Intestinal REG3 Lectins Protect against Alcoholic Steatohepatitis by Reducing Mucosa-Associated Microbiota and Preventing Bacterial Translocation

• Published in: Cell host & microbe Vol. 19; no. 2; pp. 227 - 239
• Main Authors: Wang, Lirui, Fouts, Derrick E., Stärkel, Peter, Hartmann, Phillipp, Chen, Peng, Llorente, Cristina, DePew, Jessica, Moncera, Kelvin, Ho, Samuel B., Brenner, David A., Hooper, Lora V., Schnabl, Bernd
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.02.2016
• Subjects: Animals; Bacteria - classification; Bacteria - genetics; Bacteria - isolation & purification; Bacterial Translocation; Ethanol - adverse effects; Fatty Liver, Alcoholic - genetics; Fatty Liver, Alcoholic - metabolism; Fatty Liver, Alcoholic - microbiology; Fatty Liver, Alcoholic - prevention & control; Female; Gastrointestinal Microbiome; Humans; Liver - microbiology; Lymph Nodes - microbiology; Mice; Mice, Knockout; Mucous Membrane - microbiology; Pancreatitis-Associated Proteins; Proteins - genetics; Proteins - metabolism
• ISSN: 1931-3128; 1934-6069; 1934-6069
• DOI: 10.1016/j.chom.2016.01.003

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. [Display omitted] •REG3 lectins restrict the access of bacteria to the intestinal epithelium•REG3 proteins reduce bacterial translocation associated with ethanol administration•Decreased bacterial translocation protects mice from alcohol-induced steatohepatitis•Mucosa-adherent bacteria are increased in the duodenum of alcohol-dependent patients The mechanism by which chronic alcohol consumption alters the microbial composition in the intestine is unknown. Wang et al. demonstrate that alcohol reduces intestinal expression of REG3 lectins, increasing the number of mucosa-associated bacteria. The subsequent translocation of bacteria to mesenteric lymph nodes and liver exacerbates alcoholic liver disease.