Peng Chen1, Manolito Torralba2, Justin Tan3, Mallory Embree3, Karsten Zengler3, Peter Stärkel4, Jan-Peter van Pijkeren5, Jessica DePew2, Rohit Loomba1, Samuel B Ho6, Jasmohan S Bajaj7, Ece A Mutlu8, Ali Keshavarzian8, Hidekazu Tsukamoto9, Karen E Nelson2, Derrick E Fouts2, Bernd Schnabl10. 1. Department of Medicine, University of California San Diego, La Jolla, California. 2. J. Craig Venter Institute, Rockville, Maryland. 3. Department of Bioengineering, University of California San Diego, La Jolla, California. 4. St Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium. 5. Department of Food Science, University of Wisconsin-Madison, Madison, Wisconsin. 6. Department of Medicine, University of California San Diego, La Jolla, California; Department of Medicine, VA San Diego Healthcare System, San Diego, California. 7. Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia. 8. Department of Medicine, Rush University Medical Center, Chicago, Illinois. 9. Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, Department of Pathology, Keck School of Medicine of the University of Southern California, Greater Los Angeles VA Healthcare System, Los Angeles, California. 10. Department of Medicine, University of California San Diego, La Jolla, California. Electronic address: beschnabl@ucsd.edu.
Abstract
BACKGROUND & AIMS: Alcoholic liver disease is a leading cause of mortality. Chronic alcohol consumption is accompanied by intestinal dysbiosis, and development of alcoholic liver disease requires gut-derived bacterial products. However, little is known about how alterations to the microbiome contribute to pathogenesis of alcoholic liver disease. METHODS: We used the Tsukamoto-French mouse model, which involves continuous intragastric feeding of isocaloric diet or alcohol for 3 weeks. Bacterial DNA from the cecum was extracted for deep metagenomic sequencing. Targeted metabolomics assessed concentrations of saturated fatty acids in cecal contents. To maintain intestinal metabolic homeostasis, diets of ethanol-fed and control mice were supplemented with saturated long-chain fatty acids (LCFA). Bacterial genes involved in fatty acid biosynthesis, amounts of lactobacilli, and saturated LCFA were measured in fecal samples of nonalcoholic individuals and patients with active alcohol abuse. RESULTS: Analyses of intestinal contents from mice revealed alcohol-associated changes to the intestinal metagenome and metabolome, characterized by reduced synthesis of saturated LCFA. Maintaining intestinal levels of saturated fatty acids in mice resulted in eubiosis, stabilized the intestinal gut barrier, and reduced ethanol-induced liver injury. Saturated LCFA are metabolized by commensal Lactobacillus and promote their growth. Proportions of bacterial genes involved in fatty acid biosynthesis were lower in feces from patients with active alcohol abuse than controls. Total levels of LCFA correlated with those of lactobacilli in fecal samples from patients with active alcohol abuse but not in controls. CONCLUSIONS: In humans and mice, alcohol causes intestinal dysbiosis, reducing the capacity of the microbiome to synthesize saturated LCFA and the proportion of Lactobacillus species. Dietary approaches to restore levels of saturated fatty acids in the intestine might reduce ethanol-induced liver injury in patients with alcoholic liver disease.
BACKGROUND & AIMS:Alcoholic liver disease is a leading cause of mortality. Chronic alcohol consumption is accompanied by intestinal dysbiosis, and development of alcoholic liver disease requires gut-derived bacterial products. However, little is known about how alterations to the microbiome contribute to pathogenesis of alcoholic liver disease. METHODS: We used the Tsukamoto-French mouse model, which involves continuous intragastric feeding of isocaloric diet or alcohol for 3 weeks. Bacterial DNA from the cecum was extracted for deep metagenomic sequencing. Targeted metabolomics assessed concentrations of saturated fatty acids in cecal contents. To maintain intestinal metabolic homeostasis, diets of ethanol-fed and control mice were supplemented with saturated long-chain fatty acids (LCFA). Bacterial genes involved in fatty acid biosynthesis, amounts of lactobacilli, and saturated LCFA were measured in fecal samples of nonalcoholic individuals and patients with active alcohol abuse. RESULTS: Analyses of intestinal contents from mice revealed alcohol-associated changes to the intestinal metagenome and metabolome, characterized by reduced synthesis of saturated LCFA. Maintaining intestinal levels of saturated fatty acids in mice resulted in eubiosis, stabilized the intestinal gut barrier, and reduced ethanol-induced liver injury. Saturated LCFA are metabolized by commensal Lactobacillus and promote their growth. Proportions of bacterial genes involved in fatty acid biosynthesis were lower in feces from patients with active alcohol abuse than controls. Total levels of LCFA correlated with those of lactobacilli in fecal samples from patients with active alcohol abuse but not in controls. CONCLUSIONS: In humans and mice, alcohol causes intestinal dysbiosis, reducing the capacity of the microbiome to synthesize saturated LCFA and the proportion of Lactobacillus species. Dietary approaches to restore levels of saturated fatty acids in the intestine might reduce ethanol-induced liver injury in patients with alcoholic liver disease.
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