The role of Enterococcus faecalis in alcoholic liver disease

酗酒和酒精相关疾病是退伍军人发病和死亡的主要原因。 慢性酒精中毒与肠道微生物群的变化，肠道通透性增加， 以及细菌产物的全身水平升高。慢性酒精使用如何导致肠道生态失调， 具体的细菌种类是否介导酒精性肝病尚不清楚。我们实验室的结果 表明粪肠球菌（粪肠球菌）足以引起轻度脂肪变性肝病， 加重小鼠酒精性肝病。最重要的是，我们观察到E 与健康对照组相比，患有或不患有肝病的酒精依赖患者的粪便样本中的粪球菌。 我们的初步数据进一步表明，酒精介导的抗菌蛋白再生抑制 胰岛衍生的3-氨基葡萄糖（REG 3G）允许粪肠球菌在肠粘膜表面定居并移位至 肝脏粪肠球菌通过与枯否细胞上的病原体识别受体结合诱导肝脏炎症。一 随后炎性细胞因子白细胞介素（IL）-1β的表达和分泌增加有助于 酒精引起的肝病的发展。我们的研究结果支持了这一点， Toll样受体（TLR）-2对骨髓来源的细胞减少粪肠球菌加重酒精性肝 疾病本申请的重点是表征粪肠球菌在酒精性结肠炎临床前模型中的作用。 肝病和酗酒的退伍军人。我们假设粪肠球菌是一个重要的致病因素 调节肝脏炎症和酒精性肝病的发展。我们的实验 方法是使用慢性酒精喂养的小鼠模型来研究酒精诱导的 抑制肠道REG 3G。下肠REG 3G促进粘膜上粪肠球菌的过度生长 肠道表面和易位到肝脏（目的1）。我们将研究 粪肠球菌移位如何在酒精性肝期间促成肝脏炎症和肝细胞死亡 疾病（目标2）。使用精确微生物组方法，我们将测试靶向操纵的假设， 酒精相关的生态失调可以改善酒精性肝病（目的3）。我们相信这些研究将 为微生物群对酒精性肝病的贡献提供了新的见解。创新新颖 将制定预防或改善退伍军人酒精性肝病的策略。

Alcohol abuse and alcohol-related diseases are a major cause of morbidity and mortality among Veterans. Chronic alcoholism is associated with changes in the intestinal microbiota, increased intestinal permeability, and elevated systemic levels of bacterial products. How chronic alcohol use results in intestinal dysbiosis and whether specific bacterial species mediate alcoholic liver disease is not known. Results from our laboratory indicate that Enterococcus faecalis (E faecalis) is sufficient to cause mild steatotic liver disease and to exacerbate alcoholic liver disease in mice. Most importantly, we observed significantly greater numbers of E faecalis in fecal samples from alcohol-dependent patients with or without liver disease than healthy controls. Our preliminary data further shows that alcohol-mediated suppression of the antimicrobial protein regenerating islet derived-3 (REG3G) allows E faecalis colonization of intestinal mucosal surfaces and translocation to the liver. E faecalis induces liver inflammation via binding to pathogen recognition receptors on Kupffer cells. A subsequent increase in expression and secretion of the inflammatory cytokine interleukin (IL)-1β contributes to the development of ethanol-induced liver disease. This is supported by our findings that chimeric mice lacking toll-like receptor (TLR)-2 on bone-marrow derived cells have reduced E faecalis-exacerbated alcoholic liver disease. The focus of this application is to characterize the role of E faecalis in preclinical models of alcoholic liver disease and Veterans with alcohol abuse. We hypothesize that E faecalis is an important etiological factor in the modulation of hepatic inflammation and the development of alcoholic liver disease. Our experimental approach is to use mouse models of chronic alcohol feeding to investigate the role of alcohol-induced suppression of intestinal REG3G. Lower intestinal REG3G facilitates overgrowth of E faecalis on mucosal surfaces in the intestine and translocation to the liver (Aim 1). We will investigate the molecular mechanism of how translocation of E faecalis contributes to hepatic inflammation and hepatocyte death during alcoholic liver disease (Aim 2). Using a precision-microbiome approach, we will test the hypothesis that targeted manipulation of alcohol-associated dysbiosis can ameliorate alcoholic liver disease (Aim 3). We believe these studies will provide novel insights into the contribution of the microbiota to alcoholic liver disease. Innovative and novel strategies will be developed to prevent or ameliorate alcoholic liver disease in Veterans.