Project 1 Title: Gut microbial metabolites as drivers of ethanol-induced liver injury

ABSTRACT Recent evidence has emerged that microbes resident in the human intestine represent a key transmissible environmental factor contributing to a number of human diseases. However, mechanisms by which gut microbial-derived factors signal to the host to promote these diseases are largely unknown. We have recently discovered a metaorganismal pathway where nutrients present in high fat foods (phosphatidylcholine, choline, and L- carnitine) can be metabolized by the gut microbial enzymes to generate trimethylamine (TMA), which is then further metabolized by the host enzyme flavin-containing monooxygenase 3 (FMO3) to produce trimethylamine-N-oxide (TMAO). Here we show that pharmacologic inhibition of the gut microbial choline TMA lyase enzyme CutC/D protects mice against alcoholic liver disease. Unexpectedly, this protection is associated with reorganization of the host circadian clock. Our specific aims are: Aim 1. Testing the hypothesis that alcohol-induced circadian disruption depends on gut microbial TMA production, and that TMA lyase inhibitors represent a gut microbe-targeted chronotherapy; and Aim 2. Testing the hypothesis that the microbe-derived metabolite TMA activates the host G protein-coupled receptor trace amine-associated receptor 5 (TAAR5) to Promote Ethanol-Driven Sarcopenia. These studies will be significant because they have the potential to uncover the first ever described diet-microbe-derived zeitgeber. Successful completion of this project will be transformative by providing proof of concept that a non- antibiotic drug targeting a specific microbial enzyme can serve as a therapeutic strategy for alcohol-induced tissue injury.