Effects of Human Milk Oligosaccharides and Gut Microbiome on Growth and Morbidity in HIV-Exposed Uninfected Infants

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PROJECT SUMMARY/ABSTRACT Despite the success in global health efforts to prevent mother-to-child transmission of HIV, there is a growing and often overlooked HIV-exposed uninfected (HEU) population with substantially higher risk of growth faltering, infectious morbidity, and mortality than HIV-unexposed uninfected (HUU) infants. The mechanisms responsible for poor growth and susceptibility to infection in HEU infants are unclear, but recent evidence implicates perturbations in the infant gut microbiome as a critical mechanism. Breast milk seeds the infant gut microbiome, contributing nearly one-third of bacterial communities. The third largest component of breast milk are human milk oligosaccharides (HMOs). HMOs serve as prebiotics, supporting growth of commensal gut bacteria and influencing development of the immune system. Thus, breast milk contains prebiotics (HMOs) and probiotics (bacteria) fundamental for colonization and development the infant gut microbiome. Little is known about the relationship between specific HMOs and specific gut bacteria that may be associated with growth and morbidity in HEU infants. Emerging evidence suggests that maternal HIV infection alters HMO composition and HEU infants have reduced microbial diversity than HUU infants. Given the influence of HMOs on microbiome development and immune function, even a small difference in HMO composition could have important implications for growth and health outcomes in HEU infants. HMOs may be a feasible intervention to improve growth and morbidity in HEU infants. The proposed study will evaluate the association between maternal HIV infection, HMO composition, and the infant gut microbiome, and identify HMO-mediated pathways associated with morbidity and linear growth in HEU infants. We will prospectively enroll and follow HIV-infected and HIV-uninfected women and their infants in Kenya, a region with high prevalence of HIV and poor childhood growth. The study aims to: 1) evaluate the differences in HMO composition and breast milk microbiota between HIV-infected and HIV-uninfected women over time, 2) understand how breast milk as a synbiotic influences bacterial communities and infant microbiome diversity, and 3) determine whether HMOs are associated with linear growth and incidence of diarrhea, pneumonia, and enteric dysfunction in HEU and HUU infants. Results from this longitudinal study will inform our understanding of mechanisms of growth and the role of HMOs and the infant gut microbiome, providing critical data for the design of interventions to optimize growth and health outcomes in HEU children in Africa, a vulnerable and growing population.