AhR/IL-22 pathway as new target for the treatment of post-infectious irritable bowel syndrome symptoms

Gut Microbes. 2022 Jan-Dec;14(1):2022997. doi: 10.1080/19490976.2021.2022997.

Abstract

Alterations in brain/gut/microbiota axis are linked to Irritable Bowel Syndrome (IBS) physiopathology. Upon gastrointestinal infection, chronic abdominal pain and anxio-depressive comorbidities may persist despite pathogen clearance leading to Post-Infectious IBS (PI-IBS). This study assesses the influence of tryptophan metabolism, and particularly the microbiota-induced AhR expression, on intestinal homeostasis disturbance following gastroenteritis resolution, and evaluates the efficacy of IL-22 cytokine vectorization on PI-IBS symptoms. The Citrobacter rodentium infection model in C57BL6/J mice was used to mimic Enterobacteria gastroenteritis. Intestinal homeostasis was evaluated as low-grade inflammation, permeability, mucosa-associated microbiota composition, and colonic sensitivity. Cognitive performances and emotional state of animals were assessed using several tests. Tryptophan metabolism was analyzed by targeted metabolomics. AhR activity was evaluated using a luciferase reporter assay method. One Lactococcus lactis strain carrying an eukaryotic expression plasmid for murine IL-22 (L. lactisIL-22) was used to induce IL-22 production in mouse colonic mucosa. C. rodentium-infected mice exhibited persistent colonic hypersensitivity and cognitive impairments and anxiety-like behaviors after pathogen clearance. These post-infectious disorders were associated with low-grade inflammation, increased intestinal permeability, decrease of Lactobacillaceae abundance associated with the colonic layer, and increase of short-chain fatty acids (SCFAs). During post-infection period, the indole pathway and AhR activity were decreased due to a reduction of tryptophol production. Treatment with L. lactisIL-22 restored gut permeability and normalized colonic sensitivity, restored cognitive performances and decreased anxiety-like behaviors. Data from the video-tracking system suggested an upgrade of welfare for mice receiving the L.lactisIL-22 strain. Our findings revealed that AhR/IL-22 signaling pathway is altered in a preclinical PI-IBS model. IL-22 delivering alleviate PI-IBS symptoms as colonic hypersensitivity, cognitive impairments, and anxiety-like behaviors by acting on intestinal mucosa integrity. Thus, therapeutic strategies targeting this pathway could be developed to treat IBS patients suffering from chronic abdominal pain and associated well-being disorders.

Keywords: Post-infectious ibs; ahr; citrobacter rodentium; colonic-associated microbiota; il-22; lactococcus lactis; tryptophan; well-being disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacteria / classification
  • Bacteria / genetics
  • Bacteria / isolation & purification
  • Bacteria / metabolism
  • Cognition
  • Depression / etiology*
  • Depression / genetics
  • Depression / metabolism
  • Depression / psychology
  • Fatty Acids, Volatile / metabolism
  • Gastrointestinal Microbiome
  • Humans
  • Interleukin-22
  • Interleukins / genetics
  • Interleukins / metabolism*
  • Intestines / metabolism
  • Intestines / microbiology
  • Irritable Bowel Syndrome / complications*
  • Irritable Bowel Syndrome / metabolism
  • Irritable Bowel Syndrome / microbiology
  • Irritable Bowel Syndrome / psychology*
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / metabolism*

Substances

  • Fatty Acids, Volatile
  • Interleukins
  • Receptors, Aryl Hydrocarbon

Grants and funding

This work was supported by co-financing from the Region Auvergne-Rhône-Alpes and FEDER in 2015 (“Thématiques émergentes”) and in 2018 (“Pack Ambition Recherche” CNSBACT and CPER Nex-N-Mob). It has also been funded by the French government IDEX-ISITE initiative (Grant number: 16-IDEX-0001-CAP 20-25) of the University of Clermont Auvergne. Maëva Meynier, Elodie Baudu, Romain Villéger and Manon Defaye received grants from the Auvergne-Rhône-Alpes Region, CPER and the FEDER. This work was supported by the « Ministère de la Recherche et de la Technologie », INSERM and University of Clermont Auvergne [UMR1071, UMR1107]; INRAE [USC-2018]; CNRS [UMR6023].