{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T20:05:11Z","timestamp":1790625911912,"version":"4.1.0"},"reference-count":42,"publisher":"BMJ","issue":"8","funder":[{"name":"European Research Council (ERC) Advanced Grant"},{"name":"Flanders Fund for Innovation by Science and Technology"},{"DOI":"10.13039\/501100004040","name":"KU Leuven","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004040","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["Gut"],"accepted":{"date-parts":[[2018,10,18]]},"published-print":{"date-parts":[[2019,8]]},"abstract":"<jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>\n                      Vagus nerve stimulation (VNS), most likely via enteric neurons, prevents postoperative ileus (POI) by reducing activation of alpha7 nicotinic receptor (\u03b17nAChR) positive\n                      <jats:italic>muscularis<\/jats:italic>\n                      macrophages (mM\u03c6) and dampening surgery-induced intestinal inflammation. Here, we evaluated if 5-HT4 receptor (5-HT4R) agonist prucalopride can mimic this effect in mice and human.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>\n                      Using Ca\n                      <jats:sup>2+<\/jats:sup>\n                      imaging, the effect of electrical field stimulation (EFS) and prucalopride was evaluated in situ on mM\u03c6 activation evoked by ATP in jejunal\n                      <jats:italic>muscularis<\/jats:italic>\n                      tissue. Next, preoperative and postoperative administration of prucalopride (1\u20135\u2009mg\/kg) was compared with that of preoperative VNS in a model of POI in wild-type and \u03b17nAChR knockout mice. Finally, in a pilot study, patients undergoing a Whipple procedure were preoperatively treated with prucalopride (n=10), abdominal VNS (n=10) or sham\/placebo (n=10) to evaluate the effect on intestinal inflammation and clinical recovery of POI.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      EFS reduced the ATP-induced Ca\n                      <jats:sup>2+<\/jats:sup>\n                      response of mM\u03c6, an effect that was dampened by neurotoxins tetrodotoxin and \u03c9-conotoxin and mimicked by prucalopride. In vivo, prucalopride administered before, but not after abdominal surgery reduced intestinal inflammation and prevented POI in wild-type, but not in \u03b17nAChR knockout mice. In humans, preoperative administration of prucalopride, but not of VNS, decreased\n                      <jats:italic>Il6<\/jats:italic>\n                      and\n                      <jats:italic>Il8<\/jats:italic>\n                      expression in the\n                      <jats:italic>muscularis externa<\/jats:italic>\n                      and improved clinical recovery.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Enteric neurons dampen mM\u03c6 activation, an effect mimicked by prucalopride. Preoperative, but not postoperative treatment with prucalopride prevents intestinal inflammation and shortens POI in both mice and human, indicating that preoperative administration of 5-HT4R agonists should be further evaluated as a treatment of POI.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"NCT02425774\" ext-link-type=\"url\">NCT02425774<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/gutjnl-2018-317263","type":"journal-article","created":{"date-parts":[[2018,11,26]],"date-time":"2018-11-26T04:32:38Z","timestamp":1543206758000},"page":"1406-1416","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":99,"title":["Preoperative administration of the 5-HT4 receptor agonist prucalopride reduces intestinal inflammation and shortens postoperative ileus via cholinergic enteric neurons"],"prefix":"10.1136","volume":"68","clinical-trial-number":[{"clinical-trial-number":"nct02425774","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6229-0045","authenticated-orcid":false,"given":"Nathalie","family":"Stakenborg","sequence":"first","affiliation":[{"name":"Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelien","family":"Labeeuw","sequence":"additional","affiliation":[{"name":"Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro J","family":"Gomez-Pinilla","sequence":"additional","affiliation":[{"name":"Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastiaan","family":"De Schepper","sequence":"additional","affiliation":[{"name":"Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond","family":"Aerts","sequence":"additional","affiliation":[{"name":"Department of Abdominal Surgery, University Hospital of Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gera","family":"Goverse","sequence":"additional","affiliation":[{"name":"Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders, Laboratory for Mucosal Immunology, University of Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Farro","sequence":"additional","affiliation":[{"name":"Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris","family":"Appeltans","sequence":"additional","affiliation":[{"name":"Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Meroni","sequence":"additional","affiliation":[{"name":"Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Stakenborg","sequence":"additional","affiliation":[{"name":"Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders, Laboratory for Mucosal Immunology, University of Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Francesca","family":"Viola","sequence":"additional","affiliation":[{"name":"Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Gonzalez-Dominguez","sequence":"additional","affiliation":[{"name":"Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Goele","family":"Bosmans","sequence":"additional","affiliation":[{"name":"Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeranddy