The role of Enterococcus faecalis in alcoholic liver disease

酗酒和与酒精有关的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区系改变，肠道通透性增加， 以及全身细菌产物水平的升高。长期饮酒如何导致肠道菌群失调和 目前尚不清楚特定的细菌种类是否参与了酒精性肝病。我们实验室的结果 表明粪肠球菌(粪肠球菌)足以引起轻度脂肪性肝病和 加重小鼠酒精性肝病。最重要的是，我们观察到明显更多的E 有或没有肝病的酒精依赖患者的粪便样本中的粪便标本中的粪便细菌高于健康对照组。 我们的初步数据进一步表明，酒精介导的抗菌蛋白再生受到抑制 胰岛衍生-3(REG3G)可使粪肠球菌在肠粘膜表面定植并转位至 肝脏。粪肠球菌通过与枯否细胞上的病原体识别受体结合而诱导肝脏炎症。一个 随后炎性细胞因子IL-1β表达和分泌的增加有助于 酒精性肝病的发生发展。这一点得到了我们的发现的支持，即嵌合小鼠缺乏 骨髓来源细胞上的Toll样受体-2对E粪便加重的酒精性肝的保护作用 疾病。这项应用的重点是表征粪肠球菌在酒精中毒临床前模型中的作用 肝脏疾病和酗酒的退伍军人。我们推测粪肠球菌是一个重要的致病因素。 在调节肝脏炎症和酒精性肝病的发生发展中起重要作用。我们的实验 方法是用小鼠慢性饮酒模型来研究酒精诱导的作用 抑制肠道REG3G。下肠道REG3G促进粪肠球菌在粘膜上的过度生长 肠道表面和转位到肝脏(目标1)。我们将研究其分子机制。 粪肠易位在酒精性肝损伤中对肝脏炎症和肝细胞死亡的影响 疾病(目标2)。使用精确微生物组方法，我们将检验目标操纵的假设 酒精相关的生物失调可以改善酒精性肝病(目标3)。我们相信这些研究将会 为微生物区系对酒精性肝病的贡献提供了新的见解。创新新奇 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.