Alcohol-Associated Syndemic and Microbiome Evaluation and Targeted Treatment in Persons Living with HIV

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PROJECT SUMMARY One in four people with HIV (PWH) report hazardous drinking [i.e., >7 (14) drinks per week or >3 (4) drinks per occasion for women (men)]. Of this population, 65% report depressive symptoms or smoking, and 21% report all three- constituting an alcohol-associated syndemic (i.e., interaction of 2+ conditions to increase risk for poor outcomes). This syndemic is associated with increased risk of incident cardiovascular disease (CVD). The gastrointestinal (GI) microbiome is a strong candidate mechanistic pathway for the syndemic-related excess CVD risk, through GI dysbiosis, microbial translocation (MT), and systemic inflammation. Dysbiosis is characterized as a decrease in beneficial bacteria and increase in pro-inflammatory bacteria. GI dysbiosis leads to MT, in which tight junctions of the GI lumen are compromised, driving systemic inflammation- a leading cause of CVD. HIV, hazardous drinking, smoking and depression are independently associated with GI dysbiosis, MT and inflammation. Beneficial butyrate producing bacteria, which downregulate pro-inflammatory mediators, are depleted in hazardous drinking PWH. In humans with alcohol use disorder, probiotic use attenuates MT and inflammation. Among PWH, probiotic (e.g., butyrate producing bacteria) with prebiotic use (nutrients for bacterial growth), a combination known as “synbiotic”, favorably alters the GI microbiome within 4-16 weeks. We hypothesize that the alcohol-associated syndemic is associated with GI dysbiosis and subsequent CVD related biomarkers and that targeted supplementation may restore GI microbiome homeostasis and reduce inflammation. With a transdisciplinary mentoring panel at Vanderbilt University Medical Center (VUMC), my career development plan will advance skills in clinical investigation of alcohol syndemic phenotypes; microbiome structure, function, diversity and immunology; clinical & translational research; and primary data collection, responsible conduct of research, and leadership. Aim 1 will identify changes in the GI microbiome among PWH with the alcohol-associated syndemic over 12 months, Aim 2 will determine changes in biomarker profiles related to GI permeability, MT, and inflammation among PWH with the alcohol-associated syndemic over 12 months, and Aim 3 will evaluate the a) feasibility of administering a butyrate supplement pill followed by a multi-strain synbiotic (prebiotic + probiotic) pill and b) treatment effects on GI microbiome structures and CVD-related biomarkers among PWH with the alcohol-associated syndemic (n=40). Aims 1 & 2 leverage secondary data from an NIAAA-funded microbiome study of 200 PWH with existing GI microbiome data, sero-biomarker data, and validated self-reports of alcohol use, smoking, and depressive symptoms. Aim 3 utilizes the infrastructure of the Tennessee Center for AIDS Research at VUMC, which has a strong record of supporting Early Career Faculty. This award will facilitate my transition to an independent investigator with expertise in alcohol/CVD epidemiology, microbiome structure and function, and clinical trial development among PWH, and will also provide informative data for an R01 application.