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Increased fecal serine-protease activity in diarrheic ibs patients: a colonic lumenal factor impairing colonic permeability and sensitivity
  1. Krisztina Gecse
  1. Neuro-Gastroenterology & Nutrition Unit, INRA/EI-Purpan, Toulouse, France
    1. Richard Roka
    1. First Department of Internal Medicine, University of Szeged, Hungary
      1. Laurent Ferrier (ferrier{at}toulouse.inra.fr)
      1. Neuro-Gastroenterology & Nutrition Unit, INRA/EI-Purpan, Toulouse, France
        1. Mathilde Leveque
        1. Neuro-Gastroenterology & Nutrition Unit, INRA/EI-Purpan, Toulouse, France
          1. Helene Eutamene
          1. Neuro-Gastroenterology & Nutrition Unit, INRA/EI-Purpan, Toulouse, France
            1. Christel Cartier
            1. Neuro-Gastroenterology & Nutrition Unit, INRA/EI-Purpan, Toulouse, France
              1. Afifa Ait-Belgnaoui (afifa{at}toulouse.inra.fr)
              1. Neuro-Gastroenterology & Nutrition Unit, INRA/EI-Purpan, Toulouse, France
                1. Andras Rosztoczy
                1. First Department of Internal Medicine, University of Szeged, Hungary
                  1. Ferenc Izbeki
                  1. First Department of Internal Medicine, University of Szeged, Hungary
                    1. Jean Fioramonti (jfioramo{at}toulouse.inra.fr)
                    1. Neuro-Gastroenterology & Nutrition Unit, INRA/EI-Purpan, Toulouse, France
                      1. Tibor Wittmann
                      1. First Department of Internal Medicine, University of Szeged, Hungary
                        1. Lionel Bueno (lbueno{at}toulouse.inra.fr)
                        1. Neuro-Gastroenterology & Nutrition Unit, INRA/EI-Purpan, Toulouse, France

                          Abstract

                          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
                          • colon
                          • diarrhea
                          • permeability
                          • serine protease and PAR2

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