Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Jan-Dec;14(1):2022997.
doi: 10.1080/19490976.2021.2022997.

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

Maëva Meynier  1   2 , Elodie Baudu  1   2 , Nathalie Rolhion  3   4 , Manon Defaye  2   5   6 , Marjolène Straube  3 , Valentine Daugey  2 , Morgane Modoux  3 , Ivan Wawrzyniak  6 , Frédéric Delbac  6 , Roamin Villéger  1 , Mathieu Méleine  2 , Esther Borras Nogues  7 , Catherine Godfraind  1   8 , Nicolas Barnich  1 , Denis Ardid  2 , Philippe Poirier  1   9 , Harry Sokol  3   4   7 , Jean-Marc Chatel  7 , Philippe Langella  7 , Valérie Livrelli  1   9 , Mathilde Bonnet  1 , Frédéric Antonio Carvalho  2
Affiliations

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

Maëva Meynier et al. Gut Microbes. 2022 Jan-Dec.

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.

PubMed Disclaimer

Conflict of interest statement

HS received consultancy, or lecture fees from Carenity, Abbvie, Astellas, Danone, Ferring, Mayoly Spindler, MSD, Novartis, Roche, Tillots, Enterome, Maat, BiomX, Biose, Novartis, and Takeda; and is a co-founder of Exeliom Bioscience. PL has led research projects with several agro-food (Danone, General Mills, Dupond and Lallemand), food supplements (Pilèje), biotech (Ysopia) and pharmaceutical (Biocodex and Merck) companies. PL has received consultancy or lecture fees from Ipsen, Mayoly Spindler, Iprad, Itak, BINC Geneva, Lesaffre, l’Oréal, Bonduelle and Second Genome and is a co-founder of Exeliom Bioscience. The other authors declare nο competing interests.

Figures

Figure 1.
Figure 1.
Transient C. rodentium infection induces persistent perturbations in mice.
Figure 2.
Figure 2.
Post-infectious visceral sensitivity and anxiety-like behavior induced by C. rodentium.
Figure 3.
Figure 3.
Colonic mucosa-associated microbiota dysbiosis after C. rodentium clearance in mice.
Figure 4.
Figure 4.
AhR activity and tryptophan metabolic pathways are modified in post-infectious period.
Figure 5.
Figure 5.
IL-22 treatment reverses post-infectious anxiety-, cognition-like behaviors and ill-being induced by C. rodentium infection.
Figure 6.
Figure 6.
IL-22 treatment reverses post-infectious CHS and intestinal barrier alteration induced by C. rodentium infection independently of inflammation.
See this image and copyright information in PMC

References

    1. Drossman DA, Hasler WL.. Rome IV - Functional GI disorders: disorders of gut-brain interaction. Gastroenterology. 2016;150(6):1257–20. doi:10.1053/j.gastro.2016.03.035. - DOI - PubMed
    1. Cryan JF, O’Riordan KJ, Cowan CSM, Sandhu KV, Bastiaanssen TFS, Boehme M, Codagnone MG, Cussotto S, Fulling C, Golubeva AV, et al. The microbiota-gut-brain axis. Physiol Rev. 2019;99(4):1877–2013. doi:10.1152/physrev.00018.2018. - DOI - PubMed
    1. Card T, Enk P, Barbara G, Boeckxstaens GEe, Santos J, Azpiroz F, Mearin F, Aziz Q, Marshall J, Spiller R. Post-infectious IBS: defining its clinical features and prognosis using an internet-based survey. J United European Gastroenterology. 2018;6(8):1245–1253. doi:10.1177/2050640618779923. - DOI - PMC - PubMed
    1. Barbara G, Grover M, Bercik P, Corsetti M, Ghoshal UC, Ohman L, Rajilić-Stojanović M. Rome Foundation Working Team Report on Post-Infection Irritable Bowel Syndrome. Gastroenterology. 2019;156(1):46–58.e7. doi:10.1053/j.gastro.2018.07.011. - DOI - PMC - PubMed
    1. Wang L, Alammar N, Singh R, Nanavati J, Song Y, Chaudhary R, Mullin GE. Gut Microbial Dysbiosis in the Irritable Bowel Syndrome: a Systematic Review and Meta-Analysis of Case-Control Studies. Journal of the Academy of Nutrition and Dietetics. 2020;120(4):565–586. doi:10.1016/j.jand.2019.05.015. - DOI - PubMed

Publication types

MeSH terms