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Journal of Clinical Gastroenterology:
doi: 10.1097/MCG.0b013e3182621ed4
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Mycobacterium avium Subspecies paratuberculosis in Crohn’s Disease: The Puzzle Continues

Das, Kiron M. MD, PhD, FACG; Seril, Darren N. MD, PhD

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Robert Wood Johnson Medical School, Division of Gastroenterology, New Brunswick, NJ

The authors declare that they have nothing to disclose.

Reprints: Kiron M. Das, MD, PhD, FACG, Robert Wood Johnson Medical School, Division of Gastroenterology, New Brunswick, NJ 08901 (e-mail: daskm@umdnj.edu).

The article by Dr Thomas Julius Borody in this issue is a review of a topic that has long been debated: the role of Mycobacterium avium subspecies paratuberculosis (MAP) in the etiopathogenesis of Crohn’s disease.1 Dr Borody addresses the key elements of the MAP argument in a point-by-point manner. However, the debate is likely to continue despite the long-established role of MAP in the causation of Johne disease (a chronic, intestinal inflammatory condition in ruminants similar to Crohn’s disease), advances in the methodology of detecting MAP in human tissue samples, and a better understanding of the response of MAP to immunosuppressive and antitumor necrosis factor (TNF)-α therapy. The primary counterpoints to the MAP theory persist, however, and revolve around the challenge of establishing a causal relationship between MAP infection and the evolution of the heterogenous inflammatory processes observed in Crohn’s disease, and the absence of convincing data establishing a role for anti-MAP therapy in the treatment of Crohn’s disease.

As discussed in the article, Koch postulates have been satisfied implicating MAP as the causative factor of Johne disease. It has been argued that Koch criteria have been met implicating MAP in Crohn’s disease as well, predicated on the finding that MAP isolated from humans results in intestinal inflammation when administered orally to goats. Johne disease has many similarities to Crohn’s disease: it is a diarrheal illness characterized by chronic enteritis and granulomatous lesions.2 However, Crohn’s disease has a diverse presentation, with fistulizing and fibrostenosing disease and multiple extraintestinal manifestations. It would be more difficult to directly link MAP infection with the extraintestinal findings of Crohn’s disease, which are likely due to dysregulated immunity and autoimmunity.3

The suggestion of a causal relationship with MAP infection is inherently limited to correlative evidence. As summarized by the meta-analysis by Feller et al,4 studies have consistently shown that the prevalence of MAP is higher in the tissues of patients with Crohn’s disease as compared with controls, or even compared with those with ulcerative colitis. Given the finding of MAP in the tissues of individuals without Crohn’s disease, it is clear that MAP infection alone is not sufficient to cause the disease. If MAP is in fact a causative factor, it is likely that it does so in the setting of a susceptible individual. This would in part reconcile the finding that farmer’s exposed to cattle with Johne disease do not exhibit an inclination to developing Crohn’s disease, the inability to detect an association between Crohn’s disease and the consumption of MAP-containing foods, and the lack of vertical transmission of Crohn’s disease through MAP-containing breast milk.2,5 It would be important to learn whether there is a correlation between MAP infection, the presence of Crohn’s disease susceptibility genes such as NOD2 (which has been shown to take part in the clearance of intracellular MAP), and the occurrence of the disease. There have been reports of an increased prevalence of MAP infection in individuals diagnosed with Crohn’s disease at a young age in comparison with children without the disease, but this does not give us an idea of causation either. A prospective study would have the potential to reveal a temporal relationship between MAP infection and the onset of Crohn’s disease, but such a study would be technically unfeasible. Given the lack of information regarding cause-and-effect between the presence of MAP and the onset of disease, the higher frequency of MAP in tissues of patients with Crohn’s disease compared with nondiseased controls can be interpreted in another way. Perhaps the higher prevalence of MAP represents an increased susceptibility of the compromised intestinal mucosa of patients with Crohn’s disease to colonization by a bacterium that is ubiquitous in the environment.

The identification of MAP in human tissues has been hampered historically by the technical challenges of visualizing and culturing the organism, likely because of a combination of the cell wall–deficient form of MAP in human cells and unique culture requirements. The identification of MAP DNA and RNA, including the MAP-specific IS900 DNA sequence, is also subject to interinvestigator variation because of the need to isolate genetic material from an organism that replicates within the human cell.2 Improvements in the reproducibility of these methods are essential to any effort to establish the role of MAP in the pathogenesis of Crohn’s disease, and to studies assessing response to MAP-specific therapy.

