Microbial and inflammatory features linked to distal sensory polyneuropathy in people with HIV.

Persistent immune activation and gut dysbiosis have been implicated in HIV-related comorbidities, but their contribution to distal sensory polyneuropathy (DSP) remains unclear. We examined relationships among systemic inflammatory markers, gut microbiome composition, and DSP in a cross-sectional cohort of 61 people with HIV (PWH) with DSP, 93 PWH without DSP, and 64 people without HIV and DSP. Gut microbiota were profiled by 16S-rRNA sequencing and serum cytokines by multiplex immunoassays. Inflammatory profiles differed across groups overall, but not between PWH with and without DSP, indicating that the serum inflammatory markers assessed did not distinguish DSP status within PWH. In contrast, gut microbiome composition differed across all groups, including between PWH with and without DSP. Bayesian differential abundance analysis identified the greatest number of altered taxa in the comparison of PWH with versus without DSP, with enrichment of taxa assigned most frequently to Enterocloster and Bacteroides_H genera in DSP. A log-ratio derived from differentially abundant taxa captured HIV- and DSP-related microbial signatures. In integrated XGBoost models, combined demographic, clinical, inflammatory, and microbial features classified DSP with moderate accuracy (AUC = 0.83), with the DSP-associated microbial log-ratio and age emerging as the strongest predictors. Exploratory mediation analysis showed no evidence that the microbial log-ratio mediated the association between age and DSP. These findings identify gut microbial signatures linked to DSP in PWH and support a potential role for gut dysbiosis in neuropathic vulnerability. Longitudinal studies are needed to test causality and evaluate microbiome-based biomarkers and therapeutic targets for HIV-associated DSP.