OBJECTIVES: Luminal serine-proteases lead to increased colonic paracellular permeability and visceral hypersensitivity in patients with diarrhea-predominant irritable bowel syndrome (IBS-D). Other proteases, namely cysteine-proteases (CPs), increase airway permeability by digesting epithelial tight junction proteins. In this study, we focused on constipation-predominant IBS (IBS-C) and we aimed to (i) evaluate CP levels in two cohorts of IBS patients, (ii) test if IBS-C fecal supernatant (FSN) affects permeability, and visceral sensitivity after repeated administrations in mice, and (iii) evaluate occludin expression in IBS-C colonic biopsies. METHODS: Fecal CP activity was determined using selective substrate and inhibitor (E64). The effect of papain, as positive control, and IBS-C FSN administrations were evaluated on colonic paracellular permeability and mucosal occludin levels in mice and T84 monolayers. Occludin protein levels were evaluated in IBS-C colonic biopsies. Sensitivity to colorectal distension (CRD) was measured after repeated administrations of IBS-C FSN. RESULTS: We found in a subset of IBS-C patients an enhanced fecal CP activity, in comparison with healthy controls and IBS-D patients. CP activity levels positively correlated with disease severity and abdominal pain scoring. This association was confirmed by receiver operating characteristic curve analysis. In mice, repeated application of IBS-C FSN into colon triggered increased permeability, linked to the enzymatic degradation of occludin, and was associated with enhanced visceral sensitivity to CRD. Finally, occludin levels were found decreased in colonic biopsies from IBS-C patients, and IBS-C FSNs were able to degrade recombinant human occludin in vitro. All these effects were abolished by preincubation of IBS-C FSN with a CP inhibitor, E64. CONCLUSIONS: These data suggest that luminal CPs may represent a new factor contributing to the genesis of symptoms in IBS.
OBJECTIVES: Luminal serine-proteases lead to increased colonic paracellular permeability and visceral hypersensitivity inpatients with diarrhea-predominant irritable bowel syndrome (IBS-D). Other proteases, namely cysteine-proteases (CPs), increase airway permeability by digesting epithelial tight junction proteins. In this study, we focused on constipation-predominant IBS (IBS-C) and we aimed to (i) evaluate CP levels in two cohorts of IBSpatients, (ii) test if IBS-C fecal supernatant (FSN) affects permeability, and visceral sensitivity after repeated administrations in mice, and (iii) evaluate occludin expression in IBS-C colonic biopsies. METHODS: Fecal CP activity was determined using selective substrate and inhibitor (E64). The effect of papain, as positive control, and IBS-C FSN administrations were evaluated on colonic paracellular permeability and mucosal occludin levels in mice and T84 monolayers. Occludin protein levels were evaluated in IBS-C colonic biopsies. Sensitivity to colorectal distension (CRD) was measured after repeated administrations of IBS-C FSN. RESULTS: We found in a subset of IBS-C patients an enhanced fecal CP activity, in comparison with healthy controls and IBS-Dpatients. CP activity levels positively correlated with disease severity and abdominal pain scoring. This association was confirmed by receiver operating characteristic curve analysis. In mice, repeated application of IBS-C FSN into colon triggered increased permeability, linked to the enzymatic degradation of occludin, and was associated with enhanced visceral sensitivity to CRD. Finally, occludin levels were found decreased in colonic biopsies from IBS-C patients, and IBS-C FSNs were able to degrade recombinant humanoccludin in vitro. All these effects were abolished by preincubation of IBS-C FSN with a CP inhibitor, E64. CONCLUSIONS: These data suggest that luminal CPs may represent a new factor contributing to the genesis of symptoms in IBS.
Authors: Olga Bednarska; Susanna A Walter; Maite Casado-Bedmar; Magnus Ström; Eloísa Salvo-Romero; Maria Vicario; Emeran A Mayer; Åsa V Keita Journal: Gastroenterology Date: 2017-07-13 Impact factor: 22.682
Authors: Shoko Edogawa; Adam L Edwinson; Stephanie A Peters; Lakshmikanth L Chikkamenahalli; Wendy Sundt; Sara Graves; Sakteesh V Gurunathan; Margaret Breen-Lyles; Stephen Johnson; Roy Dyer; Rondell Graham; Jun Chen; Purna Kashyap; Gianrico Farrugia; Madhusudan Grover Journal: Gut Date: 2019-03-28 Impact factor: 23.059
Authors: Paul Enck; Qasim Aziz; Giovanni Barbara; Adam D Farmer; Shin Fukudo; Emeran A Mayer; Beate Niesler; Eamonn M M Quigley; Mirjana Rajilić-Stojanović; Michael Schemann; Juliane Schwille-Kiuntke; Magnus Simren; Stephan Zipfel; Robin C Spiller Journal: Nat Rev Dis Primers Date: 2016-03-24 Impact factor: 52.329
Authors: Hannah Ceuleers; Nikita Hanning; Jelena Heirbaut; Samuel Van Remoortel; Jurgen Joossens; Pieter Van Der Veken; Sven M Francque; Michelle De Bruyn; Anne-Marie Lambeir; Joris G De Man; Jean-Pierre Timmermans; Koen Augustyns; Ingrid De Meester; Benedicte Y De Winter Journal: Br J Pharmacol Date: 2018-07-23 Impact factor: 8.739
Authors: Stephanie A Peters; Shoko Edogawa; Wendy J Sundt; Roy B Dyer; Daniel A Dalenberg; Amelia Mazzone; Ravinder J Singh; Natalie Moses; Thomas C Smyrk; Christopher Weber; David R Linden; Wallace K MacNaughton; Jerrold R Turner; Michael Camilleri; David A Katzka; Gianrico Farrugia; Madhusudan Grover Journal: Am J Gastroenterol Date: 2017-03-21 Impact factor: 10.864