Gut permeability and variations in bio-available vitamin D as mechanisms of adverse cognitive development in HIV-affected & control children - Anested Pilot Study

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Vitamin D deficiency (VDD) is common in the general population, especially among people living in higher altitudes or areas with limited sunshine as well as persons living with HIV (PLWH). VDD impacts the gut microbiome and disturbances along the gut-brain microbiota axis may influence the central nervous system (CNS) homeostasis, alter innate and adaptive immune systems, and increase intestinal permeability and microbial translocation making the gut and blood-brain barriers leaky. VDD is also associated with higher prevalence of developmental disorders like autism spectrum disorder (ASD), attention deficit and hyperactivity disorder (ADHD), and poor socio-emotional adjustment in children. Studies among cART treated persons suggest ART further dysregulates vitamin D metabolome in potentially regimen dependent fashion. For children HIV exposed but uninfected, whether peripartum-ART exposure during sensitive developmental windows results in long-lasting changes in the metabolome of vitamin D with consequence for gut microbial profile and neurodevelopmental trajectory remains unknown. Our ongoing RO1 study aims to develop a Cognitive Risk Index (CRI) by combining data on nutrition, immune parameters and HIV status and their interactions to validate CRI as a predictor of neurocognitive disorders at 12 months. In this pilot study we collect preliminary data for future definitive investigations and inform existing knowledge gap by investigating HIV status and early ART exposure related dysregulations in vitamin D metabolome and gut- microbial dysbiosis as modifiable mechanisms of adverse cognitive development and developmental disorder risk in vulnerable children. Specific aims include: To a) Assess vitamin D metabolites using a metabolomic approach to quantify relative abundance of bioactive forms of the respective Vitamin-D canonical forms (D2, D3). b) Assess biomarkers of intestinal permeability and its relationship with VDD, and HIV status. c) Clinically evaluate and diagnose 100 children selected per baseline disorder probability scores estimated per the Behavioral Assessment System for Children, Third Edition (BASC3) and the social Responsiveness Scale, Second Edition. Overall Impact: This data will provide preliminary data that serves as proof of concept to further establish the scientific rationale for a more definitive mechanistic study of variations in the metabolome of vitamin D and gut-microbial dysbiosis as modifiable determinants of adverse neurodevelopment among Ugandan HIV-affected and control children.