Gut microbiota-mediated fiber fermentation in HIV-associated cardiovascular disease

PROJECT ABSTRACT: While antiretroviral therapy has significantly increased lifespan of people with HIV (PWH), heightened rates of cardiovascular comorbidities continue to occur in this population as compared to HIV-seronegative individuals. The mechanistic basis of this elevated cardiovascular disease (CVD) risk in PWH remains poorly understood and constitutes a barrier to devising effective treatments. Hypertension increases CVD risk and recent work has uncovered a role for gut microbial metabolism in modulating hypertension. The gut microbiota is significantly altered in antiretroviral-treated PWH, and the most robustly observed change in the HIV-associated gut microbiota is a depletion of microbes capable of metabolizing dietary fiber into short chain fatty acids (SCFAs). Prior work from outside the realm of HIV research suggests a depletion of SCFAs can cause increased blood pressure and consequently increase cardiovascular disease incidence. Whether the loss of gut microbial SCFA producers in PWH contributes to elevated cardiovascular disease risk remains an important but unexplored question. Through this Catalyst Award, I will test the impact of the HIV- associated gut microbiota on bioavailable SCFA production and investigate effects of fiber fermentation on hypertension and manifestations of cardiovascular disease using a combination of murine gnotobiotic and specific pathogen-free models, omics technologies, and computational biology. Mechanisms of host SCFA uptake and utilization as well as methods to augment SCFA production within the HIV-associated microbiota will be explored to identify pathways that can be targeted to alleviate hypertension in PWH. This high-risk series of studies have potential to elucidate mechanisms of CVD risk in PWH and identify microbiota-directed therapeutic modalities.