Can the theory of an infectious etiology of the disease be reconciled with the known effectiveness of immunosuppressive therapy, and specifically anti-TNF-α antibodies, in the therapy of Crohn’s disease? Borody presents the argument that because of the intracellular nature of MAP and its inability to survive outside of the human cell, simply extending the findings on the response of Mycobacterium tuberculosis infection to immunosuppressive therapy to MAP would be inappropriate. Immune suppression is known to promote dissemination of M. tuberculosis, but MAP is incapable of dissemination. Indeed, as Dr Borody describes, there are data that immunosuppressive medications traditionally used to treat Crohn’s disease have inhibitory effects on MAP. Could the therapeutic benefit of immunosuppressive medications such as 6-mercaptopurine, and the anti-TNF-α antibodies such as infliximab, in part be due to effects on MAP? It is an important and intriguing possibility that requires further investigation.

A telling piece of evidence in the MAP story, and the most clinically relevant, would be whether therapy targeting the organism has the effect of inducing and maintaining remission of Crohn’s disease. Many studies have been unable to establish a beneficial role for antibiotic therapy in Crohn’s disease treatment. However, as Borody points out, there are several studies using antimycobacterium regimens, which include a macrolide component, that have shown promising results. These studies have used antibiotics with presumed effectiveness against the intracellular compartment-dwelling MAP. Certainly more work is needed to better define optimal antibiotic dosing and duration of therapy for the treatment of Crohn’s disease. There are other deficiencies that require further study as well. The work by Selby and colleagues is a case in point. Therapy with the combination of clarithromycin, rifabutin, and clofazimine was associated with a greater rate of remission in patients with active Crohn’s disease as compared with placebo treatment after 16 weeks.6 However, the ability of the antibiotic regimen to maintain remission was not durable, although subsequent reevaluation of the data suggested that the effect was longer lasting if an intention-to-treat analysis was used.7 Similar to other studies, corticosteroid cotherapy was used to induce remission. In addition, as expected, many of the patients in the study were taking other therapies, including a large number of patients on immunomodulators. Importantly, similar to other studies assessing the effect of the so-called “MAP-specific” antibiotic regimens, there was no correlation between response to therapy and the detection of MAP in tissue samples. Without this information, the specificity of the therapy comes into question. Multiple other types of bacteria have been isolated from the tissues of patients with inflammatory bowel disease. Correlating a decrease in MAP at the tissue level with successful therapy would provide evidence that MAP is in fact targeted. However, again, this would depend on a reliable and reproducible test to identify MAP-specific DNA and RNA in tissues.

Dr Borody again raises the puzzling question: Is an infection the cause of Crohn’s disease? Is the dysregulated inflammatory response associated with Crohn’s disease initiated and sustained by MAP? Similar challenges have been met in establishing infectious etiologies for other complex inflammatory diseases, including rheumatoid arthritis. However, many questions remain. Will reliable and reproducible methods of detecting MAP arise, which will facilitate our understanding of the role of MAP infection in Crohn’s disease, and the study of anti-MAP therapy? If MAP does promote the development of Crohn’s disease, is it the only infection that does so? Could infection with other organisms, in the setting of a susceptible individual, also result in Crohn’s disease? Is there a theoretical basis for therapy with combinations of anti-MAP regimens and anti-TNF-α antibodies or immunomodulator medications? Will the future of Crohn’s disease treatment include directing anti-MAP therapy to patients with established MAP infection in the setting of genetic susceptibility? The debate will likely continue, but the article by Dr Borody proposes that MAP may be the missing piece (or rather, given the long history of association between MAP and Crohn’s disease, the overlooked piece) of the Crohn’s disease puzzle!

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REFERENCES

1. Gitlin L, Borody TJ, Chamberlin W, et al. Mycobacterium avium ss paratuberculosis-associated diseases; piecing the Crohn’s puzzle together. J Clin Gastroenterol. 2012;46:649–655

2. Chacon O, Bermudez LE, Barletta RG. Johne’s disease, inflammatory bowel disease, and Mycobacterium paratuberculosis. Annu Rev Microbiol. 2004;58:329–363

3. Das KM. Immunologic basis for extraintestinal manifestations in inflammatory bowel disease. UpToDate. 2011

4. Feller M, Huwiler K, Stephan R, et al. Mycobacterium avium subspecies paratuberculosis and Crohn’s disease: a systemic review and meta-analysis. Lancet Infect Dis. 2007;7:607–613

5. Behr MA, Kapur V. The evidence for Mycobacterium paratuberculosis in Crohn’s disease. Curr Opin Gastroenterol. 2008;24:17–21

6. Selby W, Pavli P, Crotty B, et al. The Antibiotics in Crohn’s Disease Study Group. Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn’s disease. Gastroenterology. 2007;132:2513–2519

7. Behr MA, Hanley J. Antimicrobial therapy for Crohn’s disease: a reanalysis. Lancet Infect Dis. 2008;8:344

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This article has been cited 1 time(s).

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