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Abstract
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.
- prucalopride
- ileus
- enteric neuron
- Macrophages
- anti-inflammatory
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Footnotes
NS, EL and PJG-P contributed equally.
GM and GEB contributed equally.
Contributors NS, EL, PJG-P, KT, GM and GEB planned and designed experiments. NS, EL, PJG-P, GF, IA, EM, MS, MFV, GB, EG-D, YAA, PA, SD, GG, EW, RD, AW, RA, ADH, KV, SV, MM, CG, MV, KT and PVDB performed or supervised the experiments. NS, EL, PJGP, GM and GEB reviewed data and wrote the manuscript. All other authors corrected and approved the final version of the manuscript.
Funding This work was supported by the European Research Council (ERC) Advanced Grant (ERC-2013-Adg: 340101 Cholstim) to GEB. GEB is also supported by Flanders Fund for Innovation by Science and Technology (IWT-TBM; 110699), and Research Foundation—Flanders (FWO): Odysseus programme (G.0905.07) and two FWO grants (G.0566.12N and G.0890.18N). NS, PJG-P, YAA, GG, SV and GM are supported by a postdoctoral research fellowship of FWO. GM is supported by an FWO grant (G.0D83.17N) and by KU Leuven grants (ZKD2906-C14/17/097 and ZKC9531-C12/15/016).
Competing interests None declared.
Patient consent Obtained.
Ethics approval This study was approved by KU Leuven Animal Ethics Committee and Medical Ethics Committee UZ KU Leuven.
Provenance and peer review Not commissioned; externally peer reviewed.