The role of alcohol-associated microbiota membrane vesicles in mucosal immunity

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A significant portion of the global burden of AUD (Alcohol use disorder) derives from an increased risk and susceptibility to diseases including infection, cirrhosis, and cancer. These diseases are influenced by the composition of the intestinal microbiota, which is altered by alcohol use. Though it has been accepted that change to the microbiota contributes to disease establishment and progression in AUD, our understanding of the mechanisms by which this occurs is inadequate. These mechanisms likely involve a variety of microbiota- derived products (membrane vesicles, excreted chemicals, cellular components, LPS, etc.). The preliminary data addressed herein support the proposition that microbiota-derived membrane vesicles (MVs) are an important driver of alcohol-driven tissue injury. To address this possibility, this proposal will examine the effects of alcohol on the composition and frequency of microbiota derived MVs. This proposal will also evaluate the effects of alcohol-associated MVs on promoting tissue injury and mucosal infection. Our preliminary data demonstrate that alcohol alters the composition of MVs generated by the gut microbiota, and that isolated alcohol-associated MVs increase susceptibility to respiratory infection, independent of alcohol use, suggesting that MVs influence mucosal host defense. We hypothesize that MVs from an alcohol-associated microbiota will have increased inflammatory properties and increase susceptibility to mucosal infections via epithelial inflammation and barrier dysfunction. Understanding the alterations to bacterial MVs following alcohol exposure may give new insight into disease pathogenesis, which may inspire future therapies centered on modulating MVs.