Increased faecal serine protease activity in diarrhoeic IBS patients: a colonic lumenal factor impairing colonic permeability and sensitivity

• Published in: Gut Vol. 57; no. 5; pp. 591 - 599
• Main Authors: Gecse, K, Róka, R, Ferrier, L, Leveque, M, Eutamene, H, Cartier, C, Ait-Belgnaoui, A, Rosztóczy, A, Izbéki, F, Fioramonti, J, Wittmann, T, Bueno, L
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and British Society of Gastroenterology 01.05.2008; BMJ; BMJ Publishing Group LTD
• Subjects: Adult; Aged; Aged, 80 and over; Animals; Antigens; Biological and medical sciences; Biomarkers - metabolism; Colon - enzymology; Diarrhea; Diarrhea - enzymology; Family medical history; Feces - enzymology; Female; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Inflammation; Inflammatory bowel disease; Intestinal Mucosa - enzymology; Irritable bowel syndrome; Irritable Bowel Syndrome - diagnosis; Irritable Bowel Syndrome - enzymology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Middle Aged; Permeability; Phosphorylation; Proteases; Proteins; Receptor, PAR-2 - metabolism; Rodents; Serine Endopeptidases - metabolism; Studies; Human; Peptidases; Sensitivity; Enzyme; Aminoacid; Serine; Gastroenterology; Hydrolases; Colon; Feces; Permeability
• ISSN: 0017-5749; 1468-3288; 1468-3288
• DOI: 10.1136/gut.2007.140210

Objectives: Diarrhoea-predominant irritable bowel syndrome (IBS-D) is characterised by elevated colonic lumenal serine protease activity. The aims of this study were (1) to investigate the origin of this elevated serine protease activity, (2) to evaluate if it may be sufficient to trigger alterations in colonic paracellular permeability (CPP) and sensitivity, and (3) to examine the role of the proteinase-activated receptor-2 (PAR-2) activation and signalling cascade in this process. Patients and methods: Faecal enzymatic activities were assayed in healthy subjects and patients with IBS, ulcerative colitis and acute infectious diarrhoea. Following mucosal exposure to supernatants from control subjects and IBS-D patients, electromyographic response to colorectal balloon distension was recorded in wild-type and PAR-2–/– 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 threefold increase in faecal serine protease activity seen in IBS-D patients compared with constipation-predominant IBS (IBS-C) or infectious diarrhoea is of neither epithelial nor inflammatory cell origin, nor is it coupled with antiprotease activity of endogenous origin. Mucosal application of faecal 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.