A","family":"Alpizar","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, Laboratory of Ion Channel Research, KU Leuven; VIB Center for Brain & Disease Research, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Wolthuis","sequence":"additional","affiliation":[{"name":"Department of Abdominal Surgery, University Hospital of Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andre","family":"D\u2019Hoore","sequence":"additional","affiliation":[{"name":"Department of Abdominal Surgery, University Hospital of Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim","family":"Van Beek","sequence":"additional","affiliation":[{"name":"Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Verheijden","sequence":"additional","affiliation":[{"name":"Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marleen","family":"Verhaegen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University Hospital of Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Derua","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, Laboratory of Protein Phosphorylation and Proteomics, Universitiy of Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etienne","family":"Waelkens","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, Laboratory of Protein Phosphorylation and Proteomics, Universitiy of Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milena","family":"Moretti","sequence":"additional","affiliation":[{"name":"CNR, Neuroscience Institute-Milano, Biometra University of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Gotti","sequence":"additional","affiliation":[{"name":"CNR, Neuroscience Institute-Milano, Biometra University of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Augustijns","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Drug Delivery and Disposition, University of Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karel","family":"Talavera","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, Laboratory of Ion Channel Research, KU Leuven; VIB Center for Brain & Disease Research, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pieter","family":"Vanden Berghe","sequence":"additional","affiliation":[{"name":"Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders, Laboratory for Enteric Neuroscience, University of Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluca","family":"Matteoli","sequence":"additional","affiliation":[{"name":"Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders, Laboratory for Mucosal Immunology, University of Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy E","family":"Boeckxstaens","sequence":"additional","affiliation":[{"name":"Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2018,11,24]]},"reference":[{"key":"2025120523161810000_68.8.1406.1","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/164_2016_108","article-title":"Postoperative ileus: pathophysiology, current therapeutic approaches","volume":"239","author":"Stakenborg","year":"2017","journal-title":"Handb Exp Pharmacol"},{"issue":"Suppl 2","key":"2025120523161810000_68.8.1406.2","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1111\/j.1743-3150.2004.00559.x","article-title":"Clinical perspective on postoperative ileus and the effect of opiates","volume":"16","author":"Delaney","year":"2004","journal-title":"Neurogastroenterol Motil"},{"key":"2025120523161810000_68.8.1406.3","doi-asserted-by":"crossref","unstructured":"Traut U , Br\u00fcgger L , Kunz R , et al . Systemic prokinetic pharmacologic treatment for postoperative adynamic ileus following abdominal surgery in adults. Cochrane Database Syst Rev 2008:CD004930.doi:10.1002\/14651858.CD004930.pub3","DOI":"10.1002\/14651858.CD004930.pub3"},{"key":"2025120523161810000_68.8.1406.4","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1007\/s11605-016-3140-0","article-title":"Pharmacological management to prevent ileus in major abdominal surgery: a systematic review and meta-analysis","volume":"20","author":"Drake","year":"2016","journal-title":"J Gastrointest Surg"},{"key":"2025120523161810000_68.8.1406.5","doi-asserted-by":"publisher","DOI":"10.1053\/gast.1999.0029900378"},{"key":"2025120523161810000_68.8.1406.6","doi-asserted-by":"publisher","DOI":"10.1097\/00000658-199811000-00004"},{"key":"2025120523161810000_68.8.1406.7","doi-asserted-by":"publisher","DOI":"10.1097\/00000658-200303000-00003"},{"key":"2025120523161810000_68.8.1406.8","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2005.089615"},{"key":"2025120523161810000_68.8.1406.9","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.surg.2009.12.010","article-title":"Transient perioperative pharmacologic inhibition of muscularis macrophages as a target for prophylaxis of postoperative ileus does not affect anastomotic healing in mice","volume":"148","author":"Pantelis","year":"2010","journal-title":"Surgery"},{"key":"2025120523161810000_68.8.1406.10","doi-asserted-by":"publisher","DOI":"10.1038\/ni1229"},{"key":"2025120523161810000_68.8.1406.11","doi-asserted-by":"publisher","DOI":"10.1111\/nmo.13075"},{"key":"2025120523161810000_68.8.1406.12","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2013-304676"},{"key":"2025120523161810000_68.8.1406.13","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1111\/j.1365-2982.2011.01824.x","article-title":"Neuroanatomical evidence demonstrating the existence of the vagal anti-inflammatory reflex in the intestine","volume":"24","author":"Cailotto","year":"2012","journal-title":"Neurogastroenterol