Systems analysis of gut microbiome influence on metabolic disease in HIV and high-risk populations

Abstract

Poor metabolic health, characterized by insulin resistance and dyslipidemia, is higher in people living with HIV (PLWH) and has been linked with inflammation, anti-retroviral therapy (ART) drugs, and ART-associated lipodystrophy (LD). Metabolic disease is associated with gut microbiome composition outside the context of HIV but has not been deeply explored in HIV infection nor in high-risk men who have sex with men (HR-MSM), who have a highly altered gut microbiome composition. Furthermore, the contribution of increased bacterial translocation and associated systemic inflammation that has been described in HIV-positive and HR-MSM individuals has not been explored. We used a multi-omic approach to explore relationships between gut microbes, immune phenotypes, diet, and metabolic health across ART-treated PLWH with and without LD; untreated PLWH; and HR-MSM. For PLWH on ART, we further explored associations with the plasma metabolome. Sixty-nine measures of diet, gut microbes, inflammation, and demographics were associated with impaired metabolic health defined using fasting blood markers including lipids, glucose and hormones. We found microbiome-associated metabolites associated with metabolic disease including the microbially produced metabolites, dehydroalanine and bacteriohopane-32,33,34,35-tetrol. Our central result was that elevated plasma lipopolysaccharide binding protein (LBP) was the most important predictor of metabolic disease in PLWH and HR-MSM, with network analysis of predictors showing that LBP formed a hub joining correlated microbial and immune predictors of metabolic disease. Our results suggest the role of inflammatory processes linked with bacterial translocation (measured by LBP) and interaction with dietary components and the gut microbiome in metabolic disease among PLWH and HR-MSM.