Crohn's disease: exploring the causes

The reason that this is so disputed is because the other main theory for the cause of Crohn's is that there is a strong genetic aspect of the disease which would mean that an infectious cause would be completely irrelevant.

Not necessarily. Genetic susceptibility to complications from a given infectious agent is potential middle ground between the two hypotheses.

Rachel,
A genetic (or hereditary to be more precise) link in Crohn's is not mutually exclusive with an infectious (partial) cause.

In my previous life as a grad student, I worked on superantigenic toxins (PTSAgs) from S. aureus. My work resulted in the discovery of several new ones (there are dozen's known now). In the context of this work I learned that these toxins work by targeting certain V-beta regions of the T-cell receptor. This results in non-antigen specific activation of a T-cell subset, and corresponding immune overrreaction, including severe autoimmune activity. The final result is toxic shock syndrome in some cases, necrotizing fasciitis in others.

Totally unrelated to the topic, you say? Not so!

One of the things I found in the course of doing this research was that Crohn's disease is associated with a pattern of "V-beta skewing", which is a hallmark of PTSAg activity. I'm not sure if anyone ever followed up on this (I certainly didn't), but it was a tantalizing clue/coincidence nonetheless. The reason this relates to your statement about genetic/infectious etiology is that Vbeta profile of an individual is complexly linked to genetics (people can lack certain V-beta region alleles, for instance), so there can be a hereditary linkage, even though an infectious agent is required for the disease state. All of this is obviously speculative, though!

Aside to Tara, this is a great series and a terrific use of the blog as a teaching tool! Good work!

Nice write-up. It's always good to see people learning about Crohn's. It's a tough disease to deal with because the symptoms aren't visible, and let's face it: No one wants to talk about your GI problems at a party.

You might also be interested in this short comic about living with Crohn's disease, by Tom Humberstone

I'd also caution that the link between MAP and Crohn's is likely overstated. Many patients have been found without MAP, and several different types of pathogenic bacteria have been implicated (including strains of enteroadherent E. Coli). (1)

Association studies have found several mutations that appear to be linked to CD, including NOD2, which helps the immune system recognize bacterial antigens, and ATG16L1, which is involved in autophagy, or the body's ability to engulf and destroy bacterial invaders. This suggests that the defect is with the body's ability to successfully defend against bacterial invasion in the lining of the gut. All these different types of bacteria researchers are finding are likely just taking advantage of the body's inability to clear them out once they start invading.

Once the body realizes what's going on, the bacteria are already past the (defective) first-line defenses, and so the alarm is sounded. Massive inflammation results, making life pretty miserable for the unlucky patient. All this inflammation makes the membrane more susceptible to attack, and the patient enters something of a vicious cycle.

One of the big unknowns is what triggers the onset of the disease. Why does a patient rapidly transition from phenotypically normal to diseased in a very short period of time? Heavy use of NSAIDs, like ibuprofen, and viral and bacterial pathogens have been anecdotally linked to onset. This is where nasty bacteria like MAP may play a big role, by burrowing their way in, eliciting an inflammation response, and starting the vicious cycle that is CD.

Wow - that turned out to be long. Oh well - in addition to doing my qualifying exam on this stuff, I also have CD, so I keep pretty up to date on the research. The wikipedia page on CD is actually a fairly solid place to start going in-depth, if you can ignore the occasional messy transition due to frequent editing. It cites most of the major research in the field.

1) Baumgart, M., et al. (2007). "Culture independent analysis of ileal mucosa reveals a selective increase in invasive Escherichia coli of novel phylogeny relative to depletion of Clostridiales in Crohn's disease involving the ileum (advance online publication)". The ISME Journal. doi:10.1038

Hi Rachel, good blog!

My personal take on it:

Johne's affects more than just cows. It affects many other animals including PRIMATES!

MAP is generally present in animals before clinical onset of disease.

A lot of the genetic mutations (e.g. NOD2) association with crohn's are associated with recognition of intracellular bacteria and similar things, which would reinforce the mycobacterial aetiology. Moreover, genetics don't change as quickly as the disease has increased in incidence. Accordingly, the genetic factors were likely always there, but instead of causing the disease, they predispose one to the disease. Also, not all these genetic factors are found in all crohn's patients - see asians. MAP bacteria, however, is present in all these asian countries and the western countries as well. check out www.johnes.org (great slideshow presentations by the President of the International Association for Paratuberculosis.

Also, check out these videos with Professor John Hermon-Taylor (microbiologist, immunologist, gastroenterologist) http://www.stage6.com/user/javi_garci/videos/?notice=400
The interview is especially interesting (slow starting but tons of information later on; a must watch) and the presentation is the same one he gave to the GIs at his hospital in London.

