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Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease
  1. M Llopis1,2,3,4,
  2. A M Cassard1,2*,
  3. L Wrzosek1,2,
  4. L Boschat3,4,
  5. A Bruneau3,4,
  6. G Ferrere1,2,
  7. V Puchois1,2,
  8. J C Martin5,6,
  9. P Lepage3,4,
  10. T Le Roy3,4,
  11. L Lefèvre7,
  12. B Langelier3,4,
  13. F Cailleux1,2,
  14. A M González-Castro8,
  15. S Rabot3,4,
  16. F Gaudin9,
  17. H Agostini10,
  18. S Prévot2,11,
  19. D Berrebi1,12,
  20. D Ciocan1,2,13,
  21. C Jousse14,
  22. S Naveau1,2,13,
  23. P Gérard3,4,
  24. G Perlemuter1,2,13*
  1. 1INSERM UMR996—Inflammation, Chemokines and Immunopathology, Clamart, France
  2. 2Univ Paris-Sud, Univ Paris-Saclay, DHU Hepatinov, Labex Lermit, CHU Bicêtre, Kremlin-Bicêtre, France
  3. 3INRA, UMR1319 Micalis, Jouy-en-Josas, France
  4. 4AgroParisTech, UMR Micalis, Jouy-en-Josas, France
  5. 5Faculté de Médecine, Aix-Marseille University, Marseille, France
  6. 6INSERM, UMR1062 NORT, Marseille, France
  7. 7INRA, UMR 1313, GABI-LGS Plateforme ICE, Jouy-en-Josas, France
  8. 8Department of Gastroenterology, Digestive System Research Unit, Hospital University Vall d'Hebron and VHIR, UAB, Spain
  9. 9IPSIT, IFR141, Faculté de Pharmacie, Univ Paris-Sud, Châtenay-Malabry, France
  10. 10AP-HP, Hôpital Bicêtre, Unité de recherche clinique Paris-Sud, Kremlin-Bicêtre, France
  11. 11AP-HP, Anatomie-pathologique, Hôpital Antoine-Béclère, Clamart, France
  12. 12AP-HP, Anatomie et de Cytologie Pathologiques, Hôpital Robert Debré, Paris, France
  13. 13AP-HP, Hepatogastroenterology and Nutrition, Hôpital Antoine-Béclère, Clamart, France
  14. 14Université Clermont Auvergne, Institut de Chimie de Clermont-Ferrand UMR CNRS 6296, Clermont-Ferrand, France
  1. Correspondence to Professor Gabriel Perlemuter Service d'Hépato-Gastroentérologie et Nutrition, Hôpital Antoine-Béclère, 157 rue de la Porte de Trivaux, Clamart cedex F-92141, France; gabriel.perlemuter{at} Doctor Anne-Marie Cassard Inserm URM996, 32 rue des carnets, Clamart, F-92140, France;


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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