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.