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Etude des perturbations du microbiote intestinal à la suite d'une infection par des Entérobactéries : conséquences sur le "bien-être" et le comportement de l'hôte

Abstract : Disturbances of brain-gut-microbiota axis are the focus of many studies to develop new treatments for chronic intestinal pathologies such as irritable bowel syndrome (IBS). In some cases, after a gastrointestinal Enterobacteriaceae infection, despite pathogen elimination, transit disorders and chronic abdominal pain persist and can lead to the development of anxiety and depression symptoms. This is referred to post-infectious IBS (PI-IBS). By developing a preclinical model of Citrobacter rodentium infection, the aim of my thesis project focused on (1) study the impact of a cytokine IL-22 on the symptoms associated with PI-IBS, (2) study of tryptophan (Trp) metabolism and especially the AhR expression induced by its microbiota-derived ligands and (3) study of gut microbiota and its fecal metabolome on the disorders of intestinal homeostasis following the gastrointestinal infection. We have shown that the mouse model of C. rodentium infection developed, during the post-infectious period, a persistent colonic hypersensitivity (CHS), anxiety-related behavior as well as cognitive-related alterations, associated with a dysbiosis, a low-grade inflammation and an increased intestinal permeability demonstrating that it is a relevant model to investigate physiopathological mechanisms of PI-IBS. First, targeted metabolomics analysis revealed fecal functional perturbations during post-infectious phase. Trytophan metabolism is altered with an indole pathway downregulation and AhR activity as well as a decrease of tryptophol production. The production of IL-22 cytokine can be activated by AhR pathway and represents a pivotal mechanism in the maintenance of intestinal homeostasis. Thus, efficacy of IL-22 delivery using a Lactococcus lactis strain carrying an eukaryotic expression plasmid for murine IL-22 (L. lactisIL-22) was tested in this animal model of PI-IBS. L. lactisIL-22 treatment alleviates disturbances associated with C. rodentium infection during the post-infectious phase. Our results suggest that targeting AhR/IL-22 signaling pathway improves the PI-IBS symptoms by acting on the intestinal epithelial barrier integrity and microbiota-derived Trp metabolites. Metabolomics studies were expanded to identify infection-induced functional disturbances of fecal microbiota. This work allowed to clarify pathophysiology associated with PI-IBS and to identify new potential therapeutic targets such as AhR/IL-22 pathway. In addition, role of others infections on host cognitive and emotional behaviors was studied in two animal models. A chronic parasitic infection with Blastocystis in rats was used to mimic IBS, as well as a chronic infection with colibactin-producing Escherichia coli (CoPEC), another Enterobacteria associated with colorectal cancer (CRC).
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https://tel.archives-ouvertes.fr/tel-03859842
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Submitted on : Friday, November 18, 2022 - 1:40:06 PM
Last modification on : Saturday, November 19, 2022 - 3:26:38 AM

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2022UCFAC008_MEYNIER.pdf
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  • HAL Id : tel-03859842, version 1

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Maëva Meynier. Etude des perturbations du microbiote intestinal à la suite d'une infection par des Entérobactéries : conséquences sur le "bien-être" et le comportement de l'hôte. Médecine humaine et pathologie. Université Clermont Auvergne, 2022. Français. ⟨NNT : 2022UCFAC008⟩. ⟨tel-03859842⟩

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