Influence of infant gut microbiome and breastmilk HMOs on neurodevelopment in children exposed to HIV

ABSTRACT
The advent of universal maternal antiretroviral therapy (test and treat and Option B Plus) has vastly improved
health, development, and survival prospects for children exposed to HIV but uninfected (HEU), a population that
grows by 1.5 million each year. However, poor outcomes in these domains have persisted, and underlying
mechanisms remain unclear, particularly for neurodevelopment. Recent prospective studies of birth and infant
cohorts suggest mild to moderate neurodevelopmental compromise in motor, language and cognitive outcomes.
This study will examine neurodevelopment in a unique longitudinal cohort of children with HEU versus HIV
unexposed uninfected (HUU) in sub-Saharan Africa (SSA). Additionally, we will examine plausible and potentially
modifiable mechanisms, including alterations in the gut microbiome and breastmilk composition. Proper
establishment of a healthy gut microbiome in infancy is increasingly recognized as influential for brain
development. The infant gut microbiome could be compromised by numerous factors relevant for HEU children,
including maternal drug exposure and poor health, infant antibiotic exposure, feeding practice, and breastmilk
composition. Recent studies suggest differences in composition and profile of the infant gut microbiome in HEU
children vs. their age-matched HUU counterparts. Profile and concentration of certain human milk
oligosaccharides, which are nonnutritive glycans that can function as prebiotics, as pathogen blockers, or as
immune modulators, may also differ in lactating women infected with HIV. Strategic emphasis of certain
complementary foods as prebiotics and supplementation of human breastmilk using specific HMOs offer two
promising avenues for intervention for HEU children and are strategies that may also benefit other subsets of
the general population at risk for poor neurodevelopmental outcomes. This novel project will leverage an ongoing
cohort with detailed serial specimen collection for gut microbiome and breastmilk HMO profile in both HEU and
HUU children. In Aim 1, we will compare motor, language, cognition, self-regulation and executive function skills
in HEU vs HUU children at 24 and 36 months to inform on the impact of HIV exposure on neurodevelopment in
early childhood. In Aim 2, we will examine the relation between these outcomes and early infant gut microbiome
diversity and composition, and will add to still nascent literature on early infant gut microbiome changes and
neurodevelopment both in and outside the context of HIV. In Aim 3, we will examine the relation between
concentration of specific HMOs and neurodevelopmental outcomes, and will directly inform efforts to identify and
test candidate HMO supplements for promoting infant health and growth. This project will generate critical
evidence to inform future clinical trials for use in SSA and other low-resource settings to improve development
in HEU children and strategies to complement existing efforts to promote breastfeeding.

Grant Number: 4P01HD107669-02
NIH Institute/Center: NIH
Principal Investigator: SARAH BENKI-NUGENT