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Theses

Dialogue entre le microbiote intestinal et l'hôte via le métabolisme du L-tryptophane

Abstract : L-tryptophan (L-trp) is an essential amino acid whose microbial and human metabolites possess immunomodulatory effects through their binding to the aryl hydrocarbon receptor (AhR). At the interface between the host and the microbiota, AhR has a strong therapeutic potential in inflammatory diseases. Deciphering the mechanisms of its activation and regulation by microbiota metabolites is crucial for understanding the consequences of dysbiosis, which is the basis of many pathologies. We have shown a synergistic activation of AhR in the presence of L-trp metabolites with short-chain fatty acids both in in vitro cell lines and in human colonic explants. Our initial investigations showed that butyrate did not affect the AhR activation cascade. The study of indirect mechanisms of AhR activation showed that butyrate did not inhibit cytochrome activity, did not act via its receptors and did not act via its proteasome inhibitory activity to activate AhR. The synergy appeared to be based on epigenetic modifications confirmed by chromatin immunoprecipitation method showing an increase in AhR recruitment at the CYP1A1 promoter when butyrate was added to FICZ and using the HDAC inhibitor trichostatin A to mimic the effect of butyrate on FICZ-mediated AhR activation. In conclusion, these results support the existence of complex interactions between multiple gut-derived metabolites that deserve further exploration.
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https://tel.archives-ouvertes.fr/tel-03724038
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Submitted on : Friday, July 15, 2022 - 3:03:17 PM
Last modification on : Tuesday, August 2, 2022 - 4:30:05 AM

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  • HAL Id : tel-03724038, version 1

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Morgane Modoux. Dialogue entre le microbiote intestinal et l'hôte via le métabolisme du L-tryptophane. Biochimie, Biologie Moléculaire. Sorbonne Université, 2022. Français. ⟨NNT : 2022SORUS112⟩. ⟨tel-03724038⟩

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