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. 2021 Jul;70(7):1299-1308.
doi: 10.1136/gutjnl-2020-321565. Epub 2020 Oct 1.

Microbiota tryptophan metabolism induces aryl hydrocarbon receptor activation and improves alcohol-induced liver injury

Laura Wrzosek #  1 , Dragos Ciocan #  1   2 , Cindy Hugot  1 , Madeleine Spatz  1 , Margot Dupeux  1 , Camille Houron  1 , Vanessa Lievin-Le Moal  1 , Virginie Puchois  1 , Gladys Ferrere  1 , Nicolas Trainel  1 , Françoise Mercier-Nomé  3 , Sylvere Durand  4 , Guido Kroemer  4   5 , Cosmin Sebastian Voican  1   2 , Patrick Emond  6   7 , Marjolène Straube  8 , Harry Sokol  8   9 , Gabriel Perlemuter  10   2 , Anne-Marie Cassard  10
Affiliations

Microbiota tryptophan metabolism induces aryl hydrocarbon receptor activation and improves alcohol-induced liver injury

Laura Wrzosek et al. Gut. 2021 Jul.

Abstract

Objective: Chronic alcohol consumption is an important cause of liver-related deaths. Specific intestinal microbiota profiles are associated with susceptibility or resistance to alcoholic liver disease in both mice and humans. We aimed to identify the mechanisms by which targeting intestinal microbiota can improve alcohol-induced liver lesions.

Design: We used human associated mice, a mouse model of alcoholic liver disease transplanted with the intestinal microbiota of alcoholic patients and used the prebiotic, pectin, to modulate the intestinal microbiota. Based on metabolomic analyses, we focused on microbiota tryptophan metabolites, which are ligands of the aryl hydrocarbon receptor (AhR). Involvement of the AhR pathway was assessed using both a pharmacological approach and AhR-deficient mice.

Results: Pectin treatment modified the microbiome and metabolome in human microbiota-associated alcohol-fed mice, leading to a specific faecal signature. High production of bacterial tryptophan metabolites was associated with an improvement of liver injury. The AhR agonist Ficz (6-formylindolo (3,2-b) carbazole) reduced liver lesions, similarly to prebiotic treatment. Conversely, inactivation of the ahr gene in alcohol-fed AhR knock-out mice abrogated the beneficial effects of the prebiotic. Importantly, patients with severe alcoholic hepatitis have low levels of bacterial tryptophan derivatives that are AhR agonists.

Conclusions: Improvement of alcoholic liver disease by targeting the intestinal microbiota involves the AhR pathway, which should be considered as a new therapeutic target.

Keywords: alcohol-induced injury; alcoholic liver disease; intestinal bacteria; mucus; prebiotic.

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Conflict of interest statement

Competing interests: Disclosures: DC received travel funds from Biocodex and Gilead, lecture fees from Gilead, and royalties from John Libbey Eurotext. GK is a cofounder of everImmune. HS received unrestricted study grants from Danone, Biocodex, and Enterome and board membership, 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 cofounder of Exeliom Biosciences. GP received travel funds from Janssen and Gilead, consulting fees from Bayer, Biocodex, Roche, Gilead, Pierre Fabre, and Servier, and royalties from Elsevier-Masson, Solar, Flammation/Versilio, and John Libbey Eurotext. A-MC received travel funds and consulting fees from Biocodex and royalties from Elsevier-Masson, Solar, Flammation/Versilio and John Libbey Eurotext. All other authors declare no conflicts of interest.

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