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Original research
Effect of resolvins on sensitisation of TRPV1 and visceral hypersensitivity in IBS
  1. Eluisa Perna1,
  2. Javier Aguilera-Lizarraga1,
  3. Morgane V Florens1,
  4. Piyush Jain1,
  5. Stavroula A Theofanous1,
  6. Nikita Hanning2,
  7. Joris G De Man2,
  8. Maya Berg2,
  9. Benedicte De Winter2,
  10. Yeranddy A Alpizar3,
  11. Karel Talavera4,
  12. Pieter Vanden Berghe5,
  13. Mira Wouters1,
  14. Guy Boeckxstaens1
  1. 1Center of Intestinal Neuro-Immune Interaction, Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
  2. 2Laboratory of Experimental Medicine and Pediatrics (LEMP) and Infla-Med, research consortium of excellence, University of Antwerp, Antwerp, Belgium
  3. 3BIOMED, UHasselt, Hasselt, Limburg, Belgium
  4. 4Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, VIB Center for Brain & Disease Research, Leuven, Belgium
  5. 5Laboratory for Enteric Neuroscience, Translational Research Center for Gastrointestinal (TARGID), Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
  1. Correspondence to Professor Guy Boeckxstaens, Department of Chronic Diseases, Metabolism and Ageing, Center of Intestinal Neuro-Immune Interaction, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven 3000, Belgium; guy.boeckxstaens{at}kuleuven.be

Abstract

Objective Resolvins (RvD1, RvD2 and RvE1) are endogenous anti-inflammatory lipid mediators that display potent analgesic properties in somatic pain by modulating transient receptor potential vanilloid 1 (TRPV1) activation. To what extent these molecules could also have a beneficial effect on TRPV1 sensitisation and visceral hypersensitivity (VHS), mechanisms involved in IBS, remains unknown.

Design The effect of RvD1, RvD2 and RvE1 on TRPV1 activation and sensitisation by histamine or IBS supernatants was assessed on murine dorsal root ganglion (DRG) neurons using live Ca2+ imaging. Based on the results obtained in vitro, we further studied the effect of RvD2 in vivo using a murine model of post-infectious IBS and a rat model of post-inflammatory VHS. Finally, we also tested the effect of RvD2 on submucosal neurons in rectal biopsies of patients with IBS.

Results RvD1, RvD2 and RvE1 prevented histamine-induced TRPV1 sensitisation in DRG neurons at doses devoid of an analgesic effect. Of note, RvD2 also reversed TRPV1 sensitisation by histamine and IBS supernatant. This effect was blocked by the G protein receptor 18 (GPR18) antagonist O-1918 (3–30 µM) and by pertussis toxin. In addition, RvD2 reduced the capsaicin-induced Ca2+ response of rectal submucosal neurons of patients with IBS. Finally, treatment with RvD2 normalised pain responses to colorectal distention in both preclinical models of VHS.

Conclusions Our data suggest that RvD2 and GPR18 agonists may represent interesting novel compounds to be further evaluated as treatment for IBS.

  • abdominal pain
  • ION channels
  • irritable bowel syndrome
  • visceral hypersensitivity
  • neurogastroenterology

Data availability statement

Data are available upon reasonable request. All the relevant data generated and analysed during the current study are available upon reasonable request to the corresponding author.

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Data availability statement

Data are available upon reasonable request. All the relevant data generated and analysed during the current study are available upon reasonable request to the corresponding author.

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Footnotes

  • EP and JA-L contributed equally.

  • Correction notice This article has been corrected since it published Online First. The order of figures 1-6 have been corrected.

  • Contributors EP, MVF, MW and GB planned and designed the experiments. BDW, NH, JGDM and MB planned and designed the experiments in the post-TNBS colitis model. EP, JA-L and PJ performed and analysed the Ca2+ experiments in DRG neurons and rectal biopsies experiments. MVF carried out the in vivo animal protocol and analysed visceromotor responses and compliance. MVF and JA-L performed and analysed colonic permeability assessments. NH and JGDM performed and analysed the experiments in the post-TNBS colitis model. SAT and JA-L performed the staining in retrograde labelled DRG neurons. PVB, YAA and KT provided technical expertise. EP, MVF, JA-L and GB wrote and revised the manuscript. All other authors corrected and approved the final version of the manuscript.

  • Funding This work was supported by the Research Foundation—Flanders (FWO-SBO grant nr. S001017). MVF, MMW, PJ, JA-L and YAA were supported by an FWO doctoral or postdoctoral fellowship (1110017N/1110019N, 1248513N, 12R5219N, 12X9820N and 12H8217N). EP was supported by an Early Stage Researcher Marie Curie fellowship (NeuroGUT).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.