Cross-site multi-omic analysis links microbial dysbiosis, systemic inflammation and metabolomic disruptions to serious non-AIDS event risk in treated HIV infection

Serious non-AIDS events (SNAEs) including non-AIDS malignancies, cardiovascular events, and hepatic disease are major causes of mortality in treated HIV infection. These outcomes are driven by chronic immune activation, systemic inflammation, and metabolic dysfunction that continue despite viral suppression with antiretroviral therapy (ART). To investigate mechanisms underlying SNAE pathogenesis, we conducted a cross-site, multi-omic analysis integrating plasma proteins, plasma metabolites, and mucosal microbiomes (ileum and rectum) in 82 ART-treated people with HIV (PWH) from the United States and Mexico. Geography was the dominant source of variation, particularly within lipid classes, yet individuals at high risk for SNAEs, defined by low CD4 T cell counts and CD4/CD8 ratios, shared a consistent signature of systemic inflammation, mitochondrial dysfunction, and microbial dysbiosis. High-risk participants exhibited elevated plasma IL-6, omega-oxidation products (adipic and suberic acids), bile acid and polyamine metabolites, and depletion of short-chain fatty acid-producing commensals in the gut mucosa including Akkermansia muciniphila, Bacteroides uniformis, and Ruminococcus. Correlation analysis notably linked A. muciniphila abundance to reduced IL-6 concentrations, reduced HIV RNA-producing cells in lymph nodes, and increased CD4/CD8 ratios, suggesting that loss of this taxon in the mucosa contributes to immune activation and impaired immune restoration. Integrated modeling (DIABLO) across omic layers achieved high discrimination of SNAE risk (AUROC = 0.87). Together, these findings reveal a shared phenotype of systemic inflammation, mitochondrial dysfunction, and microbial dysbiosis in PWH, and implicates A. muciniphila as a potential microbiome-based therapeutic to reduce immune activation and SNAE risk in treated HIV infection.