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.
| You, Min (2018) Obesity and Binge Drinking: Two Hits Driving Liver Fibrosis Progression? Cell Mol Gastroenterol Hepatol 5:424-425 |
| You, Min; Zhou, Zhou; Daniels, Michael et al. (2018) Endocrine Adiponectin-FGF15/19 Axis in Ethanol-Induced Inflammation and Alcoholic Liver Injury. Gene Expr 18:103-113 |
| Roberts, Adam B; Gu, Xiaodong; Buffa, Jennifer A et al. (2018) Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential. Nat Med 24:1407-1417 |
| Gromovsky, Anthony D; Schugar, Rebecca C; Brown, Amanda L et al. (2018) ?-5 Fatty Acid Desaturase FADS1 Impacts Metabolic Disease by Balancing Proinflammatory and Proresolving Lipid Mediators. Arterioscler Thromb Vasc Biol 38:218-231 |
| Dasarathy, Srinivasan; Hatzoglou, Maria (2018) Hyperammonemia and proteostasis in cirrhosis. Curr Opin Clin Nutr Metab Care 21:30-36 |
| Lindenmeyer, Christina C; McCullough, Arthur J (2018) The Natural History of Nonalcoholic Fatty Liver Disease-An Evolving View. Clin Liver Dis 22:11-21 |
| Manterola, Andrea; Bernal-Chico, Ana; Cipriani, Raffaela et al. (2018) Deregulation of the endocannabinoid system and therapeutic potential of ABHD6 blockade in the cuprizone model of demyelination. Biochem Pharmacol 157:189-201 |
| McCullough, Rebecca L; McMullen, Megan R; Poulsen, Kyle L et al. (2018) Anaphylatoxin Receptors C3aR and C5aR1 Are Important Factors That Influence the Impact of Ethanol on the Adipose Secretome. Front Immunol 9:2133 |
| Chen, Li; Chen, Ruju; Kemper, Sherri et al. (2018) Pathways of production and delivery of hepatocyte exosomes. J Cell Commun Signal 12:343-357 |
| McCullough, Rebecca L; McMullen, Megan R; Sheehan, Megan M et al. (2018) Complement Factor D protects mice from ethanol-induced inflammation and liver injury. Am J Physiol Gastrointest Liver Physiol 315:G66-G79 |
Showing the most recent 10 out of 42 publications
