 2002 Aug;59(2):159-63). Anyway, it would be a good thing people are starting to get some idea in this area.
 
Qin: I see you are always thinking on this subject.
Thank You, for your efforts.
Old Mike
Thanks Old Mike. With millions of people suffering from such devastating diseases as Crohn’s disease and ulcerative colitis, I felt obligated to warn the world what I perceived as the possible cause and glad to participate in the challenging exploration for the possible mechanism.
 
Frankly, I frequently feel frustrated, as it was more than a decade ago that I perceived IBD could be simply resulted from the inhibition of gut bacteria by dietary chemicals like saccharin, etc, and the resultant damage of gut barrier by the poorly inactivated digestive proteases (Qin XF. Impaired inactivation of digestive proteases by deconjugated bilirubin: the possible mechanism for inflammatory bowel disease. Med Hypotheses. 2002 Aug;59(2):159-63. http://www.ncbi.nlm.nih.gov/pubmed/12208202 ). Since then, I have taken great efforts advocating to check out this possibility. However, it failed to raise any attention and action. In contrast to this, although the emergence and dramatic increase of IBD in last century clearly suggested environmental factors would have played the predominant role, the finding of the link between NOD2 and Crohn’s disease at about the same time was treated as a big breaking through in IBD and followed by many studies.

