Investigating Microbiome-Epigenome Crosstalk in HIV-Associated Neurocognitive Disorder Among Adults in South West Nigerian Cohorts

HIV-associated neurocognitive disorder (HAND) affects up to 50 percent of people living with HIV despite antiretroviral therapy, yet the mechanistic pathways linking gut microbiome dysbiosis, systemic inflammation, and epigenetic modifications driving neurocognitive decline in African populations on ART have not been investigated. This dissertation investigates microbiome-epigenome crosstalk in HAND among HIV-positive adults at antiretroviral clinics in Lagos and Ogun States, South West Nigeria. A case-control design enrolled 80 HAND cases (defined by International Neuropsychological Society criteria) and 80 cognitively normal HIV-positive controls matched for ART regimen, CD4 count, and age. Stool microbiome profiling by 16S rRNA sequencing and peripheral blood DNA methylation analysis by reduced representation bisulfite sequencing (RRBS) were performed alongside plasma cytokine quantification. Integration of microbiome, methylome, and cytokine data used a joint multi-omics factor analysis (MOFA2) framework. HAND cases showed Bacteroidetes depletion, Proteobacteria enrichment, and elevated plasma IL-6 and sCD14 levels. MOFA2 identified a latent factor driven by Prevotella-derived LPS elevation associated with hypomethylation of neuroinflammation-related gene promoters including TNF and IL1B. Mendelian randomisation analysis supported causal relationships between gut Prevotella abundance and neurocognitive decline. The dissertation introduces the Microbiome-Epigenome Neurocognitive Axis (MENA) theoretical framework, providing mechanistic insight into microbiome-mediated neuroinflammation as a HAND pathway in sub-Saharan African populations. Keywords: HAND, HIV, gut microbiome, epigenomics, South West Nigeria