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.
- alcoholic liver disease
- alcohol-induced injury
- intestinal bacteria
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LW and DC contributed equally.
Contributors LW and DC: contributed equally to this work for the study concept and design, acquisition, analysis, and interpretation of data, and drafting of the manuscript. CHu, MSp, CHo, VL-LM, VP, GF, NT and MSt: technical support. MD and FMN: histological analysis. SD, PE and GK: faecal metabolite quantification. CSV: provided patients. HS: provided AhR KO mice. HS and PE: tryptophan metabolite analysis. GP: critical revision of the manuscript, obtained funding and provided patients. A-MC: study concept, design, and supervision, analysis and interpretation of the data, drafting of the manuscript and funding raising.
Funding This work was supported by INSERM, Université Paris-Sud, 'Fondation pour la recherche médicale' (FRM (DEQ-20170336743)), the National French Society of Gastroenterology (SNFGE), 'Association Française pour l'Etude du Foie' (AFEF), 'Fondation pour la Recherche en Alcoologie' (FRA/IREB (2017/29)), 'Institut de Recherches Internationales Servier' (IRIS), and 'Groupement transversal INSERM sur le microbiote' (GPT microbiota). DC received a grant from Biocodex. MSp received a grant from the Laboratory of Excellence LERMIT supported by the 'Agence Nationale de la Recherche' (ANR-10-LABX-33). MD received a grant from FRM. CHo received a CIFRE (Conventions Industrielles de Formation par la Recherche) scholarship in collaboration with the IRIS. HS received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (ERC-2016-StG-71577).
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.
Patient consent for publication Not required.
Ethics approval The study was carried out in accordance with the Helsinki Declaration and was approved by the Ile de France VII ethics committee (Bicêtre Hospital, 94 270 le Kremlin-Bicêtre, France).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as online supplemental information. N/A.
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