{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,11]],"date-time":"2026-11-11T00:44:33Z","timestamp":1794357873649,"version":"4.9.0"},"reference-count":26,"publisher":"BMJ","issue":"10","content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["Gut"],"accepted":{"date-parts":[[2016,12,26]]},"published-print":{"date-parts":[[2017,10]]},"abstract":"<jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>Proteases are key mediators of pain and altered enteric neuronal signalling, although the types and sources of these important intestinal mediators are unknown. We hypothesised that intestinal epithelium is a major source of trypsin-like activity in patients with IBS and this activity signals to primary afferent and enteric nerves and induces visceral hypersensitivity.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Design<\/jats:title>\n                  <jats:p>Trypsin-like activity was determined in tissues from patients with IBS and in supernatants of Caco-2 cells stimulated or not. These supernatants were also applied to cultures of primary afferents. mRNA isoforms of trypsin (<jats:italic>PRSS1<\/jats:italic>, <jats:italic>2<\/jats:italic> and <jats:italic>3<\/jats:italic>) were detected by reverse transcription-PCR, and trypsin-3 protein expression was studied by western blot analysis and immunohistochemistry. Electrophysiological recordings and Ca<jats:sup>2+<\/jats:sup> imaging in response to trypsin-3 were performed in mouse primary afferent and in human submucosal neurons, respectively. Visceromotor response to colorectal distension was recorded in mice administered intracolonically with trypsin-3.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We showed that stimulated intestinal epithelial cells released trypsin-like activity specifically from the basolateral side. This activity was able to activate sensory neurons. In colons of patients with IBS, increased trypsin-like activity was associated with the epithelium. We identified that trypsin-3 was the only form of trypsin upregulated in stimulated intestinal epithelial cells and in tissues from patients with IBS. Trypsin-3 was able to signal to human submucosal enteric neurons and mouse sensory neurons, and to induce visceral hypersensitivity in vivo, all by a protease-activated receptor-2-dependent mechanism.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>In IBS, the intestinal epithelium produces and releases the active protease trypsin-3, which is able to signal to enteric neurons and to induce visceral hypersensitivity.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/gutjnl-2016-312094","type":"journal-article","created":{"date-parts":[[2017,1,17]],"date-time":"2017-01-17T21:40:32Z","timestamp":1484689232000},"page":"1767-1778","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":136,"title":["Epithelial expression and function of trypsin-3 in irritable bowel syndrome"],"prefix":"10.1136","volume":"66","author":[{"given":"Claire","family":"Rolland-Fourcade","sequence":"first","affiliation":[{"name":"IRSD, Universit\u00e9 de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Denadai-Souza","sequence":"additional","affiliation":[{"name":"IRSD, Universit\u00e9 de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Cirillo","sequence":"additional","affiliation":[{"name":"Laboratory for Enteric Neuroscience (LENS), TARGID, University of Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cintya","family":"Lopez","sequence":"additional","affiliation":[{"name":"Gastrointestinal Diseases Research Unit, , General Hospital, Queen's University School of Medicine, Kingston, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josue Obed","family":"Jaramillo","sequence":"additional","affiliation":[{"name":"Gastrointestinal Diseases Research Unit, , General Hospital, Queen's University School of Medicine, Kingston, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cleo","family":"Desormeaux","sequence":"additional","affiliation":[{"name":"IRSD, Universit\u00e9 de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Cenac","sequence":"additional","affiliation":[{"name":"IRSD, Universit\u00e9 de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Paul","family":"Motta","sequence":"additional","affiliation":[{"name":"IRSD, Universit\u00e9 de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muriel","family":"Larauche","sequence":"additional","affiliation":[{"name":"Oppenheimer Family Center for Neurobiology of Stress and Resilience and CURE: Digestive Diseases Research Center, Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA David Geffen School of Medicine, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvette","family":"Tach\u00e9","sequence":"additional","affiliation":[{"name":"Oppenheimer Family Center for Neurobiology of Stress and Resilience and CURE: Digestive Diseases Research Center, Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA David Geffen School of Medicine, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pieter Vanden","family":"Berghe","sequence":"additional","affiliation":[{"name":"Laboratory for Enteric Neuroscience (LENS), TARGID, University of Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Neunlist","sequence":"additional","affiliation":[{"name":"Inserm, UMR913, Nantes, France"},{"name":"Nantes University, Nantes, France"},{"name":"Institut des Maladies de l'Appareil Digestif, IMAD, CHU Nantes, Hopital H\u00f4tel-Dieu, Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Coron","sequence":"additional","affiliation":[{"name":"Inserm, UMR913, Nantes, France"},{"name":"Nantes University, Nantes, France"},{"name":"Institut des Maladies de l'Appareil Digestif, IMAD, CHU Nantes, Hopital H\u00f4tel-Dieu, Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvain","family":"Kirzin","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Digestive