RT Journal Article SR Electronic T1 Preoperative administration of the 5-HT4 receptor agonist prucalopride reduces intestinal inflammation and shortens postoperative ileus via cholinergic enteric neurons JF Gut JO Gut FD BMJ Publishing Group Ltd and British Society of Gastroenterology SP gutjnl-2018-317263 DO 10.1136/gutjnl-2018-317263 A1 Nathalie Stakenborg A1 Evelien Labeeuw A1 Pedro J Gomez-Pinilla A1 Sebastiaan De Schepper A1 Raymond Aerts A1 Gera Goverse A1 Giovanna Farro A1 Iris Appeltans A1 Elisa Meroni A1 Michelle Stakenborg A1 Maria Francesca Viola A1 Erika Gonzalez-Dominguez A1 Goele Bosmans A1 Yeranddy A Alpizar A1 Albert Wolthuis A1 Andre D’Hoore A1 Kim Van Beek A1 Simon Verheijden A1 Marleen Verhaegen A1 Rita Derua A1 Etienne Waelkens A1 Milena Moretti A1 Cecilia Gotti A1 Patrick Augustijns A1 Karel Talavera A1 Pieter Vanden Berghe A1 Gianluca Matteoli A1 Guy E Boeckxstaens YR 2018 UL http://gut.bmj.com/content/early/2018/11/23/gutjnl-2018-317263.abstract AB Objectives Vagus nerve stimulation (VNS), most likely via enteric neurons, prevents postoperative ileus (POI) by reducing activation of alpha7 nicotinic receptor (α7nAChR) positive muscularis macrophages (mMφ) 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.Design Using Ca2+ imaging, the effect of electrical field stimulation (EFS) and prucalopride was evaluated in situ on mMφ activation evoked by ATP in jejunal muscularis tissue. Next, preoperative and postoperative administration of prucalopride (1–5 mg/kg) was compared with that of preoperative VNS in a model of POI in wild-type and α7nAChR 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.Results EFS reduced the ATP-induced Ca2+ response of mMφ, an effect that was dampened by neurotoxins tetrodotoxin and ω-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 α7nAChR knockout mice. In humans, preoperative administration of prucalopride, but not of VNS, decreased Il6 and Il8 expression in the muscularis externa and improved clinical recovery.Conclusion Enteric neurons dampen mMφ 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.Trial registration number NCT02425774.