Review
Mycobacterium avium subspecies paratuberculosis and Crohn's disease: a systematic review and meta-analysis

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Summary

This systematic review assesses the evidence for an association between Mycobacterium avium subspecies paratuberculosis (MAP) and Crohn's disease. We analysed 28 case-control studies comparing MAP in patients with Crohn's disease with individuals free of inflammatory bowel disease (IBD) or patients with ulcerative colitis. Compared with individuals free of IBD, the pooled odds ratio (OR) from studies using PCR in tissue samples was 7·01 (95% CI 3·95–12·4) and was 1·72 (1·02–2·90) in studies using ELISA in serum. ORs were similar for comparisons with ulcerative colitis patients (PCR, 4·13 [1·57–10·9]; ELISA, 1·88 [1·26–2·81]). The association of MAP with Crohn's disease seems to be specific, but its role in the aetiology of Crohn's disease remains to be defined.

Introduction

Crohn's disease is a chronic inflammatory bowel disease (IBD) of unknown cause, the incidence of which is on the increase in high-income countries.1 Since the first description of the similarities between Crohn's disease and Johne's disease in cattle in 1913,2 it has been argued that Mycobacterium avium subspecies paratuberculosis (MAP), which causes Johne's disease, might also be a cause of Crohn's disease, and that the dysregulated immune responses are a secondary phenomenon.3, 4, 5 Conversely, critics of the mycobacterial theory argue that MAP is a secondary invader rather than a causal factor.6

The association of MAP with Crohn's disease is supported by identification of MAP in patients with Crohn's disease, but not in appropriate controls. The gold standard for detection of MAP is based on isolation of the organism through culture methods.2, 7, 8, 9, 10 However, this method is time consuming because of the organism's fastidious nature and slow growth. Molecular and serological methods are widely used alternatives, including immunocytochemistry,11 nucleic acid hybridisation,12 and PCR techniques.13, 14, 15 ELISA is commonly used to investigate the immunological evidence of a MAP infection.16, 17, 18, 19

A causal association of MAP with Crohn's disease would have important implications for both prevention and therapy, and is a continuing matter of concern for public-health agencies.20, 21, 22 Since viable MAP organisms are occasionally isolated from commercial pasteurised milk,23 the efficacy of some heat-treatment procedures of milk would have to be assessed and improved. Additionally, the search for effective treatment regimens against MAP would need to be intensified.

Our aim was to do a systematic review of case-control studies to assess the evidence that is available on MAP and its association with Crohn's disease.

Section snippets

Literature search

Literature searches were done in Medline (1966 to December, 2006). Keywords denoting MAP, Crohn's disease or IBD, and the study design were used: “paratuberculosis” (Medical Subject Heading, [MeSH]) or “Mycobacterium paratuberculosis” (MeSH) or “paratuberculosis” (free text); and “Crohn disease” (MeSH) or “inflammatory bowel disease” (MeSH) or “rectal fistula” (MeSH) or “Crohn” (free text); and “case-control studies” (MeSH) or “case-control” (free text). No language restrictions were applied.

Results

We identified 85 potentially eligible publications, and excluded 29 studies on the basis of title and abstract. 56 studies were examined in detail, of which 28 were excluded for the following reasons: 16 studies reported insufficient information to allow calculation of the OR (including small studies with no positive tests in either group),19, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 two studies were excluded because the serological data from the control group were used to

Discussion

On the basis of 28 case-control studies, this systematic review and meta-analysis shows that tests positive for MAP are substantially more common in patients with Crohn's disease, independently of whether PCR in tissue samples or ELISA in serum is used, or whether patients with Crohn's disease are compared with individuals without IBD or patients with ulcerative colitis.

The results of some of the case-control studies included in our review may have been affected by confounding and bias. In

Conclusions

A causal association of MAP would have important implications for the processing of milk and other dairy products. The occurrence of MAP in milk of productive livestock is well documented, and several studies have shown that viable MAP organisms can survive standard (high-temperature short-time) pasteurisation methods and the processes used for cheese production if high numbers of bacteria are present.23, 82, 83, 84 There are concerns that use of more thorough heat treatments, which eliminate

Search strategy and selection criteria

These are described in detail in the Methods section on page 607.

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