Sunday, June 2, 2013

IBD RoadMAP


Mycobacterium avium paratuberculosis (MAP) and IBD


Potentially the most controversial topic with Crohn’s disease – the one that generates the most passionate postings in the message boards – is the role (if any) of mycobacterium avium subspecies paratuberculosis (MAP) in causing or “activating” Crohn’s disease.  Proponents believe that MAP (and by association milk consumption) should be a major research focus, and that by curing MAP infections the underlying Crohn’s disease will be cured.  A good, early debate on the subject can be found in Gut, but there have been developments on both sides since its publication [Note to the publisher of Gut: In the Internet age, calling your debate “Mycobacterium avium subspecies paratuberculosis is a cause of Crohn’s disease” leads to bad search result-based conclusions] (1)

MAP is the known cause of Johne’s disease, a condition that mimics the symptoms of Crohn’s disease.  It affects the small intestines, forming granulomas and causing malnutrition and severe diarrhea.  With limited exceptions, Johne’s disease impacts only ruminants (though many other mammals can be carriers of MAP), with cattle and goats being particularly susceptible (sheep are infected by a different variant).  Transmission is primarily oral (though sexual transmission is possible), with environmental contamination through consumption of manure of infected animals being a primary pathway.(2)  There is evidence of MAP being present in milk, suggesting nursing as a possible secondary transmission pathway, though the presence of environmental MAP on the teats may also be a cause.(3)

While MAP had been found in 1980s in a few isolated case reports of individuals with Crohn’s, a small study of 40 individuals in 1992 provided the basis for most of the current interest.  In the study, Sanderson et al took samples from 103 individuals, 40 with Crohn’s, 40 with no disease, and 23 with UC, and found that there was MAP present in 65% of those with Crohn’s, 12.5% of the controls, and 4.3% of the UC patients, leading them to conclude:

The presence in two thirds of Crohn's disease tissues but in less than 5% of ulcerative colitis tissues is consistent with an aetiological role for Mparatuberculosis in Crohn's disease.(4)

The authors rightfully note the difficulty in culturing MAP and accurately identifying early stage infections. 
Based on their work, there have been multiple follow-on studies looking at the correlation factors.  While individual results have been divergent, the meta-analyses looking across the board showed that there is a significant increase in the incidence of MAP in individuals with Crohn’s disease.  The numbers appear to confirm they are within the same order of magnitude as Sanderson et al.(5,6) 

While Sanderson et al’s conclusion is accurate, it is potentially misleading as well – their results may have been due to sampling factors, due to environmental differences between the patients (e.g. differing diets due to the disease), due to individuals with Crohn’s being unable to fight MAP and ending up as secondary carriers, or to many other unknown factors.  Their study only showed correlation (on a limited sample), not causation, as have the other follow-on studies. 

The above results show a correlation in some trials between MAP infection and Crohn’s disease.  Calling MAP a cause for Crohn’s is very premature, however, based on other research.  One prominent arguments against comes from a meta-analysis looking at long term antibiotic treatments as a way to combat Crohn’s.  Their analysis showed that there was no significant efficacy of the traditional MAP treatments against Crohn’s disease, though they acknowledge the underlying trials were fairly small.(7)  This could mean that MAP is not a causative factor for Crohn’s, or that the drugs are ineffective in treating MAP in intestinal tissue, but it puts a minus in the likelihood column. 

Another negative in the likelihood column comes from the epidemiological evidence.  Crohn’s disease is more prevalent in developed nations with more urbanized environments.  Locations where humans and cattle live in close proximity tend, on average, to have lower incidence and prevalence numbers for Crohn’s. 

While there is some promising evidence of an infectious cause for Crohn’s, calling MAP the cause (or even a contributory factor) is still premature.  It is convenient to cite the great story of H. Pylori causing ulcers as a parallel David v. Goliath story, but there are a substantial number of individuals looking for a potential infections cause for IBD.  That said, MAP has not been completely ruled out as a factor in Crohn’s disease, but there are equally compelling argument for other pathogens.  There is room for additional research on MAP and Crohn’s, but the initial evidence is not so compelling that it warrants a laser-like focus to the exclusion of other potential causes.

Bottom Line

·         MAP is more likely to be prevalent in the intestines of those with Crohn’s disease.
·         Despite a higher prevalence, compelling evidence of a causal relationship has not been established by current research.
·         Some further research (with appropriately tempered enthusiasm) is warranted into a MAP-IBD link.
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3.       Taylor, T. K., C. R. Wilks, and D. S. McQueen. "Isolation of Mycobacterium paratuberculosis from the milk of a cow with Johne's disease." Veterinary Record 109, no. 24 (1981): 532-533.
4.       Sanderson, J. D., M. T. Moss, M. L. Tizard, and J. Hermon-Taylor. "Mycobacterium paratuberculosis DNA in Crohn's disease tissue." Gut 33, no. 7 (1992): 890-896.
5.       Feller, Martin, Karin Huwiler, Roger Stephan, Ekkehardt Altpeter, Aijing Shang, Hansjakob Furrer, Gaby E. Pfyffer, Thomas Jemmi, Andreas Baumgartner, and Matthias Egger. "Mycobacterium avium subspecies paratuberculosis and Crohn's disease: a systematic review and meta-analysis." The Lancet infectious diseases 7, no. 9 (2007): 607.
6.       Abubakar, I., D. Myhill, S. H. Aliyu, and P. R. Hunter. "Detection of Mycobacterium avium subspecies paratuberculosis from patients with Crohn's disease using nucleic acidbased techniques: a systematic review and metaanalysis." Inflammatory bowel diseases 14, no. 3 (2008): 401-410.
7.       Feller, Martin, Karin Huwiler, Alain Schoepfer, Aijing Shang, Hansjakob Furrer, and Matthias Egger. "Long-term antibiotic treatment for Crohn's disease: systematic review and meta-analysis of placebo-controlled trials." Clinical infectious diseases 50, no. 4 (2010): 473-480.

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