Unhealthy alcohol use is common in people living with HIV (PLWH) and is associated with cardiovascular disease (CVD) and mortality risk. Prior work suggests that heavy drinking alters gastrointestinal microbial composition (i.e., gut dysbiosis) and gut dysbiosis may contribute to CVD risk. Gut dysbiosis impacts the production of short chain fatty acids (SCFAs e.g., butyrate), bile acids (e.g., deoxycholic acid), and choline metabolites (e.g., trimethylamine N-oxide, TMAO). Whether these microbiome-dependent metabolites are associated with incident CVD and death and contribute to the excess risk of CVD among PLWH who are heavy drinkers is unknown. Each of these three metabolic pathways (SCFA, bile acids, and choline), if associated with CVD in PLWH, could serve as a potential therapeutic target to reduce CVD risk among PLWH who are heavy drinkers. The central hypotheses in the Microbiome, Metabolites, and Alcohol in HIV to reduce CVD (META HIV CVD) program project grant are that among PLWH, a probiotic can mitigate alcohol-associated dysbiosis and reduce microbial translocation, inflammation and harmful microbiome-dependent metabolites (Project 1); and that altered SCFA, bile acid and TMAO metabolism are associated with increased risk of CVD and death (Project 2). Our preliminary data support the scientific premise that unhealthy alcohol use, gut dysbiosis and resulting metabolite alterations contribute to gut permeability, immune dysfunction, CVD, and death. META HIV CVD Cohort (Project 2), is a prospective, observational cohort study led by Dr. So-Armah (Lead), Dr. Freiberg, and Dr. Barve. The study will use existing data and biospecimens from the Veterans Aging Cohort Study (VACS). New data to be obtained include targeted metabolomics and updated adjudication of major adverse cardiac events (myocardial infarction, ischemic stroke, coronary revascularization, heart failure, peripheral artery disease). We will assess 3 microbiome-dependent metabolic pathways and determine the association of metabolites from these pathways with alcohol, CVD, and death by HIV status. Aim 1 assesses SCFA metabolic pathways focusing primarily on butyrate, a metabolite necessary for intestinal cell health. Aim 2 assesses choline metabolic pathways focusing primarily on trimethylamine N-oxide (TMAO), a metabolite associated with increased CVD risk. Aim 3 assesses bile acid metabolic pathways focusing on the deoxycholic acid to cholic acid ratio, which may be associated with dyslipidemia. For each aim, we will identify metabolites independently associated with alcohol use, CVD, and/or death and determine whether these associations are unique to or accentuated among PLWH vs. people without HIV. Aim 4 will replicate the associations of heavy drinking and these metabolites with baseline data from the META HIV CVD clinical trial participants (Project 1). IMPACT: This study advances understanding of how alcohol-associated gut dysbiosis and dependent metabolites contribute to CVD and death. If our hypotheses are confirmed, these results could lead to the identification of new therapeutic targets for reducing CVD among PLWH who are heavy drinkers.

Unhealthy alcohol consumption and HIV infection are independently linked to heart disease, so people with HIV who drink heavily are at very high risk for heart disease. Alcohol changes the gut bacteria (called the microbiome) which in turn changes their breakdown products, decreasing beneficial products and increasing harmful ones. This study will test whether alcohol's effects on the gut bacteria and the resulting changes in breakdown products contribute to heart disease in people with HIV who drink heavily.