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

项目概要/摘要 过度饮酒和酒精相关性肝病是发病的两个主要原因， 全世界的死亡率。肠道微生物组可以改变个体酒精相关疾病进展的风险 肝脏疾病通过微生物衍生的代谢产物，如乙醇。Autobrewery综合征（ABS）， 失调的肠道微生物群产生高水平的乙醇，然后被吸收到体内的条件。 导致中毒症状的血液，是研究宿主效应的独特和理想的群体 肠道微生物乙醇的生产。我的初步数据证实了ABS患者的肠道微生物群 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 渗透性，这与酒精戒断的持续心理症状有关， 细菌移位到肝脏导致肝脏疾病进展，我们假设内源性肠道 微生物乙醇生产也会造成类似的影响。事实上，我的额外初步数据表明， 用来自ABS患者的高产乙醇肠道微生物群人源化的gnotobiotic小鼠证明， 与对照-人源化小鼠相比，增加的自愿酒精使用行为和增加的肝脏 炎症基因表达。然后我证实了一部分饮酒患者的肠道微生物群 紊乱也在培养物中产生显著量的乙醇。这些观察导致了我的中央 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 消耗和肝病恶化。因此，本申请的目的是1）表征 ABS患者的肠道微生物群，并确定负责高水平乙醇生产的微生物，2） 研究病理性肠道微生物乙醇产生如何影响宿主酒精使用和肝脏疾病进展 并测试抗菌剂作为治疗策略，和3）建立肠道微生物乙醇生产作为一种治疗策略， 酒精使用障碍和酒精相关肝脏疾病患者子集的独立风险因素。 我提出的研究将促进我们对驱动ABS的生物机制的理解， 增加酒精使用和肝病进展的易感性，并测试潜在的治疗方法。的 拟议的研究和职业发展计划，沿着我的导师，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的培训， 成为一名独立的医生科学家，在学术研究中研究肠-肝-脑轴 环境

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.