title: Intestinal REG3 Lectins Protect against Alcoholic Steatohepatitis by Reducing Mucosa-Associated Microbiota and Preventing Bacterial Translocation.
abstract: Approximately half of all deaths from liver cirrhosis, the tenth leading cause of mortality in the United States, are related to alcohol use. Chronic alcohol consumption is accompanied by intestinal dysbiosis and bacterial overgrowth, yet little is known about the factors that alter the microbial composition or their contribution to liver disease. We previously associated chronic alcohol consumption with lower intestinal levels of the antimicrobial-regenerating islet-derived (REG)-3 lectins. Here, we demonstrate that intestinal deficiency in REG3B or REG3G increases numbers of mucosa-associated bacteria and enhances bacterial translocation to the mesenteric lymph nodes and liver, promoting the progression of ethanol-induced fatty liver disease toward steatohepatitis. Overexpression of Reg3g in intestinal epithelial cells restricts bacterial colonization of mucosal surfaces, reduces bacterial translocation, and protects mice from alcohol-induced steatohepatitis. Thus, alcohol appears to impair control of the mucosa-associated microbiota, and subsequent breach of the mucosal barrier facilitates progression of alcoholic liver disease.
authors: Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, CA 92161, USA.
authors: Lirui
authors: L
authors: Wang
authors: J. Craig Venter Institute, Rockville, MD 20850, USA.
authors: Derrick E
authors: DE
authors: Fouts
authors: St. Luc University Hospital, Université Catholique de Louvain, Brussels 1200, Belgium.
authors: Peter
authors: P
authors: Stärkel
authors: Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
authors: Phillipp
authors: P
authors: Hartmann
authors: Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
authors: Peng
authors: P
authors: Chen
authors: Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, CA 92161, USA.
authors: Cristina
authors: C
authors: Llorente
authors: J. Craig Venter Institute, Rockville, MD 20850, USA.
authors: Jessica
authors: J
authors: DePew
authors: J. Craig Venter Institute, Rockville, MD 20850, USA.
authors: Kelvin
authors: K
authors: Moncera
authors: Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, CA 92161, USA.
authors: Samuel B
authors: SB
authors: Ho
authors: Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
authors: David A
authors: DA
authors: Brenner
authors: Howard Hughes Medical Institute; Department of Immunology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Lora V
authors: LV
authors: Hooper
authors: Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, CA 92161, USA. Electronic address: beschnabl@ucsd.edu.
authors: Bernd
authors: B
authors: Schnabl
mesh_terms: D000818:Animals; D001419:Bacteria / Q000145:classification / Q000235:genetics / Q000302:isolation & purification; D018988:Bacterial Translocation; D000431:Ethanol / Q000009:adverse effects; D005235:Fatty Liver, Alcoholic / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology / Q000517:prevention & control*; D005260:Female; D000069196:Gastrointestinal Microbiome; D006801:Humans; D008099:Liver / Q000382:microbiology; D008198:Lymph Nodes / Q000382:microbiology*; D051379:Mice; D018345:Mice, Knockout; D009092:Mucous Membrane / Q000382:microbiology*; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000073718:Pancreatitis-Associated Proteins; D011506:Proteins; C490253:Reg3b protein, mouse; C490255:Reg3g protein, mouse; D000431:Ethanol