Human milk oligosaccharides promote synaptogenesis and neurite outgrowth in human cortical organoids

The first 1000 days of a child's life represent a critical window for brain development, during which nutrition exerts profound effects on the trajectories of neurodevelopment. Human Milk Oligosaccharides (HMOs), a major component of human milk, are largely indigestible by infants and are known to influence immunity, microbiome composition, and gut-brain signaling, but their direct role in neurodevelopment remains poorly understood. Here, we investigated the impact of HMOs on human cortical organoids, a physiologically relevant in vitro model of early brain development. We found that HMO treatment significantly enhanced neurite outgrowth and synaptogenesis in a dose-dependent manner. Global proteomic profiling further demonstrated the upregulation of proteins associated with neuronal differentiation, synaptic maturation, and cytoskeletal remodeling. Our findings suggest that HMOs can influence neurodevelopmental processes and highlight a potential role for maternal milk components in early brain development. • Human milk oligosaccharides (HMOs) modulate synaptic density in human cortical organoids. • HMOs influence neural connectivity during early development. • Genetic background shapes HMO-mediated effects. • HMOs upregulate RNA splicing pathways in cortical organoids.