You obviously know your way around journals, but if you like you can email me and I'd be happy to send some of the most recent publications that are extremely suggestive of a causal relationship.

A recent meta-analysis came out in the Lancet showing a 7:1 odds ratio, supporting an association between crohn's and map.

www.crohns.org and www.crohnscanada.com are great sites, and so is www.nulltone.com

There is even in vitro evidence of conventional drugs having activity against MAP; could that be why they have worked in some patients?

Also, there is evidence to support the theory that some of the new biologics may kill MAP by marking TNF for destruction when it is bound to macrophages which may contain MAP...

Hi Tara, great blog! Sorry I called you Rachel.

Hi David. Just to be clear, while this is my blog, the post is Rachel's, as part of their class assignment. The Lancet meta-analysis is a good paper though; link is here.

Gotcha. Great Blog Rachel and Post Tara, I mean Tara Post Rachel, I mean great blog Tara and post Rachel...

So if Rachel is a student and this was for school, I assume she is happy to be done reading about this...ha ha...

Have you seen the "REVIEW ARTICLE:
Epidemiological evidence for Mycobacterium avium subspecies
paratuberculosis as a cause of Crohn's disease"

By J. C. U Z O I G W E , M. L. K H A I T S A A N D P. S.
G I B B S

Department of Chemistry, Biochemistry and Molecular Biology, North Dakota State University,
Fargo, ND, USA

Department of Veterinary and Microbiological Sciences, North Dakota State University, Fargo, ND, USA
(Accepted 7 March 2007)

S U M M A R Y
Mycobacterium avium subspecies paratuberculosis is the causative agent of Johne's disease, a chronic enteritis in ruminants including cattle, sheep, goats, and farmed deer. Recently, this bacterium has received an increasingly wide interest because of a rapidly growing body of scientific evidence which suggests that human infection with this microorganism may be causing some, and possibly all, cases of Crohn's disease. Recent studies have shown that a high
percentage of people with Crohn's disease are infected with M. avium subsp. paratuberculosis; whether the association of this bacterium and Crohn's disease is causal or coincidental is not known. Crohn's disease is a gastrointestinal disease in humans with similar histopathological findings to those observed in the paucibacillary form of Johne's disease in cattle. The search for risk factors in Crohn's disease has been frustrating. However, epidemiologists have gathered
enough information that points to an association between M. avium subsp. paratuberculosis and Crohn's disease. This paper reviews epidemiological models of disease causation, the major philosophical doctrines about causation, the established epidemiological criteria for causation, and the currently known epidemiological evidence of M. avium subsp. paratuberculosis as a possible cause of Crohn's disease.

Hi Chris,

I would have to say the link is understated. As someone with Crohn's who has tested positive for MAP, taken antimicrobial antibiotics and gone into remission, I feel there is good anecdotal evidence. Although, the microbial specificity of the antibiotics is unknown I guess, because common sense won't permit a scientific conclusion.

Hope you are doing well. I urge you to watch John Hermon-Taylors' videos linked in my other post.

The vicious cycle you described sounds somewhat like a MAP infection subsequently causing immune dysregulation...

"Integrating theories of the etiology of Crohn's Disease
On the etiology of Crohn's Disease: Questioning the
Hypotheses"

William M. Chamberlin1, Saleh A. Naser2

Summary
The most prominent theory describes the Crohn's Syndrome as a dysregulated, inappropriate immune response to otherwise innocuous bowel fl ora in a genetically susceptible host. The autoimmune theory assumes that a specifi c infectious agent does not exist. Data from mouse models, impairment of the mucosal epithelial barrier and the influence of gut fl ora are used to support the autoimmune theory. Critics claim that the dysregulated immune responses are not the primary disorder but secondary to an underlying infection. Two other theories are also consistent with the same data. The immunodefi ciency theory hypothesizes that defects in innate immunity leading to compensatory immune processes underlie the Crohn's phenotype and suggests that therapy should stimulate immunity rather than suppress it. The mycobacterial theory proposes that Mycobacterium avium subspecies paratuberculosis is one of the causes of the Crohn's Disease syndrome. Mycobacterial molecules dysregulate immune signaling pathways as part of the
organisms' evolved survival strategy. If MAP were to initiate the dysregulated immune response then the necessity to hypothesize that commensal gut fl ora provide the antigenic stimulus would be moot. Commensal bacteria would be relegated to a secondary role of modifying the immune
response rather than occupying the central role of providing the initiating antigens. Critics claim that MAP is merely a secondary invader. The three theories differ primarily by emphasizing different aspects of the same overall process.

I recall reading a hypothesis few years ago that Crohn's disease is due to lack of non-pathogenic parasites in the gut.
Normally these parasites would downregulate the immune system in the gut and prevent the reaction to bacteria normally found in the gut. I don't know what came of it but it sounded very interesting.

