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

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.