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 Liévin-Le Moal (1) , Virginie Puchois (1) , Gladys Ferrere (1) , Nicolas Trainel (1) , Françoise Mercier-Nomé (3) , Sylvère Durand (4, 5) , Guido Kroemer (4, 5) , Cosmin Sebastian Voican (1, 2) , Patrick Emond (6) , Marjolene Straube (7) , Harry Sokol (4, 5) , Gabriel Perlemuter (1, 2) , Anne-Marie Cassard (1)

1 MI2 - Inflammation, microbiome, immunosurveillance
2 AP-HP - Hôpital Antoine Béclère [Clamart]
3 IPSIT - Ingénierie et Plateformes au Service de l'Innovation Thérapeutique de Paris Saclay
4 IGR - Institut Gustave Roussy
5 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
6 CHRU Tours - Centre Hospitalier Régional Universitaire de Tours
7 CRSA - Centre de Recherche Saint-Antoine

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.

Mots clés: alcoholic hepatitis; indole; fecal microbiota transplantation; human microbiota associated mice; fiber; pectin; alcohol-induced injury; alcoholic liver disease; intestinal bacteria; mucus; prebiotic

Domaines: Médecine humaine et pathologie

Laura Wrzosek, Dragos Ciocan, Cindy Hugot, Madeleine Spatz, Margot Dupeux, et al.. Microbiota tryptophan metabolism induces aryl hydrocarbon receptor activation and improves alcohol-induced liver injury. Gut, 2021, 70 (7), pp.1299-1308. ⟨10.1136/gutjnl-2020-321565⟩. ⟨hal-03329872⟩