Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease
2016
Llopis, M | Cassard, Anne-Marie | Wrzosek, L | Boschat, L | Bruneau, A | Ferrere, G | Puchois, V | Martin, J | Lepage, P | Le Roy, T | Lefèvre, L | Langelier, B | Cailleux, F | González-Castro, A | Rabot, S | Gaudin, F | Agostini, H | Prévot, S | Berrebi, D | Ciocan, D | Jousse, C | Naveau, S | Gérard, P | Perlemuter, G | Cytokines, chimiokines et immunopathologie ; Université Paris-Sud - Paris 11 (UP11)-IFR13-Institut National de la Santé et de la Recherche Médicale (INSERM) | Hepatinov (DHU) ; Université Paris-Sud - Paris 11 (UP11)-Centre Hépato-Biliaire Paul Brousse | MICrobiologie de l'ALImentation au Service de la Santé (MICALIS) ; Institut National de la Recherche Agronomique (INRA)-AgroParisTech | Université Paris-Saclay | Institut National de la Santé et de la Recherche Médicale (INSERM) | Laboratory of Excellence in Research on Medication and Innovative Therapeutics (LERMIT) ; Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM) | U996 DHU Hépatinov ; Université Paris Sud (Paris 11) | FHU Paris Center for Microbiome Medicine (FHU PaCeMM) ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU) | Inflammation, microbiome, immunosurveillance (MI2) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay | Centre de recherche sur l'endocrinologie moléculaire et le développement (CREMD) ; Centre National de la Recherche Scientifique (CNRS) | Biologie des Transporteurs Mitochondriaux et Métabolisme (BIOTRAM) ; Centre National de la Recherche Scientifique (CNRS) | Physiologie de la Nutrition et du Comportement Alimentaire (PNCA) ; Institut National de la Recherche Agronomique (INRA)-Institut National Agronomique Paris-Grignon (INA P-G) | Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille) ; Université de Lille-UNICANCER | Génétique Animale et Biologie Intégrative (GABI) ; Institut National de la Recherche Agronomique (INRA)-AgroParisTech | University of Waterloo [Waterloo] | Department of Materials Science and Engineering and Canadian Centre for Electron Microscopy, McMaster University ; Department of Materials Science | Vall d'Hebron University Hospital [Barcelona] | Ingénierie et Plateformes au Service de l'Innovation Thérapeutique de Paris Saclay (IPSIT) ; Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS) | AP-HP, Hôpital Bicêtre, Unité de recherche clinique Paris-Sud, | Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL) ; UNICANCER | AP-HP, Anatomie et de Cytologie Pathologiques, Hôpital Robert Debré | AP-HP, Hepatogastroenterology and Nutrition, Hôpital Antoine-Béclère | Institut de Chimie de Clermont-Ferrand (ICCF) ; Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-SIGMA Clermont (SIGMA Clermont)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS) | DHU Hepatinov | AP-HP - Hôpital Antoine Béclère [Clamart] ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP) | FRM (Foundation for Medical Research)Institut National de la Sante et de la Recherche Medicale (Inserm)Univ Paris-SudERAB (European Research Advisory Board)
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Show more [+] Less [-]English. Objective There is substantial inter-individual diversity in the susceptibility of alcoholics to liver injury. Alterations of intestinal microbiota (IM) have been reported in alcoholic liver disease (ALD), but the extent to which they are merely a consequence or a cause is unknown. We aimed to demonstrate that a specific dysbiosis contributes to the development of alcoholic hepatitis (AH).Design We humanised germ-free and conventional mice using human IM transplant from alcoholic patients with or without AH. The consequences on alcohol-fed recipient mice were studied.Results A specific dysbiosis was associated with ALD severity in patients. Mice harbouring the IM from a patient with severe AH (sAH) developed more severe liver inflammation with an increased number of liver T lymphocyte subsets and Natural Killer T (NKT) lymphocytes, higher liver necrosis, greater intestinal permeability and higher translocation of bacteria than mice harbouring the IM from an alcoholic patient without AH (noAH). Similarly, CD45+ lymphocyte subsets were increased in visceral adipose tissue, and CD4(+) T and NKT lymphocytes in mesenteric lymph nodes. The IM associated with sAH and noAH could be distinguished by differences in bacterial abundance and composition. Key deleterious species were associated with sAH while the Faecalibacterium genus was associated with noAH. Ursodeoxycholic acid was more abundant in faeces from noAH mice. Additionally, in conventional mice humanised with the IM from an sAH patient, a second subsequent transfer of IM from an noAH patient improved alcohol-induced liver lesions.Conclusions Individual susceptibility to ALD is substantially driven by IM. It may, therefore, be possible to prevent and manage ALD by IM manipulation.
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