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

Poor metabolic health, characterized by insulin resistance and dyslipidemia, is higher in people living with HIV (PLWH) and has been linked with chronic inflammation, some anti-retroviral therapy (ART) drugs, and ART-associated lipodystrophy (LD). Metabolic disease has been associated with gut microbiome composition outside the context of HIV but has not been deeply explored in the context of HIV infection nor in high-risk men who have sex with men (HR-MSM), who have a highly altered gut microbiome composition. Furthermore, the potential 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 HIV-positive, ART-treated individuals with and without LD; untreated HIV-positive individuals; and HR-MSM. For HIV-positive individuals on ART, we further explored associations with the plasma metabolome. Sixtey-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 plasma lipopolysaccharide binding protein (LBP) as the most important predictor of metabolic disease in HIV-infected and HR-MSM. LBP also strongly correlated with several other microbial, diet, and immune predictors of metabolic disease. Our results suggest a central role of inflammatory processes linked with bacterial translocation (measured by LBP) and interaction with dietary components and the gut microbiome in metabolic disease among HIV-infected and HR-MSM.