Microbiome as Therapeutic Target in Alcoholic Hepatitis

微生物组作为酒精性肝炎的治疗靶点

基本信息

批准号：
8669778
负责人：
DAVID A. BRENNER
金额：
$ 41.47万
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：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8669778
关键词：
Acute Affect Alcohol abuse Alcoholic Hepatitis Alcoholic Liver Cirrhosis Alcoholic Liver Diseases Alcohols Antibiotics Bacteria Bacterial Infections Bacterial Translocation Benign Chronic Chronic Disease Cirrhosis Clinical Core Facility Data Developed Countries Development Enteral Ethanol Experimental Animal Model Experimental Models Fatty Acids Fatty Liver Fibrosis Functional disorder Gene Expression Profile Genes Health Hepatic Human Individual Inflammation Institutes Intervention Intestines Laboratories Lactobacillus Lead Life Lipopolysaccharides Liver Liver diseases Mediating Mediator of activation protein Medical Metabolic Metagenomics Methods Molecular Molecular Target Monitor Morbidity - disease rate Mus Nature Outcome Pathogenesis Pathway Analysis Patients Pattern Permeability Pilot Projects Plasma Pre-Clinical Model Prevention Preventive Intervention Probiotics Publications Research Ribosomal RNA Secondary to Sepsis Syndrome Severity of illness Site Steatohepatitis Supplementation Systems Biology Testing Therapeutic Therapeutic Intervention United States base biobank cohort design early onset fatty acid biosynthesis feeding improved insight liver injury metabolomics metagenome microbial microbiome mortality mouse model new therapeutic target pathogen problem drinker public health relevance pyrosequencing therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Alcohol associated health problems are a major medical burden in industrialized countries. Alcoholic liver disease comprises steatosis, steatohepatitis, alcoholic hepatitis, fibrosis, and cirrhosis. Alcoholic hepatitis is a distinct acte on chronic disease with significant morbidity and mortality. Patients with alcoholic hepatitis show intestinal bacterial overgrowth and increased intestinal permeability. Disease severity correlates with systemic levels of bacterial products or pathogen-associated molecular patterns (PAMPs), and many patients succumb to bacterial infections. Results from our laboratory suggest that quantitative changes in the intestinal microbiome occur early in a mouse model of alcoholic liver disease, while qualitative changes are characterized by a profound suppression of commensal probiotic bacteria including Lactobacillus. Pathway analysis revealed that genes involved in fatty acid biosynthesis are underrepresented in the intestinal metagenome following chronic alcohol feeding. Our central hypothesis is that chronic hepatic and systemic inflammation is an important etiological factor in alcoholic hepatitis resulting from disturbances in the gut microbia flora induced by alcohol. The focus of our application is to further characterize the host gut microbiome, metagenome, metatranscriptome and metabolome in patients and in a mouse model of alcoholic hepatitis. We speculate that intestinal bacterial overgrowth and suppression of commensal probiotic bacteria contribute to a dysfunction of the gut-liver axis in alcoholic hepatitis. Using massively parallel 454 pyrosequencing, our focus will be on the analysis of the microbiome associated with alcoholic hepatitis (Aim 1). We further hypothesize that dysbiosis-induced changes in bacterial metabolites affect the mucosal barrier function and induce liver injury. We therefore will analyze the enteric metagenome, metatranscriptome and metabolome in alcoholic hepatitis (Aim 2). We will then test potential therapeutic interventions that manipulate alcoholic hepatitis-induced dysbiosis by reducing bacterial overgrowth using non-absorbable antibiotics, by restoring eubiosis using probiotics, or by altering the enteric metabolome using fatty acid supplementation. We propose that a reversal of qualitative and/or quantitative changes in the enteric microbiome associated with alcoholic hepatitis is sufficient to improve liver disease and systemic inflammation (Aim 3). We believe these studies will provide important insights into alcohol-mediated changes of the intestinal microbiome that result in quantitative and qualitative changes in the intestinal microflora and bacterial translocation. Eventually this approach might lead to new therapeutic targets for patients with alcoholic hepatitis.

描述（由申请人提供）：与酒精相关的健康问题是工业化国家的主要医疗负担。酒精性肝病包括脂肪变性、脂肪性肝炎、酒精性肝炎、纤维化和肝硬化。酒精性肝炎是一种独特的慢性疾病，具有显着的发病率和死亡率。酒精性肝炎患者表现肠道细菌过度生长和肠道通透性增加。疾病的严重程度与细菌产物或病原体相关分子模式（PAMP）的全身水平相关，许多患者死于细菌感染。我们实验室的结果表明，在酒精性肝病小鼠模型的早期，肠道微生物组发生了量的变化，而质的变化的特点是对包括乳酸菌在内的共生益生菌的深度抑制。通路分析显示，长期饮酒后肠道宏基因组中参与脂肪酸生物合成的基因代表性不足。我们的中心假设是，慢性肝脏和全身炎症是酒精性肝炎的重要病因，其原因是酒精引起肠道菌群紊乱。我们应用的重点是进一步表征患者和酒精性肝炎小鼠模型中的宿主肠道微生物组、宏基因组、宏转录组和代谢组。我们推测肠道细菌过度生长和共生益生菌的抑制导致酒精性肝炎中肠肝轴功能障碍。使用大规模并行 454 焦磷酸测序，我们的重点将是分析与酒精性肝炎相关的微生物组（目标 1）。我们进一步假设生态失调引起的细菌代谢物变化影响粘膜屏障功能并诱发肝损伤。因此，我们将分析酒精性肝炎的肠道宏基因组、宏转录组和代谢组（目标 2）。然后，我们将测试潜在的治疗干预措施，通过使用不可吸收的抗生素减少细菌过度生长，使用益生菌恢复生态平衡，或使用脂肪酸补充剂改变肠道代谢组，来控制酒精性肝炎引起的生态失调。我们建议逆转与酒精性肝炎相关的肠道微生物组的质和/或量的变化足以改善肝脏疾病和全身炎症（目标 3）。我们相信这些研究将为酒精介导的肠道微生物组变化提供重要的见解，这些变化会导致肠道微生物群和细菌易位的量和质的变化。最终，这种方法可能会为酒精性肝炎患者带来新的治疗靶点。