Dysregulation of Gut Microbiota‐Derived Neuromodulatory Amino Acid Metabolism in Human Immunodeficiency Virus‐Associated Neurocognitive Disorder: An Integrative Metagenomic and Metabolomic Analysis

Objective Although accumulating evidence implicating altered gut microbiota in human immunodeficiency virus (HIV) infection and neurodegenerative disorders; however, the association between dysbiosis of the gut microbiota and metabolites in the pathogenesis of HIV‐associated neurocognitive disorder (HAND) remains unclear. Methods Fecal and plasma samples were obtained from 3 cohorts (HAND, HIV–non‐HAND, and healthy controls), metagenomic analysis and metabolomic profiling were performed to investigate alterations in the gut microbial composition and circulating metabolites in HAND. Results The gut microbiota of people living with HIV (PLWH) had an increased relative abundance of Prevotella and a decreased relative abundance of Bacteroides . In contrast, Prevotella and Megamonas were substantially decreased, and Bacteroides and Phocaeicola were increased in HAND patients. Moreover, untargeted metabolomics identified several neurotransmitters and certain amino acids associated with neuromodulation, and the differential metabolic pathways of amino acids associated with neurocognition were depleted in HAND patients. Notably, most neuromodulatory metabolites are associated with an altered abundance of specific gut bacteria. Interpretation Our findings provide new insights into the intricate interplay between the gut and microbiome‐brain axis in the pathogenesis of HAND, highlighting the potential for developing novel therapeutic strategies that specifically target the gut microbiota. ANN NEUROL 2024;96:306–320