AhR/IL-22 pathway as new target for the treatment of post-infectious irritable bowel syndrome symptoms. (31st December 2022)

• Record Type: Journal Article
• Authors: Meynier, Maëva; Baudu, Elodie; Rolhion, Nathalie; Defaye, Manon; Straube, Marjolène; Daugey, Valentine; Modoux, Morgane; Wawrzyniak, Ivan; Delbac, Frédéric; Villéger, Romain; Méleine, Mathieu; Borras Nogues, Esther; Godfraind, Catherine; Barnich, Nicolas; Ardid, Denis; Poirier, Philippe; Sokol, Harry; Chatel, Jean-Marc; Langella, Philippe; Livrelli, Valérie; Bonnet, Mathilde; Carvalho, Frédéric Antonio
• Is Part Of: Gut microbes. Volume 14:Isuse 1(2022)
• Publication Date: 2022-12-31
• Subjects: Post-infectious ibs -- colonic-associated microbiota -- citrobacter rodentium -- tryptophan -- ahr -- il-22 -- lactococcus lactis -- well-being disorders; Gastrointestinal system -- Microbiology -- Periodicals; Microbiology -- Periodicals; Intestine, Small -- Periodicals; 616.3
• DOI: 10.1080/19490976.2021.2022997
• Languages: English
• ISSNs: 1949-0984

Abstract

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. lactis IL−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. lactis IL−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.lactis IL−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.