Alimentary TractMolecular evidence for Mycobacterium avium subspecies paratuberculosis (MAP) in Crohn's disease correlates with enhanced TNF-α secretion
Introduction
The cause of chronic inflammation in the gut of subjects with Crohn's disease (CD) is unclear, though two hypotheses are widely held. The first is that genetically influenced defects in mucosal immune regulation and/or mucosal barrier protection, underpin a heightened inflammatory response to enteric bacteria that have accessed the gut mucosal compartment [19]. The second is that a specific infection drives mucosal inflammation, with the most popular candidate being Mycobacterium avium subspecies paratuberculosis (MAP). The prevalence of MAP in CD would appear to vary, although much of this variation may be a reflection of the different methodologies used [13], [10], [18]. Any relationship between MAP infection and disease is complicated by the observations that MAP may not be necessary for CD; that MAP is found in gut disease other than CD, as well as in normal subjects [10], [18]; and that the clinical benefits claimed for rifabutin/macrolide antibiotic combinations developed to eradicate MAP have not yet been correlated with the presence of MAP infection [4]. The argument for a role of MAP in the pathogenesis of CD would be strengthened by identifying a mechanism whereby MAP could induce tissue damage. The aim of this study was to determine whether the presence of MAP in CD correlated with a particular pattern of cytokine secretion by the gut mucosa. We report data that link the presence of MAP in CD with a selective enhancement of tumour necrosis factor-α (TNF-α) secretion from the gut mucosa, a known contributor to the inflammatory response that mediates tissue damage characteristic of this disease.
Section snippets
Subjects
The study was approved by the Centre for Digestive Diseases Human Research Ethics Committee, Sydney and Human Research Ethics Committee, University of Newcastle, Australia, and was performed in accordance with the principles of the 2000 Declaration of Helsinki. Informed consent was obtained from all subjects. Diagnosis was based on clinical criteria and the results of the pathological examination [15]. Patients presenting both for review and initial diagnosis were included. During colonoscopic
Results
Subjects were assessed in four groups: Crohn's disease (CD) (n = 63), ulcerative colitis (UC) (n = 53), irritable bowel syndrome (IBS) (n = 45) and normal controls (n = 74). The diagnosis was based on classical clinical, endoscopic and histological criteria. Of the 63 subjects with CD, 52 subjects had active inflammation (defined at colonoscopy as inflammation and/or ulceration and confirmed in biopsies) (11 for MAP-positive and 41 for MAP-negative) observed at colonoscopy and 11 had no inflammation (4
Discussion
The demonstration of enhanced TNF-α secretion in the gut of subjects with CD who are positive for MAP is the first potential evidence of a mechanism that could link the presence of MAP with gut disease. The selective effect of MAP infection on TNF-α secretion in CD compared to an absence of such an effect in normal and disease controls, points to a specific defect in the cellular handling of MAP in CD.
The high concentration of TNF-α in the supernatants of gut mucosal cultures in subjects with
Conflict of interest statement
None declared.
Acknowledgements
The study was funded by the Broad Medical Research Program of the Eli and Edythe L. Broad Foundation, USA. Authors are grateful to Evelyn Vigano for her skillful technical assistance. We thank Professor Tom Borody for providing clinical data and comments.
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