title: Supplementation of saturated long-chain fatty acids maintains intestinal eubiosis and reduces ethanol-induced liver injury in mice.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California.
authors.forename: Peng
authors.initials: P
authors.lastname: Chen
authors.affiliation: J. Craig Venter Institute, Rockville, Maryland.
authors.forename: Manolito
authors.initials: M
authors.lastname: Torralba
authors.affiliation: Department of Bioengineering, University of California San Diego, La Jolla, California.
authors.forename: Justin
authors.initials: J
authors.lastname: Tan
authors.affiliation: Department of Bioengineering, University of California San Diego, La Jolla, California.
authors.forename: Mallory
authors.initials: M
authors.lastname: Embree
authors.affiliation: Department of Bioengineering, University of California San Diego, La Jolla, California.
authors.forename: Karsten
authors.initials: K
authors.lastname: Zengler
authors.affiliation: St Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Stärkel
authors.affiliation: Department of Food Science, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Jan-Peter
authors.initials: JP
authors.lastname: van Pijkeren
authors.affiliation: J. Craig Venter Institute, Rockville, Maryland.
authors.forename: Jessica
authors.initials: J
authors.lastname: DePew
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California.
authors.forename: Rohit
authors.initials: R
authors.lastname: Loomba
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California; Department of Medicine, VA San Diego Healthcare System, San Diego, California.
authors.forename: Samuel B
authors.initials: SB
authors.lastname: Ho
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia.
authors.forename: Jasmohan S
authors.initials: JS
authors.lastname: Bajaj
authors.affiliation: Department of Medicine, Rush University Medical Center, Chicago, Illinois.
authors.forename: Ece A
authors.initials: EA
authors.lastname: Mutlu
authors.affiliation: Department of Medicine, Rush University Medical Center, Chicago, Illinois.
authors.forename: Ali
authors.initials: A
authors.lastname: Keshavarzian
authors.affiliation: 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.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tsukamoto
authors.affiliation: J. Craig Venter Institute, Rockville, Maryland.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Nelson
authors.affiliation: J. Craig Venter Institute, Rockville, Maryland.
authors.forename: Derrick E
authors.initials: DE
authors.lastname: Fouts
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California. Electronic address: beschnabl@ucsd.edu.
authors.forename: Bernd
authors.initials: B
authors.lastname: Schnabl
mesh_terms: D000818:Animals; D001419:Bacteria / Q000145:classification / Q000302:isolation & purification / Q000378:metabolism*; D018988:Bacterial Translocation; D019587:Dietary Supplements; D004195:Disease Models, Animal; D064806:Dysbiosis; D000431:Ethanol; D005227:Fatty Acids / Q000008:administration & dosage* / Q000096:biosynthesis; D005243:Feces / Q000737:chemistry / Q000382:microbiology; D054884:Host-Pathogen Interactions; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000382:microbiology*; D007778:Lactobacillus / Q000378:metabolism; D008108:Liver Diseases, Alcoholic / Q000209:etiology / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control*; D008297:Male; D055432:Metabolomics; D054892:Metagenome; D008810:Mice, Inbred C57BL; D010539:Permeability; D013997:Time Factors
chemical_list: D005227:Fatty Acids; D000431:Ethanol
keywords: Metabolomics; Metagenomics; Microbiome; Microbiota