Award
NIH Reporter #2P50AA024333-11
Project One - Gut Microbial Metabolites as Drivers of Ethanol-Induced Injury
Recipient
Cleveland Clinic Lerner College of Medicine of Case Western Reserve University
Award Amount
$327,433.00
Ceiling
$327,433.00
Awarded
July 30, 2026
Identifier
2P50AA024333-11
This award supports research investigating how gut microbial metabolites influence alcohol-associated liver disease (ALD), aiming to identify biomarkers and therapeutic targets to improve ALD outcomes.
Description
Recent evidence has emerged that microbes resident in the human intestine represent a key transmissible environmental factor contributing to alcohol-associated liver disease (ALD). However, mechanisms by which gut microbial-derived factors signal to the host to promote ALD are largely unknown. We have recently discovered that metaorganismal (i.e., microbe and host) metabolism of aromatic amino acids is altered in ALD. In particular, gut microbe-derived tryptophan metabolites (indole-3-propionic acid, indoxyl sulfate, and serotonin) and tyrosine metabolites (p-cresol sulfate and p-cresol glucuronide) were strongly decreased in ALD. To follow up, we have developed innovative gnotobiotic mouse models to manipulate gut microbe-driven metabolism of aromatic amino acids and show that metaorganismal tryptophan and tyrosine metabolism protects against ethanol-induced liver injury in mice. Here, we will test the central hypothesis that gut bacterially-derived aromatic amino acid metabolites are biomarkers of and therapeutic targets in ALD. These studies will be significant because they have the potential to identify new biomarkers of ALD that originate from gut microbes. The development of circulating gut microbe-focused metabolomic biomarkers to distinguish patients with alcoholic hepatitis (AH), metabolic-associated fatty liver disease (MetALD), and metabolic dysfunction-associated steatohepatitis (MASH) will address an important unmet clinical need. Furthermore, understanding the mechanisms by which gut microbial aromatic amino acid metabolism improves liver injury will facilitate the design of rational therapeutic interventions that raise beneficial bacterial metabolites to improve ALD outcomes.