Objectives: Diarrhea-predominant irritable bowel syndrome (IBS-D) is characterized by elevated colonic lumenal serine-protease activity. The aims of this study were (i) to investigate the origin of this elevated serine-protease activity, (ii) to evaluate if it may be sufficient to trigger alterations in colonic paracellular permeability (CPP) and sensitivity and (iii) to examine the role of proteinase-activated receptor-2 (PAR-2) activation and signaling cascade in this process.
Patients & Methods: Fecal enzymatic activities were assayed in healthy subjects and patients with IBS, ulcerative colitis and acute infectious diarrhea. Following mucosal exposure to supernatants of control subjects and IBS-D patients, EMG response to colorectal balloon distension was recorded in WT and PAR2-/- mice and CPP was evaluated on colonic strips in Ussing chambers. Zonula occludens-1 (ZO-1) and phosphorylated myosin light chain were detected by immunohistochemistry.
Results: The three-times increase in fecal serine-protease activity seen in IBS-D patients compared with IBS-C or infectious diarrhea, is neither of epithelial or inflammatory cell origin, nor is it coupled with anti-protease activity of endogenous origin. Mucosal application of fecal supernatants from IBS-D patients in mice evoked allodynia and increased CPP by 92%, both of which effects were prevented by serine-protease inhibitors and dependent on PAR-2 expression. In mice, colonic exposure to supernatants from IBS-D patients resulted in a rapid increase in the phosphorylation of myosin light chain and delayed redistribution of ZO-1 in colonocytes.
Conclusions: Elevated colonic lumenal serine-protease activity of IBS-D patients evokes a PAR-2 mediated colonic epithelial barrier dysfunction and subsequent allodynia in mice, suggesting a novel organic background in the pathogenesis of IBS.
- Irritable bowel syndrome
- serine protease and PAR2
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