The Role of the Intestinal Mycobiome in Alcoholic Liver Disease

肠道菌群在酒精性肝病中的作用

基本信息

批准号：
9900694
负责人：
Bernd G. Schnabl
金额：
$ 32.79万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-10 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9900694
关键词：
Affect Alcohol abuse Alcohol dependence Alcoholic Liver Diseases Alcoholism Alcohols Animal Model Antifungal Agents Bacteria Belgium Blood Circulation California Candida albicans Chronic Collaborations Data Developed Countries Development Disease Disease model Endotoxins Etiology Experimental Animal Model Functional disorder Germ-Free Goals Health Hepatic Human Immune system Inflammation Inflammatory Infrastructure Institutes Interleukin-1 beta International Intervention Intestinal permeability Intestines Kupffer Cells Laboratories Lead Leaky Gut Ligation Lipopolysaccharides Liver Liver diseases Mediating Medical Methods Modeling Molecular Morbidity - disease rate Mus Nature Pathogenesis Patients Pharmacology Population Pre-Clinical Model Preventive Intervention Principal Investigator Probiotics Publications Research Research Personnel Role Saccharomyces Severity of illness Supplementation Testing Therapeutic Intervention United States Universities University Hospitals Virulence Factors Virus bacteriome base beta-Glucans cohort cytokine dectin 1 deep sequencing design dysbiosis early onset feeding fungus gut microbiome gut-liver axis innovation insight intestinal barrier liver inflammation microbial microbiome research microbiota mortality mouse model mycobiome new therapeutic target novel pre-clinical prevent probiotic supplementation receptor

项目摘要

Project Summary Alcohol associated health problems are a major medical burden in industrialized countries. Patients with alcoholic liver disease show intestinal bacterial dysbiosis and increased intestinal permeability. Disease severity correlates with systemic levels of translocated bacterial products. Although there is considerable progress in understanding the interaction between the host and intestinal bacteria, the role of the intestinal fungal microbiome (also called mycobiome) in alcoholic liver disease has not been investigated. Results from an international collaboration by Schnabl, Stärkel and Fouts laboratories suggest that quantitative changes in the intestinal mycobiome and translocation of fungal products occur in a mouse model of alcoholic liver disease, while deep sequencing demonstrates intestinal fungal dysbiosis in patients with chronic alcohol abuse. Reducing intestinal fungal overgrowth with antifungals or restoring intestinal barrier function using probiotic Saccharomyces boulardii ameliorates experimental alcoholic liver disease. The central hypothesis of this proposed collaborative research application implicates disturbances in the intestinal mycobiome as an important etiological factor in the modulation of hepatic and systemic inflammation, and the development of alcoholic liver disease. We predict that chronic alcohol suppresses the intestinal immune system and facilitates qualitative and quantitative changes in the intestinal mycobiome. Fungal products such as β-glucan translocate to the portal circulation and liver, and cause progression of alcoholic liver disease. Towards this goal, we will use pharmacological interventions, supplementation of probiotics and genetically modified mice in preclinical mouse models of alcoholic liver disease (Aim 1). We will characterize the intestinal mycobiome in patients with alcohol abuse, mild and progressive alcoholic liver disease. We predict that translocated fungal products correlate with levels of systemic and hepatic inflammation, and with the degree of liver disease (Aim 2). We believe these studies will provide important insights into alcohol-mediated changes of the intestinal mycobiome that result in fungal translocation. Eventually this approach might lead to new therapeutic targets for patients with alcoholic liver disease.

项目摘要酒精相关的健康问题是工业化国家的主要医疗烧伤。患者酒精性肝病表现出肠道细菌营养不良和肠道通透性的增加。疾病严重程度与全身易位细菌产物水平相关。虽然有很多理解宿主与肠道细菌之间相互作用的进展，肠的作用尚未研究真菌肝病中的真菌微生物组（也称为Mycobiome）。结果从施纳布尔（Schnabl）的国际合作中，斯特克尔（Stärkel）和福特实验室肠道菌组合体的变化和真菌产品的易位发生在鼠标模型中酒精性肝病，而深度测序表明患有慢性酒精滥用。用抗真菌剂减少肠道真菌过度生长或恢复肠壁使用益生菌糖含量的Boulardii的功能可以改善实验性酒精性肝病。这该提议的协作研究应用程序的中心假设在肠道菌组作为肝和全身性调节的重要病因。炎症和酒精性肝病的发展。我们预测慢性酒精会抑制肠道免疫系统并促进肠道的质量和定量变化 mycobiome。真菌产品，例如β-葡聚糖转移到门户循环和肝脏，并导致酒精性肝病的进展。为了实现这一目标，我们将使用药物干预措施，在酒精肝的临床前小鼠模型中补充益生菌和一般修饰的小鼠疾病（目标1）。我们将在酗酒，轻度和进行性酒精性肝病。我们预测，易位的真菌产品与全身和肝注射，以及肝病的程度（AIM 2）。我们相信这些研究将提供对肠道霉菌组的酒精介导的变化的重要见解，从而导致真菌易位。最终，这种方法可能会为患者带来新的治疗靶点酒精性肝病。