Role of urolithin A in progression of alcohol-associated liver disease

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Abstract Excessive consumption of alcohol is a global problem and is the world’s third largest risk factor for diseases and disabilities, and accounting for 5.9% of all deaths worldwide. Alcohol-associated liver disease (ALD) is a spectrum of disease that starts with steatosis progressing to fibrosis and finally cirrhosis in ~20 to 30% patients of in chronic excessive alcohol drinkers. However, rest of the 70-80% with alcohol use disorders (AUD) patients may not progress into severe ALD. Therefore, we asked what are factors that potentially prevent AUD patients to progress in to ALD. The composition of gut microbiota and their metabolites are significantly vary in ALD patients compared to AUD and healthy subjects and play a critical role in manifesting ALD pathogenesis. Our pilot studies in mouse of ALD showed that treatment with gut microbial metabolite Urolithin A (UroA) significantly reduced ALD pathogenesis. UroA treatment decreased EtOH-induced gut permeability, hepatic steatosis and hepatitis in chronic, chronic+binge ALD mouse models. UroA is a dietary microbial metabolite produced from ellagitannin/ellagic acid-rich diets such as pomegranate, walnuts and berries. We postulate that harboring UroA- producing bacteria in healthy or AUD subjects may prevent from developing severe ALD. In this exploratory project, we will test the hypothesize that microbiota and their metabolites (urolithins) in healthy and AUD without ALD differ from AUD patients with ALD, and presence of UroA-producing bacteria when combined with diets rich in EA/ET or with direct supplementation of UroA will protect from ALD progression. To test this hypothesis, we proposed two specific aims. In aim 1, we will collect stool samples from healthy, AUD and severe ALD patients and determine their ability to produce UroA in vitro cultures. Next, we will generate humanized microbiota mice (HMM) by fecal microbiota transplantation (FMT) of UroA-producing or non-producing stool samples (collected from healthy/AUD/ALD subjects) in to germ free mice. In aim 2, these humanized microbiota mice (UroA producers vs non-producers) will subjected to chronic+binge (10+1) ALD model and determine extent of ALD development in these mice upon supplementing with EA. Further, we will test whether direct supplementation of UroA mitigate severe ALD in these humanized microbiota mice. Upon successful completion of these studies, we will determine whether UroA-producing microbiota and/or direct supplementation of UroA provides protection against ALD in humanized microbiota mice. These studies would unravel potential of microbiota dependent personalized dietary patterns to control ALD.