Motil"},{"key":"2025120523161810000_68.8.1406.14","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2982.2004.00505.x"},{"key":"2025120523161810000_68.8.1406.15","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2982.2007.01059.x"},{"key":"2025120523161810000_68.8.1406.16","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":"2025120523161810000_68.8.1406.17","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2012-302615"},{"key":"2025120523161810000_68.8.1406.18","first-page":"219","article-title":"Novel method for studying postoperative ileus in mice","volume":"4","author":"van Bree","year":"2012","journal-title":"Int J Physiol Pathophysiol Pharmacol"},{"key":"2025120523161810000_68.8.1406.19","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/s00384-015-2435-z","article-title":"The pig as preclinical model for laparoscopic vagus nerve stimulation","volume":"31","author":"Wolthuis","year":"2016","journal-title":"Int J Colorectal Dis"},{"key":"2025120523161810000_68.8.1406.20","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/S1470-2045(13)70126-8","article-title":"Pancreaticojejunostomy versus pancreaticogastrostomy reconstruction after pancreaticoduodenectomy for pancreatic or periampullary tumours: a multicentre randomised trial","volume":"14","author":"Topal","year":"2013","journal-title":"Lancet Oncol"},{"key":"2025120523161810000_68.8.1406.21","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2013-304676"},{"key":"2025120523161810000_68.8.1406.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2013.01.019"},{"key":"2025120523161810000_68.8.1406.23","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-2999(01)01087-1"},{"key":"2025120523161810000_68.8.1406.24","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2007.07.022"},{"key":"2025120523161810000_68.8.1406.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.12.023"},{"key":"2025120523161810000_68.8.1406.26","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-01-00133.2000"},{"key":"2025120523161810000_68.8.1406.27","doi-asserted-by":"publisher","DOI":"10.1124\/mol.114.093377"},{"key":"2025120523161810000_68.8.1406.28","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.ejso.2012.12.010","article-title":"Clinical risk factors of delayed gastric emptying in patients after pancreaticoduodenectomy: a systematic review and meta-analysis","volume":"39","author":"Qu","year":"2013","journal-title":"Eur J Surg Oncol"},{"key":"2025120523161810000_68.8.1406.29","doi-asserted-by":"crossref","first-page":"55","DOI":"10.9738\/CC63.1","article-title":"Management of postoperative complications following splenectomy","volume":"98","author":"Qu","year":"2013","journal-title":"Int Surg"},{"key":"2025120523161810000_68.8.1406.30","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0087785","article-title":"Neuro-anatomical evidence indicating indirect modulation of macrophages by vagal efferents in the intestine but not in the spleen","volume":"9","author":"Cailotto","year":"2014","journal-title":"PLoS One"},{"key":"2025120523161810000_68.8.1406.31","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.3.2181"},{"key":"2025120523161810000_68.8.1406.32","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.1991.260.1.R200"},{"key":"2025120523161810000_68.8.1406.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2011.12.020"},{"key":"2025120523161810000_68.8.1406.34","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2010.227546"},{"key":"2025120523161810000_68.8.1406.35","doi-asserted-by":"publisher","DOI":"10.1007\/s10350-008-9407-0"},{"key":"2025120523161810000_68.8.1406.36","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1007\/s11605-011-1567-x","article-title":"Mosapride citrate improves postoperative ileus of patients with colectomy","volume":"15","author":"Toyomasu","year":"2011","journal-title":"J Gastrointest Surg"},{"key":"2025120523161810000_68.8.1406.37","doi-asserted-by":"crossref","first-page":"A-138","DOI":"10.1016\/S0016-5085(08)60640-X","article-title":"934 Evaluation of the efficacy, safety and tolerability of prucalopride (Resolor\u00ae) given subcutaneously in patients undergoing elective partial colectomies","volume":"134","author":"Galandiuk","year":"2008","journal-title":"Gastroenterology"},{"key":"2025120523161810000_68.8.1406.38","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1111\/apt.13557","article-title":"Randomised clinical trial: prucalopride, a colonic pro-motility agent, reduces the duration of post-operative ileus after elective gastrointestinal surgery","volume":"43","author":"Gong","year":"2016","journal-title":"Aliment Pharmacol Ther"},{"key":"2025120523161810000_68.8.1406.39","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1145-09.2009"},{"key":"2025120523161810000_68.8.1406.40","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00284.2011"},{"key":"2025120523161810000_68.8.1406.41","doi-asserted-by":"publisher","DOI":"10.5056\/jnm.2014.20.1.17"},{"key":"2025120523161810000_68.8.1406.42","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2982.2010.01474.x"}],"container-title":["Gut"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/gutjnl-2018-317263","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T07:16:25Z","timestamp":1765005385000},"score":1,"resource":{"primary":{"URL":"https:\/\/gut.bmj.com\/lookup\/doi\/10.1136\/gutjnl-2018-317263"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,11,24]]},"references-count":42,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2019,7,5]]},"published-print":{"date-parts":[[2019,8]]}},"alternative-id":["10.1136\/gutjnl-2018-317263"],"URL":"https:\/\/doi.org\/10.1136\/gutjnl-2018-317263","relation":{},"ISSN":["0017-5749","1468-3288"],"issn-type":[{"value":"0017-5749","type":"print"},{"value":"1468-3288","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,11,24]]}}}