Project 1: Gut Microbial Metabokites as Drivers of Ethanol-Induced Liver Injury

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ABSTRACT Advanced alcoholic liver disease (ALD) represents a substantial public health burden, threatening the lives of more than ten million people in the United States. While many studies have linked commensal bacteria to the promotion of ALD, the current view is that this link is established through bacterial translocation into the circulation, which promotes activation of pro-inflammatory toll like receptors in the liver. Here we propose the novel concept that gut microbes do not have to translocate into the circulation to impact ALD. Alternatively, we propose that gut microbe-dependent metabolism of common nutrients produce a microbial metabolite called trimethylamine (TMA), which is subsequently sensed by the host G protein coupled receptor Taar5 to promote ALD progression. Importantly, we find that elevated levels of the gut microbe-derived metabolite TMA are associated with acute alcoholic hepatitis (ASH) in humans, and TMA elevation worsens ethanol-induced liver injury in mice. Further, we have found that hepatic expression of the host TMA oxygenase enzyme FMO3 is reduced in ALD. Importantly, pharmacologic elevation of circulating TMA promotes hepatic leukocyte infiltration, inflammation, and endoplasmic reticulum (ER) stress by a mechanism involving suppression of a key membrane remodeling enzyme lysophosphatidylcholine acyltransferase 3 (LPCAT3). In specific aim 1, we will determine whether persistent elevation the gut microbial metabolite TMA can accelerate ethanol-driven progression of simple steatosis to ASH and fibrosis, and determine whether ethanol-induced liver injury is transmissible by gut microbial transplantation. In specific aim 2, we will determine whether the host G protein coupled receptor Taar5 is necessary for TMA to exacerbate ethanol-induced liver injury. In specific aim 3, we will define the role of LPCAT3-driven phosphatidylcholine (PC) remodeling in ethanol-induced liver injury. We anticipate the proposed studies will reveal new molecular mechanisms regulating ALD, broadly impacting drug discovery programs targeting microbe-host interactions driving inflammatory diseases such as ALD.