Diseases, Pole Digestif, CHU Toulouse, Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillaume","family":"Portier","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Digestive Diseases, Pole Digestif, CHU Toulouse, Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delphine","family":"Bonnet","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Digestive Diseases, Pole Digestif, CHU Toulouse, Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Alric","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Digestive Diseases, Pole Digestif, CHU Toulouse, Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Vanner","sequence":"additional","affiliation":[{"name":"Gastrointestinal Diseases Research Unit, , General Hospital, Queen's University School of Medicine, Kingston, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celine","family":"Deraison","sequence":"additional","affiliation":[{"name":"IRSD, Universit\u00e9 de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Vergnolle","sequence":"additional","affiliation":[{"name":"IRSD, Universit\u00e9 de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France"},{"name":"Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2017,1,17]]},"reference":[{"key":"2025090723374938000_66.10.1767.1","doi-asserted-by":"crossref","unstructured":"Sperber AD , Dumitrascu D , Fukudo S , et al . The global prevalence of IBS in adults remains elusive due to the heterogeneity of studies: a Rome Foundation working team literature review. Gut 2016. doi: 10.1136\/gutjnl-2015-311240. [Epub ahead of print 27 Jan 2016]. doi:10.1136\/gutjnl-2015-311240","DOI":"10.1136\/gutjnl-2015-311240"},{"key":"2025090723374938000_66.10.1767.2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2009.07.005"},{"key":"2025090723374938000_66.10.1767.3","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2015.04.011"},{"key":"2025090723374938000_66.10.1767.4","doi-asserted-by":"publisher","DOI":"10.1038\/ajg.2013.241"},{"key":"2025090723374938000_66.10.1767.5","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2008.150722"},{"key":"2025090723374938000_66.10.1767.6","doi-asserted-by":"crossref","first-page":"e0155037","DOI":"10.1371\/journal.pone.0155037","article-title":"Limited nesting stress alters maternal behavior and in vivo intestinal permeability in male wistar pup rats","volume":"11","author":"Moussaoui","year":"2016","journal-title":"PLoS ONE"},{"key":"2025090723374938000_66.10.1767.7","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2982.2012.01980.x"},{"key":"2025090723374938000_66.10.1767.8","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00072.2009"},{"key":"2025090723374938000_66.10.1767.9","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2009.192567"},{"key":"2025090723374938000_66.10.1767.10","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2982.2011.01748.x"},{"key":"2025090723374938000_66.10.1767.11","doi-asserted-by":"crossref","first-page":"9226","DOI":"10.1038\/srep09226","article-title":"Isolation of high-purity myenteric plexus from adult human and mouse gastrointestinal tract","volume":"5","author":"Grundmann","year":"2015","journal-title":"Sci Rep"},{"key":"2025090723374938000_66.10.1767.12","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00255.2003"},{"key":"2025090723374938000_66.10.1767.13","doi-asserted-by":"publisher","DOI":"10.1515\/BC.2006.086"},{"key":"2025090723374938000_66.10.1767.14","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3615"},{"key":"2025090723374938000_66.10.1767.15","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.8.5702"},{"key":"2025090723374938000_66.10.1767.16","doi-asserted-by":"crossref","first-page":"158ra44","DOI":"10.1126\/scitranslmed.3004212","article-title":"Food-grade bacteria expressing elafin protect against inflammation and restore colon homeostasis","volume":"4","author":"Motta","year":"2012","journal-title":"Sci Transl Med"},{"key":"2025090723374938000_66.10.1767.17","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262"},{"key":"2025090723374938000_66.10.1767.18","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0902171"},{"key":"2025090723374938000_66.10.1767.19","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2012-304042"},{"key":"2025090723374938000_66.10.1767.20","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2982.2008.01100.x"},{"key":"2025090723374938000_66.10.1767.21","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.662429"},{"key":"2025090723374938000_66.10.1767.22","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.609560"},{"key":"2025090723374938000_66.10.1767.23","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M703840200"},{"key":"2025090723374938000_66.10.1767.24","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2011.08.006"},{"key":"2025090723374938000_66.10.1767.25","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2011.08.034"},{"key":"2025090723374938000_66.10.1767.26","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2004.048876"}],"container-title":["Gut"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/gutjnl-2016-312094","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T06:38:01Z","timestamp":1757313481000},"score":1,"resource":{"primary":{"URL":"https:\/\/gut.bmj.com\/lookup\/doi\/10.1136\/gutjnl-2016-312094"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,1,17]]},"references-count":26,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2017,9,6]]},"published-print":{"date-parts":[[2017,10]]}},"alternative-id":["10.1136\/gutjnl-2016-312094"],"URL":"https:\/\/doi.org\/10.1136\/gutjnl-2016-312094","relation":{},"ISSN":["0017-5749","1468-3288"],"issn-type":[{"value":"0017-5749","type":"print"},{"value":"1468-3288","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,1,17]]}}}