Alcohol is among the leading causes of death attributable to lifestyle behavior. Alcoholism is a multifaceted disease that deleteriously exerts ts effects on liver function's ability to metabolize triglyceride and to regulate immune cell infiltraion. Although it is well appreciated that alcohol promotes the translocation of endotoxin from the luminal contents of the intestine to the blood stream it is unclear whether this is the only gut derived signal that promotes alcohol induced liver injury. Recently, a novel pathway involving gut microbiota-dependent generation of trimethylamine (TMA) and subsequent hepatic conversion of TMA to trimethylamine-oxide (TMAO) has been shown to be a critical component of both non-alcoholic and alcoholic liver disease in mice. It was recently discovered that breath TMA levels strongly correlate with alcoholic hepatitis in human patients. Studies proposed here will comprehensively analyze the role of a new player in alcoholic liver disease (ALD) (flavin monooxygenase 3, FMO3), which converts TMA to TMAO in the liver. Our studies will examine the signaling role of FMO3's substrate, TMA, in regulating immune cell infiltration and thus promoting the progression of alcoholic hepatitis. We hypothesize that when ethanol and dietary constituents, such as choline and L-carnitine, are consumed the gut microbiota produce TMA. This TMA then diffuses into the plasma where it activates Taar5, a G protein-coupled receptor. We anticipate that this promotes the recruitment of peripheral monocytes and neutrophils to the liver, which are characteristic of alcoholic hepatitis. We will address our hypothesis using the standard mouse model of chronic ethanol-induced liver injury in the presence of reduced hepatic FMO3 expression. Using this model we will investigate the roles of TMA, Taar5 and hepatic FMO3 in promoting hepatic immune cell infiltration upon ethanol feeding. Collectively our studies hold the potential to elucidate the role of TMA in promoting a multiorganismal disease process, ALD.

Public Health Relevance

Alcohol induced liver disease (ALD) is a major cause of morbidity and mortality worldwide. Host immunity and resident gut flora play key roles in the pathogenesis of ALD. This novel study aims to elucidate the mechanisms by which multiorganismal metabolisms interact to propagate ALD. Discovery of a link between gut microbiota-metabolized dietary constituents, host immunity and alcoholic hepatitis would allow for the development of probiotic or other gut-flora-dependent approaches to treat or cure this devastating disease.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZAA1)
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Wang, Joe
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
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