The role of Enterococcus faecalis in alcoholic liver disease

粪肠球菌在酒精性肝病中的作用

• 批准号: 10292950
• 负责人: Bernd G. Schnabl
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292950
• 关键词: Affect; Alcohol abuse; Alcohol dependence; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcoholism; Alcohols; Bacteriophages; Binding; Biological Models; Bone Marrow; Cells; Cessation of life; Chronic; Data; Development; Disease; Endotoxins; Enterococcus faecalis; Ethanol; Etiology; Experimental Models; Feces; Functional disorder; Gnotobiotic; Health; Hepatocyte; Hepatotoxicity; Inflammatory; Interleukin-1 Receptors; Interleukin-1 beta; Intervention; Intestinal Mucosa; Intestinal permeability; Intestines; Kupffer Cells; Laboratories; Lead; Leaky Gut; Lipopolysaccharides; Liver; Liver Cirrhosis; Liver diseases; Lytic; Mediating; Medical; Modeling; Molecular; Morbidity - disease rate; Mucous Membrane; Mus; Myelogenous; Natural regeneration; Nature; Pathogenesis; Patients; Persons; Play; Pre-Clinical Model; Proteins; Publications; Research; Role; Sampling; Surface; TLR2 gene; Testing; Transgenic Organisms; Translating; United States; Veterans; Virulence Factors; anakinra; antagonist; antimicrobial; base; chronic alcohol ingestion; cytokine; defined contribution; dysbiosis; feeding; gut bacteria; gut colonization; gut microbiota; gut-liver axis; humanized mouse; innovation; insight; islet; liver inflammation; liver injury; microbial; microbiome; microbiome research; microbiota; mortality; mouse model; novel; novel strategies; pathogen; prevent; problem drinker; receptor; response

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.

酗酒和与酒精有关的疾病是退伍军人发病和死亡率的主要原因。 慢性酒精中毒与肠道菌群的变化有关，肠道通透性增加， 以及细菌产物的全身水平升高。慢性酒精的使用如何导致肠道营养不良和 特定细菌是否介导酒精性肝病。我们实验室的结果 表明粪肠球菌（E Faecalis）足以引起轻度的脂肪变性肝病和 小鼠病毒性肝病加剧。最重要的是，我们观察到E的数量明显更大 来自健康对照组的粪便样本中的粪便样品中的粪便样品。 我们的初步数据进一步表明，酒精介导的抑制抗菌蛋白再生 ISLET衍生-3（REG3G）允许肠道粘膜表面的粪便定植，并易位 肝。 E粪便通过与库普弗细胞上的病原体识别受体结合诱导肝炎。一个 随后炎性细胞因子白介素（IL）-1β的表达和分泌的增加和分泌有助于 乙醇诱导的肝病的发展。这是我们的发现，嵌合小鼠缺乏 骨髓衍生细胞上的Toll样受体（TLR）-2降低了粪肠内的酒精性肝脏 疾病。该应用的重点是表征faecalis在酒精的临床前模型中的作用 肝病和滥用酒精的退伍军人。我们假设粪便是重要的病因。 在调节肝脏注射和酒精性肝病的发展中。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作用 抑制肠reg3g。下肠reg3g促进faecalis在粘膜上的过度生长 肠道表面并易位到肝脏（AIM 1）。我们将研究 E粪便的易位如何促进酒精性肝脏期间的肝脏注射和肝细胞死亡 疾病（目标2）。使用精确 - 微生物组方法，我们将测试针对操纵的假设 与酒精相关的营养不良可以改善酒精肝病（AIM 3）。我们相信这些研究将 对微生物群对酒精性肝病的贡献提供新的见解。创新和新颖 将制定策略，以预防或改善退伍军人中酒精性肝病。