The Intestinal Microbiome and Ectopic Fat in Persons with HIV

Complications of overweight and obesity are responsible for an increasing burden of disease in an aging population of persons with HIV (PWH) in the era of modern ART. One of these complications, non-alcoholic fatty liver disease (NAFLD) is closely associated with visceral adiposity and is a leading cause of morbidity and mortality among PWH. PWH develop NAFLD at lower BMI and with greater physical activity relative to HIV-negative persons. Although the mechanisms underlying this difference are not well understood, intestinal barrier dysfunction is implicated in the pathogenesis of NAFLD and the accumulation of visceral adipose tissue in HIV-negative persons. HIV infection has been shown to alter the intestinal microbiome, change the plasma metabolome and promote intestinal barrier dysfunction; however, there are few data on the microbiome and metabolome among PWH with NAFLD and visceral adiposity. Our pilot preliminary data show that hepatic steatosis and visceral adiposity are associated with bacteria-related metabolites and lipid species [including trimethylamine N-oxide (TMAO) and phosphatidylcholine] among PWH on long-term ART.

We hypothesize that intestinal dysbiosis in PWH contributes to NAFLD and visceral adiposity through two distinct mechanisms: 1) by impairment of IBF and 2) through alteration of the metabolome to promote hepatic and visceral lipid deposition. Our primary Aim for this project is to build upon the recent AIDS Clinical Trials Group study A5350 by testing the feasibility and limited efficacy of a multi-strain probiotic and prebiotic fiber on NAFLD and visceral adipose tissue markers in a prospective trial in PWH. This trial will leverage the well-developed infrastructure and large recruitment pool of the Tennessee Center for AIDS Research. I will be supported by mentors who have a history of multiple successful prior trainees and expertise in clinical and translational HIV research, the metabolome and the microbiome. The support provided by the DRTC P&F grant will allow me to advance my career and training goals, and the data generated with this project will form a foundation for the development of an R01-level grant focused on microbiome-based therapies for PWH with NAFLD and central obesity.