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: 10046278
• 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/10046278
• 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; Hepatic; Hepatocyte; Hepatotoxicity; Inflammation; 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; Play; Pre-Clinical Model; Proteins; Publications; Research; Role; Sampling; Surface; TLR2 gene; Testing; Transgenic Organisms; Translating; United States; Veterans; Virulence Factors; anakinra; 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。长期饮酒如何导致肠道菌群失调和 我们实验室的结果尚不清楚特定细菌种类是否介导酒精性肝病。 表明粪肠球菌（E faecalis）足以引起轻度脂肪肝病并 最重要的是，我们观察到小鼠中酒精性肝病的数量显着增加。 患有或不患有肝病的酒精依赖患者的粪便样本中的粪肠球菌含量高于健康对照。 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-3 (REG3G) 允许粪肠球菌在肠粘膜表面定植并易位至 粪肠球菌通过与库普弗细胞 A 上的病原体识别受体结合诱导肝脏炎症。 随后炎症细胞因子白细胞介素 (IL)-1β 的表达和分泌增加有助于 我们发现嵌合小鼠缺乏乙醇诱导的肝病。 骨髓来源细胞上的 Toll 样受体 (TLR)-2 可减少粪肠球菌加剧的酒精肝 该应用的重点是表征粪肠球菌在酒精临床前模型中的作用。 我们发现，肝病和退伍军人酗酒是一个重要的病因。 在我们的实验中，肝脏炎症的调节和酒精性肝病的发展。 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 肠道 REG3G 的抑制促进粘膜上粪肠球菌的过度生长。 肠道表面并易位至肝脏（目标 1）。 粪肠球菌易位如何导致酒精肝期间的肝脏炎症和肝细胞死亡 疾病（目标 2），我们将使用精确微生物组方法来检验靶向操纵的假设。 酒精相关的生态失调可以改善酒精性肝病（目标 3）。 为微生物群对酒精性肝病的贡献提供新颖的见解。 将制定预防或改善退伍军人酒精性肝病的策略。