Human Milk Oligosaccharides (HMOs) in Infant Neurodevelopment: Evidence Linking Gut–brain Signaling to Cognitive Outcomes

This narrative review summarizes current evidence on the association between human milk oligosaccharides (HMOs) and infant neurodevelopment. HMOs are complex bioactive carbohydrates naturally present in human breast milk and are increasingly recognized for their potential role in supporting early brain development through interactions with the gut microbiome, immune system, and metabolic pathways. Relevant literature was identified through structured searches of PubMed, Scopus, and Web of Science covering studies published between 2000 and 2025. The review included human observational cohort studies, mechanistic research, and preclinical models that examined neurodevelopmental outcomes such as cognitive function, language acquisition, motor skills, and socio-emotional development in infants and young children. Current human evidence, although largely observational, suggests that exposure to certain HMOs—particularly fucosylated and sialylated structures such as 2′-fucosyllactose (2′-FL), 3′-sialyllactose (3′-SL), and 6′-sialyllactose (6′-SL)—may be associated with improved neurodevelopmental outcomes. Infants exposed to higher levels of these HMOs during early life have been reported to show better cognitive performance, language development, and behavioral regulation. Early-life exposure appears especially important, as this period coincides with rapid brain growth and neural network formation. Several biological mechanisms may explain these associations. HMOs influence the gut–brain axis by promoting beneficial microbiota, particularly Bifidobacterium, which produce metabolites that can affect neural signaling and brain development. Additionally, sialylated HMOs provide sialic acid, a key component required for the synthesis of gangliosides and myelin that support neuronal connectivity and signal transmission. HMOs may also contribute to immune regulation and anti-inflammatory processes, helping to protect the developing brain from inflammatory stress. Despite promising findings, causal evidence remains limited. Most studies are observational and vary in design, HMO measurement methods, and participant characteristics. Important confounding factors, including maternal secretor status, breastfeeding duration, maternal nutrition, and socioeconomic influences, may affect observed associations. Furthermore, randomized controlled trials investigating direct neurodevelopmental effects of specific HMOs are still scarce. Future research should prioritize standardized HMO quantification, larger longitudinal cohorts, integration of neuroimaging techniques, and well-designed interventional trials to better clarify the role of HMOs in early brain development and long-term cognitive outcomes.