Weing,

The "dirty immunity" theory I would call it. Countries where cleanliness was not as good did not have the same prevalence of Crohn's. At the same time though, those countries are generally poor and couldn't afford the luxury of mass farming. India has lots of parasites, and yet still Crohn's, and they do have cows and drink milk:

Presence and characterization of Mycobacterium avium subspecies paratuberculosis from clinical and suspected cases of Crohn's disease and in the healthy human population in India

A.V. Singh, S.V. Singh, G.K. Makharia, P.K. Singh, J.S. Sohal

-Veterinary Microbiology Laboratory, Animal Health Division, Central Institute for Research on Goats, Makhdoom, Farah,
Mathura (UP), 281 122 India
-Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
-Received 7 November 2006; received in revised form 1 June 2007; accepted 21 June 2007
Corresponding Editor: William Cameron, Ottawa, Canada

Summary
Objectives: To investigate and characterize Mycobacterium avium subspecies paratuberculosis (MAP) in patients with Crohn's disease, attendants of animals with suspected infection, and healthy humans, using multiple diagnostic tests.
Methods: A total of 119 samples (35 stool, 76 serum, three blood clots, and five biopsies) were collected from five patients with Crohn's disease, eight attendants of animals with Johne's disease, and 93 apparently normal control subjects (Agra region) from North India. Samples were screened for the presence of MAP by smear examination, culture of stool, blood clot and biopsies,and ELISA. Colonies obtained by culture were further characterized using polymerase chain reaction (PCR) with IS900 MAP specific primers.
Results: Using all diagnostic modalities, MAP and/or MAP antibodies were identified in 100% (5/5) of subjects with Crohn's disease; 75.0% (6/8) of attendants of MAP infected animals were positive and 38.0% (27/71) of apparently normal controls were also positive. Most sensitive test was ELISA (100%, 5/5), followed by culture (80.0%, 4/5), and acid-fast staining. Ziehl--Neelsen staining was positive in 37.5% (3/8) of subjects with active animal husbandry practices. In 71 serum samples from control subjects, seroprevalence of MAP was 38.0% using indigenous protoplasmic antigens (PPA) and 36.6% using commercial PPA. Of the serum samples from the Crohn's disease patients,
100% (5/5) were positive by ELISA using indigenous PPA and 40.0% (2/5) were positive by ELISA using commercial PPA. IS900 PCR was used to characterize tiny colonies of MAP that grew extremely slowly on Herrold's egg yolk medium, and of 15 (42.8%) cultures, 14 (93.3%) were typed
as MAP.

There is always the interesting epidemiological finding of how Crohn's is much more common in the North US than in the Southern US. Is there any data on where MAP is prevalent, either in humans or the environment? Does it correlate with Chron's? And could this explain the correlation or explain the distribution of the disease?

Sorry, lots of questions.
Tara - By the way, the CDC buildings look cool, they have been growing exponentially over the last 6 years. I can see the really nice gym though its glass....you know behind the fence as I drve to work across the street.

There is good information on MAP prevalence and Crohn's prevalence. The incidence slopes of both Johne's and Crohn's are the same.

Sorry, haha, but epidemiologists aren't going to crack this one, check out the presentation. There is too much delay from exposure to clinical symptoms; can you remember what you ate 20 years ago!!??

Dr. Collins at the University of Wisconsin: http://johnes.org/presentations.shtml There are a couple good ones, but the one to watch is called "The Emerging Paratuberculosis Epidemic and Its Implications for Food".

Also, some good videos with Dr. Hermon-Taylor are: http://www.aeii.org/DrTaylor/videos/MAPpresentation.htm and http://www.aeii.org/DrTaylor/videos/MAPpr.htm One is a presentation and the other is an interview. Both really worth watching.

Beef consumption was actually the highest food risk factor for developing Crohn's, found a study in Japan.

Check out BBC Wales March 25 for an interview with Dr. JHT

good weblog...hope be successful always.

Hi Tara, great blog! Sorry I called you Rachel.

good weblod.. Best regards.

Thank you for this very informative post on Crohnâs disease. I am one of those 500,000 people who are suffering from Crohnâs disease and your article helped me understand my disease a lot more. I was not aware of this disease before I was diagnosed with it and I believe that it is important to spread the word so that we can find a cure. By writing a blog about Crohnâs you really are making a huge impact. I hope that someday no one will ever have to suffer from Crohnâs disease again.

I think the water is a good theory. l was working for toyota & started drinking the Fremont city water daily after ten months I started having crohns like proplems real bad the plant closed years ago but I still have it & I always thought it was the water.Another thing was everyone was really sick with diaria at work when I came down with it the plant had 5000 employees so go figure