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

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

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

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

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

  1. Qin X. Does the association with NOD2, autophagy and some pathogens really mean Crohn’s disease is caused by uncontrolled infection? Journal of Crohn’s Colitis. 2013 Aug 13 [Epub ahead of print]
  2. Qin X. How NOD2 and autophagy may be related to Crohn's disease? A view shifted from live microbes to luminal bacterial debris. Journal of Crohn’s Colitis. 2013 Aug 19 [Epub ahead of print]
  3. Qin X. Have genome-wide association studies or knockout mice more reflected the true nature of inflammatory bowel disease? Journal of Crohn’s Colitis. 7(5):419-20, 2013.
  4. Qin X. Why damage is limited to the mucosa in ulcerative colitis while transmural in Crohn’s disease? World Journal of Gastrointestinal Pathophysiology. 4(3): 63-63, 2013.
  5. Qin X. How to explain the discordant change of ulcerative colitis and Crohn's disease in adjacent or even the same regions and time periods. Journal of Pediatric Gastroenterology and Nutrition. 2013 Jul 16. [Epub ahead of print]
  6. Qin X. Is the gap between the developed and developing countries in the incidence of inflammatory bowel disease disappearing? Gastroenterology 2013 (accepted)
  7. Qin X. Etiology of inflammatory bowel disease: a unified hypothesis. World Journal of Gastroenterology 18(15):1708-22, 2012.
  8. Qin X. Food additives: possible cause for recent remarkable increase of inflammatory bowel disease in children. Journal of Pediatric Gastroenterology and Nutrition. 54(4):564, 2012.
  9. Qin X. The possible cause for the rapid rise in incidence of Irish paediatric inflammatory bowel disease. Arch Dis Child. 2012 May 16. [eLetter]
  10. Qin X. What caused the recent worldwide increase of inflammatory bowel disease: Should sucralose be added as a suspect? Inflamm Bowel Dis. 17(10):E139, 2011.
  11. Qin X. What made Canada become a country with the highest incidence of inflammatory bowel disease: Could sucralose be the culprit? Can J Gastroenterol 25(9):511, 2011
  12. Qin X. The effect of dietary chemicals on gut bacteria and IBD demands further study. Journal of Crohn’s Colitis. 5(2):175, 2011.
  13. Qin X. How can we really reduce the morbidity of inflammatory bowel disease — Research on genes and cytokines, or find out the causative factors in the environment? Journal of Crohn’s Colitis 3(4):315, 2009.
  14. Qin X. Can meat and protein really increase, while vegetables and fruits decrease the risk of inflammatory bowel disease? How? J Crohn’s Colitis 3:136, 2009
  15. Qin X. What caused the extra high incidence of inflammatory bowel diseases in the industrialized countries in the west – lack of some nutrients or increased intake of some harmful agents? Inflammatory Bowel Diseases. 15: 319, 2009
  16. Qin X. Impaired inactivation of digestive proteases: a factor that may have confounded the efficacy of antibiotics aimed at reducing the exposure to luminal bacteria and their components. American Journal of Gastroenterology. 103: 2955-2956, 2008.
  17. Qin X. With the great complexity unveiling, can we still decipher the interaction between gut flora and the host in inflammatory bowel disease to find out the mechanism and cause? How? Inflammatory Bowel Diseases. 14: 1607-1608, 2008.
  18. Qin X. Has Crohn's disease really occurred anywhere in the digestive tract? Inflammatory Bowel Diseases. 140):1461-2, 2008.
  19. Qin X. Gut microbiota: A new aspect that should be taken into more consideration when assessing the toxicity of chemicals or the adverse effects and efficacy of drugs. Regulatory Toxicology and Pharmacology. 51, 251, 2008.
  20. Qin X. Reduced production of digestive proteases and the efficacy of enteral and parenteral nutrition on inflammatory bowel disease. Inflammatory Bowel Diseases. 14, 871, 2008.
  21. Qin X. Synergic effect of bacterial glycosidases and digestive proteases on mucus degradation and the reduced risk of inflammatory bowel disease-like gut damage in both germ-free and poor hygiene conditions. Inflammatory Bowel Diseases. 14, 145-146, 2008.
  22. Qin X. What is human inflammatory bowel disease (IBD) more like: Johne's disease in cattle or IBD in dogs and cats? Inflammatory Bowel Diseases. 14, 138, 2008.
  23. Qin X. Inactivation of digestive proteases: another mechanism that probiotics may have conferred a protection. American Journal of Gastroenterology. 102: 2109, 2007.
  24. Qin X. Inactivation of digestive proteases by deconjugated bilirubin: The possible evolutionary driving force for bilirubin or biliverdin predominance in animals. Gut. 56, 1641-1642, 2007.
  25. Qin X. Is the incidence of inflammatory bowel disease in the developed countries increasing again? Is that surprising? Inflammatory Bowel Diseases. 13, 804-805, 2007.
  26. Qin X. What caused the increase of autoimmune and allergic diseases: a decreased or an increased exposure to luminal microbial components? World Journal of Gastroenterology. 13, 1306-1307, 2007.
  27. Qin X. Inactivation of digestive proteases: another aspect of gut bacteria that should be taken into more consideration. World Journal of Gastroenterology. 13, 2390-2391, 2007.
  28. Qin X. Primary sclerosing cholangitis and inflammatory bowel disease: where is the link? American Journal of Gastroenterology. 102, 1332-1333, 2007.
  29. Qin X. High incidence of inflammatory bowel disease with improved hygiene and failure to get human-like IBD in laboratory animals. World Journal of Gastroenterology. 13, 3271, 2007.
  30. Qin X. Inhibition of gut bacteria by dietary chemicals and the hygiene hypothesis. Annals of Allergy, Asthma and Immunology. 98, 602, 2007.
  31. Qin, X. Impaired inactivation of digestive proteases by deconjugated bilirubin: the possible mechanism for inflammatory bowel disease. Medical Hypotheses, 59, 159-163, 2002.
 
I assure you your work is appreciated more than you know, you really are a great person for the research you've done and im so glad people like you exist, i can't thank you enough, I am really hopeful that they make a break through soon with FT therapy restoring gut bacteria, my disease seemed to be onset by long term doxycycline use, i believe that destroyed the healthy bacteria creating an extreme disbiosis or even extinction of beneficial bacteria.
 
Thanks Joshuaaa for the warm words. It encourages me to continue my efforts. I believe IBD is preventable, but at first we need finding out the causative factors in the environment. IBD would also be curable. In my opinion, this may largely rely on at first restore the gut barrier function, then followed by the restoration of normal gut flora.
 
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