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Title: | Preoperative administration of the 5-HT4 receptor agonist prucalopride reduces intestinal inflammation and shortens postoperative ileus via cholinergic enteric neurons | Authors: | Stakenborg, Nathalie Labeeuw, Evelien Gomez-Pinilla, Pedro J De Schepper, Sebastiaan Aerts, Raymond Goverse, Gera Farro, Giovanna Appeltans, Iris Meroni, Elisa Stakenborg, Michelle Viola, Maria Francesca Gonzalez-Dominguez, Erika Bosmans, Goele AGUIAR ALPIZAR, Yeranddy Wolthuis, Albert D'Hoore, Andre Van Beek, Kim Verheijden, Simon Verhaegen, Marleen Derua, Rita Waelkens, Etienne Moretti, Milena Gotti, Cecilia Augustijns, Patrick Talavera, Karel Vanden Berghe, Pieter Matteoli, Gianluca Boeckxstaens, Guy E |
Issue Date: | 2019 | Publisher: | BMJ PUBLISHING GROUP | Source: | Gut, 68 (8) , p. 1406-1416 -1416 | Abstract: | Objectives Vagus nerve stimulation (VNS), most likely via enteric neurons, prevents postoperative ileus (POI) by reducing activation of alpha7 nicotinic receptor (alpha 7nAChR) positive muscularis macrophages (mMf) 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 mMf 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 alpha 7nAChR 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 AT P-induced Ca2+ response of mMf, an effect that was dampened by neurotoxins tetrodotoxin and omega-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 alpha 7nAChR 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 mMf 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. | Other: | Randomized Controlled Trial - Research Support, Non-U.S. Gov't | Keywords: | Inhibition;Activation;Neurogenesis;Macrophages;Pancreaticoduodenectomy;Management;Motility | Document URI: | http://hdl.handle.net/1942/30193 | ISSN: | 0017-5749 | e-ISSN: | 1468-3288 | DOI: | 10.1136/gutjnl-2018-317263 | ISI #: | 000482497600009 | Rights: | Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/. | Category: | A1 | Type: | Journal Contribution |
Appears in Collections: | Research publications |
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