Gladys Ferrere1, Laura Wrzosek1, Frédéric Cailleux1, Williams Turpin2, Virginie Puchois1, Madeleine Spatz1, Dragos Ciocan1, Dominique Rainteau3, Lydie Humbert4, Cindy Hugot1, Françoise Gaudin1, Marie-Louise Noordine5, Véronique Robert5, Dominique Berrebi6, Muriel Thomas5, Sylvie Naveau7, Gabriel Perlemuter7, Anne-Marie Cassard8. 1. INSERM U996, DHU Hepatinov, Univ Paris-Sud, Université Paris-Saclay, 92140 Clamart, France; Institut Paris-Sud d'Innovation Thérapeutique (IPSIT), IFR141, Faculté de Pharmacie, Univ Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France. 2. Division of Gastroenterology, Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, ON M5T 3L9, Canada; Department of Medicine, University of Toronto, ON M5S 1A8, Canada. 3. Sorbonne Universités, UPMC Université Paris 6, Paris, France; Inflammation-Immunopathology-Biotherapy Department (DHU i2B), INSERM-ERL 1157, Paris, France; UMR 7203 Laboratoire des Biomolécules, UPMC/CNRS/ENS, Paris, France; Département PM2 Plateforme de Métabolomique, APHP, Hôpital Saint Antoine, Peptidomique et dosage de Médicaments, Paris, France. 4. Sorbonne Universités, UPMC Université Paris 6, Paris, France; Inflammation-Immunopathology-Biotherapy Department (DHU i2B), INSERM-ERL 1157, Paris, France; UMR 7203 Laboratoire des Biomolécules, UPMC/CNRS/ENS, Paris, France. 5. INRA, UMR 1319 MICALIS, AgroParisTech, Jouy-en-Josas, France. 6. INSERM U996, DHU Hepatinov, Univ Paris-Sud, Université Paris-Saclay, 92140 Clamart, France; AP-HP, Anatomie et de Cytologie Pathologiques, Hôpital Robert Debré, Paris, France. 7. INSERM U996, DHU Hepatinov, Univ Paris-Sud, Université Paris-Saclay, 92140 Clamart, France; Institut Paris-Sud d'Innovation Thérapeutique (IPSIT), IFR141, Faculté de Pharmacie, Univ Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France; AP-HP, Hepatogastroenterology and Nutrition, Hôpital Antoine-Béclère, Clamart, France. 8. INSERM U996, DHU Hepatinov, Univ Paris-Sud, Université Paris-Saclay, 92140 Clamart, France; Institut Paris-Sud d'Innovation Thérapeutique (IPSIT), IFR141, Faculté de Pharmacie, Univ Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France. Electronic address: cassard.doulcier@u-psud.fr.
Abstract
BACKGROUND & AIMS: Alcoholic liver disease (ALD) is a leading cause of liver failure and mortality. In humans, severe alcoholic hepatitis is associated with key changes to intestinal microbiota (IM), which influences individual sensitivity to develop advanced ALD. We used the different susceptibility to ALD observed in two distinct animal facilities to test the efficiency of two complementary strategies (fecal microbiota transplantation and prebiotic treatment) to reverse dysbiosis and prevent ALD. METHODS: Mice were fed alcohol in two distinct animal facilities with a Lieber DeCarli diet. Fecal microbiota transplantation was performed with fresh feces from alcohol-resistant donor mice to alcohol-sensitive receiver mice three times a week. Another group of mice received pectin during the entire alcohol consumption period. RESULTS: Ethanol induced steatosis and liver inflammation, which were associated with disruption of gut homeostasis, in alcohol-sensitive, but not alcohol resistant mice. IM analysis showed that the proportion of Bacteroides was specifically lower in alcohol-sensitive mice (p<0.05). Principal coordinate analysis showed that the IM of sensitive and resistant mice clustered differently. We targeted IM using two different strategies to prevent alcohol-induced liver lesions: (1) pectin treatment which induced major modifications of the IM, (2) fecal microbiota transplantation which resulted in an IM very close to that of resistant donor mice in the sensitive recipient mice. Both methods prevented steatosis, liver inflammation, and restored gut homeostasis. CONCLUSIONS: Manipulation of IM can prevent alcohol-induced liver injury. The IM should be considered as a new therapeutic target in ALD. LAY SUMMARY: Sensitivity to alcoholic liver disease (ALD) is driven by intestinal microbiota in alcohol fed mice. Treatment of mice with alcohol-induced liver lesions by fecal transplant from alcohol fed mice resistant to ALD or with prebiotic (pectin) prevents ALD. These findings open new possibilities for treatment of human ALD through intestinal microbiota manipulation.
BACKGROUND & AIMS:Alcoholic liver disease (ALD) is a leading cause of liver failure and mortality. In humans, severe alcoholic hepatitis is associated with key changes to intestinal microbiota (IM), which influences individual sensitivity to develop advanced ALD. We used the different susceptibility to ALD observed in two distinct animal facilities to test the efficiency of two complementary strategies (fecal microbiota transplantation and prebiotic treatment) to reverse dysbiosis and prevent ALD. METHODS:Mice were fed alcohol in two distinct animal facilities with a Lieber DeCarli diet. Fecal microbiota transplantation was performed with fresh feces from alcohol-resistant donormice to alcohol-sensitive receiver mice three times a week. Another group of mice received pectin during the entire alcohol consumption period. RESULTS:Ethanol induced steatosis and liver inflammation, which were associated with disruption of gut homeostasis, in alcohol-sensitive, but not alcohol resistant mice. IM analysis showed that the proportion of Bacteroides was specifically lower in alcohol-sensitive mice (p<0.05). Principal coordinate analysis showed that the IM of sensitive and resistant mice clustered differently. We targeted IM using two different strategies to prevent alcohol-induced liver lesions: (1) pectin treatment which induced major modifications of the IM, (2) fecal microbiota transplantation which resulted in an IM very close to that of resistant donormice in the sensitive recipient mice. Both methods prevented steatosis, liver inflammation, and restored gut homeostasis. CONCLUSIONS: Manipulation of IM can prevent alcohol-induced liver injury. The IM should be considered as a new therapeutic target in ALD. LAY SUMMARY: Sensitivity to alcoholic liver disease (ALD) is driven by intestinal microbiota in alcohol fed mice. Treatment of mice with alcohol-induced liver lesions by fecal transplant from alcohol fed mice resistant to ALD or with prebiotic (pectin) prevents ALD. These findings open new possibilities for treatment of humanALD through intestinal microbiota manipulation.