Role of Intestinal Autophagy in the Pathogenesis of Alcohol Associated Liver Disease

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Abstract: Alcohol-Associated Liver Disease (ALD) continues to be a major cause of morbidity and mortality worldwide. Currently, there are no FDA-approved therapies that block or reverse ALD progression. Understanding the key steps that promote ALD progression is essential to identifying new treatment targets and methods that alleviate ALD. Prominent among the factors that contribute to ALD progression is the alcohol-induced disruption of intestinal barrier integrity, accompanied by microbial flora imbalance (dysbiosis). Both these promote gut and liver injury. However, the cellular/molecular mechanisms by which excessive drinking triggers dysbiosis and compromises intestinal barrier integrity must be clearly established. Here, we present unique, exciting new data, showing that chronic ethanol (EtOH) feeding disrupts intestinal autophagy, a crucial intracellular catabolic process that begins with the formation of autophagosomes (AV), which sequester and deliver senescent macromolecules and organelles to lysosomes for breakdown in this organelle. The degraded species are replenished by synthesis. This process of rapid and constant turnover preserves the specialized functions of all cells, but especially intestinal cells and it regulates intestinal microbial composition as well, thereby, maintaining gut homeostasis. Our understanding of autophagy’s role in preserving intestinal barrier function has progressed significantly, but we need a better understanding of how EtOH misuse disrupts gut autophagy to impair barrier function. Our objective is to ascertain the mechanism(s) by which EtOH exposure dysregulates autophagy in intestinal cells to compromise gut barrier integrity and promotes alcohol-induced liver injury. We propose the following Specific Aims: Aim 1. Investigate how EtOH-induced lysosome disruption affects epithelial cell barrier integrity; Aim 2) Clarify the effects of EtOH-induced autophagy disruption on Paneth cell function and Aim 3) Ascertain how EtOH-induced liver injury is exacerbated by deficient intestinal autophagy but is alleviated by autophagy reactivation in the gut.