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

项目摘要/摘要 过量饮酒和与酒精相关的肝病是发病率和 全球范围内的死亡率。肠道微生物群可以改变个体与酒精相关的进展风险 通过微生物衍生的代谢物，如乙醇，导致肝脏疾病。自酿啤酒厂综合征(ABS)患者，a 肠道微生物区系失调产生高水平的乙醇，然后被吸收到 血液导致中毒症状，是研究寄主效应的独特和理想人群 肠道微生物生产乙醇的能力。我的初步数据证实，ABS患者的肠道微生物群产生了 培养物中的乙醇含量比他们对照的要多。因为长期饮酒会增加肠道功能 渗透性，这与酒精戒断的持续心理症状有关，并增加 细菌移位到肝脏导致肝病进展，我们假设内源性肠道 微生物生产乙醇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患者的高酒精产生肠道微生物群人源化的灵芝小鼠证明 与对照人源化小鼠相比，自愿饮酒行为增加，肝脏增加 炎性基因表达。然后我证实了一部分酗酒患者的肠道微生物区系 无序也会在培养中产生大量的乙醇。这些观察结果导致了我的中心 假设病理性肠道微生物产生乙醇是酒精增加的独立危险因素 消耗和加重肝病。因此，本申请的目的是1)描述 ABS患者的肠道微生物区系，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 测试抗菌剂作为一种治疗策略，以及3)建立肠道微生物乙醇生产作为一种 酒精使用障碍和酒精相关性肝病患者子集的独立危险因素。 我提出的研究将促进我们对驱动ABS和 增加饮酒和肝病进展的易感性，并测试潜在的治疗方法。这个 建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的培训 成为一名独立的内科科学家，在学术研究中研究肠道-肝脏-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.