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Impact du microbiote sur les fonctions immuno-régulatrices des cellules épithéliales intestinales humaines

Abstract : Exchange with the gut microbiota are key for immune system development and host intestinal homeostasis. Bacterial molecules sensed by epithelial cells in the intestine are challenging permanently the host immune system. In response, epithelial cells secrete numerous immuno-regulator factors favouring gut tolerance. However, the molecular mechanisms involved in these processes, remain poorly understand. We studied bacterial-dependent regulation of TGFB1 and IDO1 genes as well as the TLR independent activation of the NFκB pathway, in epithelial cells. We screened the activities of a hundred of gut bacterial species on human epithelial cell lines. We showed that short chain fatty acids, and specially butyrate secreted by Clostridiales and Fusobacterium, were potent modulators of TGFb1 and IDO1 via their histone deacetylase inhibition properties. Butyrate upregulated TGFB1 by a mechanism dependent of the SP1 transcription factor. Moreover, butyrate inhibited IDO1 by two distinct mechanisms, by down-regulating the STAT1/IFNγ pathway and by preventing IDO1 expression independently of IFNγ. Eventually, we described that specific group of gut bacteria activated NFκB in a short-chain fatty acids, TLR and MYD88 independent manner. Interestingly, some Gram+ bacteria stimulated NFκB via the NOD1 pathway. Furthermore, we identified for the first time in a non-pathogenic context, commensal bacteria promoting NFκB by the newly discovered ALPK1-TIFA-TRAF6 axis. Overall, our work support the specific functions of the intestinal epithelial cells in the regulation of the host-microbiote symbiosis.
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Camille Martin-Gallausiaux. Impact du microbiote sur les fonctions immuno-régulatrices des cellules épithéliales intestinales humaines. Médecine humaine et pathologie. Sorbonne Université, 2018. Français. ⟨NNT : 2018SORUS124⟩. ⟨tel-02926055⟩

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