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Original article
Preoperative administration of the 5-HT4 receptor agonist prucalopride reduces intestinal inflammation and shortens postoperative ileus via cholinergic enteric neurons
  1. Nathalie Stakenborg1,
  2. Evelien Labeeuw1,
  3. Pedro J Gomez-Pinilla1,
  4. Sebastiaan De Schepper1,
  5. Raymond Aerts2,
  6. Gera Goverse3,
  7. Giovanna Farro1,
  8. Iris Appeltans1,
  9. Elisa Meroni1,
  10. Michelle Stakenborg3,
  11. Maria Francesca Viola1,
  12. Erika Gonzalez-Dominguez1,
  13. Goele Bosmans1,
  14. Yeranddy A Alpizar4,
  15. Albert Wolthuis2,
  16. Andre D’Hoore2,
  17. Kim Van Beek1,
  18. Simon Verheijden1,
  19. Marleen Verhaegen5,
  20. Rita Derua6,
  21. Etienne Waelkens6,
  22. Milena Moretti7,
  23. Cecilia Gotti7,
  24. Patrick Augustijns8,
  25. Karel Talavera4,
  26. Pieter Vanden Berghe9,
  27. Gianluca Matteoli3,
  28. Guy E Boeckxstaens1
  1. 1 Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven, Belgium
  2. 2 Department of Abdominal Surgery, University Hospital of Leuven, Leuven, Belgium
  3. 3 Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders, Laboratory for Mucosal Immunology, University of Leuven, Leuven, Belgium
  4. 4 Department of Cellular and Molecular Medicine, Laboratory of Ion Channel Research, KU Leuven; VIB Center for Brain & Disease Research, Leuven, Belgium
  5. 5 Department of Anesthesiology, University Hospital of Leuven, Leuven, Belgium
  6. 6 Department of Cellular and Molecular Medicine, Laboratory of Protein Phosphorylation and Proteomics, Universitiy of Leuven, Leuven, Belgium
  7. 7 CNR, Neuroscience Institute-Milano, Biometra University of Milan, Milan, Italy
  8. 8 Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Drug Delivery and Disposition, University of Leuven, Leuven, Belgium
  9. 9 Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders, Laboratory for Enteric Neuroscience, University of Leuven, Leuven, Belgium
  1. Correspondence to Dr Guy E Boeckxstaens, Department of Chronic Diseases, Metabolism and Ageing; Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven 3000, Belgium; guy.boeckxstaens{at}kuleuven.be

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.

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