GLP-1, Ethanol, and Gut Microbiome dependent Metabolites in HIV (GEM HIV)

Vanderbilt University Medical Center, Nashville TN

Investigators

Abstract

Among people with HIV (PWH), heavy alcohol consumption increases cardiovascular disease (CVD) risk. Presently, few therapies exist that reduce alcohol consumption or mitigate alcohol’s harmful effects. Recently, however, randomized controlled trial (RCT) data suggest that GLP-1 receptor agonists reduce alcohol consumption and CVD risk. Whether increasing levels of endogenous GLP-1 could also reduce alcohol consumption and CVD risk is unknown. Short chain fatty acids (SCFA), secondary bile acids (deoxycholic acid, (DCA)) and dysbiosis derived tryptophan metabolites (e.g., indole derivatives) all stimulate GLP-1 release from intestinal L-cells. Prior work shows that acute alcohol consumption lowers GLP-1 levels, gut dysbiosis reduces SCFAs, DCA levels and indole derivatives. In contrast, probiotics may reduce alcohol consumption. Whether alcohol consumption leading to gut dysbiosis and its derived metabolites, and CVD risk are associated with lower endogenous GLP-1 levels is unknown. Answering this question is important because endogenous GLP-1 improves two CVD risk factors: glucose homeostasis and systemic inflammation. PWH have a two-fold increased risk of CVD. Thus, if true, endogenous GLP-1 may play an important role in the development of and serve as a therapeutic target for CVD among PWH who drink alcohol. For Project 1 of the STAHR Center application, (GLP-1, Ethanol, and Gut Microbiome dependent Metabolites in HIV (GEM HIV)), we hypothesize that (1) alcohol consumption, gut dysbiosis, dysbiosis derived metabolites, and CVD risk are associated with lower endogenous GLP-1 levels among PWH (Aims 1-3), and (2) a probiotic will increase endogenous GLP-1 levels (Aim 4). Our preliminary data among PWH show (1) alcohol is associated with gut dysbiosis, dysbiosis derived metabolites, and CVD; (2) gut dysbiosis is associated with inflammation and lower DCA and indole derivative levels; and (3) lower DCA levels are associated with inflammation. Together, these data provide a strong scientific premise for conducting GEM HIV, which proposes an ancillary study to our ongoing META HIV CVD RCT at the Tennessee Center for AIDS Research, which compares the effects of a probiotic vs. placebo to improve gut dysbiosis; dysbiosis derived metabolites and inflammation; CVD risk; alcohol consumption and HIV disease progression among PWH who are heavy drinkers. New data: measure GLP-1 levels in the META HIV CVD RCT. Our specific aims will determine the association between alcohol consumption and endogenous GLP-1 levels (Aim 1); the association between the characteristics of the gut microbiome (dysbiosis) and endogenous GLP-1 (Aim 2); the association between gut dysbiosis derived metabolites, biomarkers of systemic inflammation and gut permeability, CVD risk, and endogenous GLP-1 (Aim 3); and compare the effects of a probiotic vs. placebo on endogenous GLP-1 (Aim 4). GEM HIV will advance our understanding of the role of GLP-1 and alcohol, gut dysbiosis and its derived metabolites, CVD risk, and determine whether probiotics increase endogenous GLP-1 levels among PWH who drink alcohol.