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
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.
J. Craig Venter Institute, Rockville, MD 20850, USA.
Cell Host Microbe. 2016 Feb 10;19(2):227-39. 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.
在美国，肝硬化是导致死亡的第十大主要原因，约一半的肝硬化死亡与饮酒有关。长期饮酒会伴随着肠道菌群失调和细菌过度生长，但对于改变微生物组成的因素及其对肝脏疾病的影响却知之甚少。我们之前发现长期饮酒会导致肠道中抗菌的再生胰岛衍生蛋白（REG）-3凝集素水平降低。在此，我们证明REG3B或REG3G在肠道中的缺乏会增加黏膜相关细菌的数量，并增强细菌向肠系膜淋巴结和肝脏的移位，从而促进乙醇诱导的脂肪肝向脂肪性肝炎发展。在肠道上皮细胞中过表达Reg3g可限制细菌在黏膜表面的定植，减少细菌移位，并保护小鼠免受酒精诱导的脂肪性肝炎。因此，酒精似乎会损害对黏膜相关微生物群的控制，随后黏膜屏障的破坏会促进酒精性肝病的进展。
