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Activation mechanism of AhR pathway in intestinal epithelial cells by commensal bacteria

Abstract : The intestinal microbiota shapes the host physiology through the production of various metabolites. The transcription factor Aryl hydrocarbon Receptor (AhR) emerges as an actor of the host-microbiota crosstalk. Indeed, numerous bacterial molecules are described to activate AhR pathway and being involved in the intestinal homeostasis. Among them, indoles and other tryptophan-derived metabolites produced by commensal and probiotic strains were described for protecting mice from induced colitis and their abundance being inversely correlated with inflammatory bowel diseases (IBD) in humans. However, the current knowledge on bacterial molecules activating AhR pathway, is still limited, considering the complexity of the intestinal microbial community. By screening a collection of commensal bacteria on human intestinal epithelial cell lines, we identified microbial modulators of AhR pathway. The use of cells expressing an AhR reporter system allowed the identification of activating bacterial strains and discriminate different mechanisms of action. Firstly, bacteria producing short chain fatty acids (SCFA) emerged as strong activators of AhR pathway and we showed for the first time that butyrate acts as a novel AhR ligand. Additionally, some bacteria not predicted to produce butyrate nor indoles, were identified as AhR activators in our screen. Among them, some species belonging to the Actinobacteria phylum seem a promising group of AhR activators, through the production of a microbial metabolite not yet identified. In conclusion, this work sheds light on a novel role of butyrate as AhR ligand and introduces a newly potential family of AhR activator produced by Actinobacteria.
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Ludovica Marinelli. Activation mechanism of AhR pathway in intestinal epithelial cells by commensal bacteria. Biochemistry, Molecular Biology. Sorbonne Université, 2018. English. ⟨NNT : 2018SORUS451⟩. ⟨tel-02926063⟩

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