Role of gut microbial ethanol production in alcohol use disorder and alcohol-associated liver disease

肠道微生物乙醇产生在酒精使用障碍和酒精相关性肝病中的作用

基本信息

批准号：
10785985
负责人：
Cynthia Li-Shin Hsu
金额：
$ 17.57万
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：
2023
资助国家：
美国
起止时间：
2023-09-20 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10785985
关键词：
Advisory Committees Aerobic Affect Alcohol consumption Alcohol dependence Alcohol withdrawal syndrome Alcoholic Liver Diseases Alcohols Antibiotic Therapy Antibiotics Antifungal Agents Bacteria Bacterial Translocation Behavior Behavioral Biological Bioreactors Blood Circulation Brain California Chronic Cirrhosis Data Development Plans Disease Progression Disease remission Enrollment Environment Enzymes Ethanol Feces Fibrosis Flare Gene Expression Gene Family Genes Germ-Free Gnotobiotic Hepatic Histopathology Household Individual Inflammatory Intestinal permeability Intoxication Liver Liver diseases Measures Mentors Metabolism Metagenomics Methods Microbe Minority Morbidity - disease rate Mus Pathologic Pathology Patients Phase Physicians Physiological Population Predisposition Prevalence Prevention strategy Production Publishing Research Resources Risk Factors Role Scientist Symptoms Syndrome Techniques Testing Therapeutic Therapeutic Intervention Training Universities absorption alcohol abuse therapy alcohol use disorder antimicrobial behavior test career development chronic alcohol ingestion clinical diagnosis cohort craving disorder risk experimental study fatty liver disease fungus gut bacteria gut microbes gut microbiome gut microbiota humanized mouse improved interdisciplinary approach liver injury loss of function metagenomic sequencing microbial microbiota mortality mouse model mutant neuroinflammation neuropathology patient subsets progression risk psychological symptom research and development review of reported cases

项目摘要

PROJECT SUMMARY/ABSTRACT Excessive alcohol use and alcohol-associated liver disease are two of the leading causes of morbidity and mortality worldwide. The gut microbiome can modify an individual’s risk for progression of alcohol-associated liver disease via microbe-derived metabolites such as ethanol. Patients with Autobrewery Syndrome (ABS), a condition where dysregulated gut microbiota produce high levels of ethanol that is then absorbed into the bloodstream leading to symptoms of intoxication, are a unique and ideal population for studying the host effects of gut microbial ethanol production. My preliminary data confirms that gut microbiota from ABS patients produce more ethanol in culture than that of their controls. Because chronic alcohol consumption can increase gut permeability, which is associated with persistent psychological symptoms of alcohol withdrawal and increased bacterial translocation to the liver resulting in liver disease progression, we hypothesized that endogenous gut microbial ethanol production could cause similar effects. Indeed, my additional preliminary data demonstrates that gnotobiotic mice humanized with high ethanol-producing gut microbiota from ABS patients demonstrated increased voluntary alcohol use behavior compared with control-humanized mice and increased hepatic inflammatory gene expression. I then confirmed that the gut microbiota of a subset of patients with alcohol use disorder also produce significant amounts of ethanol in culture. These observations have led to my central hypothesis that pathologic gut microbial ethanol production is an independent risk factor for increased alcohol consumption and exacerbation of liver disease. Hence, the aims of this application are to 1) characterize the gut microbiota of patients with ABS and identify microbes responsible for high levels of ethanol production, 2) examine how pathologic gut microbial ethanol production affects host alcohol use and liver disease progression and test antimicrobials as a therapeutic strategy, and 3) establish gut-microbial ethanol production as an independent risk factor for a subset of patients with alcohol use disorder and alcohol-associated liver disease. My proposed studies will advance our understanding of the biological mechanisms that drive ABS and predisposition for increased alcohol use and liver disease progression, and test potential therapies. The proposed research and career development plan, along with my mentors, advisory committee, and resources at the University of California, San Diego, will provide the support and additional training necessary for me to become an independent physician scientist studying the gut-liver-brain axis in an academic research environment.

项目概要/摘要过量饮酒和酒精相关的肝病是发病率和酒精相关性肝病的两个主要原因肠道微生物组可以改变个体与酒精相关的进展风险。患有自酿酒综合症（ABS）的患者会因微生物代谢物（例如乙醇）而患上肝脏疾病。肠道微生物群失调产生高水平的乙醇，然后被吸收到肠道中导致中毒症状的血流是研究宿主效应的独特且理想的群体我的初步数据证实 ABS 患者的肠道微生物产生乙醇。培养物中的乙醇含量高于对照组，因为长期饮酒会增加肠道菌群。渗透性，这与酒精戒断的持续心理症状和增加有关细菌转移到肝脏导致肝脏疾病进展，我们追求内源性肠道事实上，我的额外初步数据表明，微生物乙醇生产可能会产生类似的影响。用来自 ABS 患者的高产乙醇肠道微生物群进行人源化的无菌小鼠已证明与对照人源化小鼠相比，自愿饮酒行为增加，肝功能增加然后我证实了一部分饮酒患者的肠道微生物群。这些观察结果导致了我的中心问题。假设病理性肠道微生物乙醇产生是酒精增加的独立危险因素因此，本应用的目的是 1) 表征。 ABS 患者的肠道微生物群并确定导致高水平乙醇产生的微生物，2) 检查病理性肠道微生物乙醇产生如何影响宿主酒精使用和肝病进展并测试抗菌药物作为一种治疗策略，3) 建立肠道微生物乙醇生产作为一种治疗策略部分患有肝脏酒精使用障碍和酒精相关疾病的患者的独立危险因素。我提出的研究将增进我们对驱动 ABS 和酒精使用增加和肝病进展的倾向，并测试潜在的治疗方法。拟议的研究和职业发展计划，以及我的导师、咨询委员会和资源加州大学圣地亚哥分校将为我提供必要的支持和额外培训成为一名独立的医师科学家，在学术研究中研究肠-肝-脑轴环境。