Human milk oligosaccharides, brain structure, and cognitive development in infants: A narrative review

Human milk oligosaccharides (HMOs) are bioactive components of human milk that support gut microbial development and may also contribute to early brain maturation and cognitive function. This narrative review aimed to synthesize preclinical and clinical evidence on the associations between HMOs, brain structure, and neurodevelopment and to examine the biological mechanisms underlying these effects. PubMed, Scopus, and Web of Science were searched in March 2025 for animal and human studies evaluating specific HMOs in relation to cognitive, behavioral, neurobiological, or neuroimaging outcomes. Of 1,238 records identified, 18 studies met the eligibility criteria and were included in a qualitative thematic synthesis. Preclinical studies indicated that 2'-fucosyllactose (2'-FL) and sialylated HMOs, including 3'-sialyllactose (3'-SL) and 6'-sialyllactose (6'-SL), may improve learning, memory, emotional regulation, and hippocampal long-term potentiation (LTP), although findings varied across experimental models. Proposed mechanisms included vagus nerve-mediated gut-brain signaling, modulation of the gut microbiota, altered neurotransmitter and neurotrophic signaling, and support of synaptogenesis and myelination. Human observational studies associated higher concentrations of 2'-FL, 3'-SL, 6'-SL, and specific HMO combinations during early lactation, particularly around one month postpartum, with better cognitive, language, motor, and executive-function outcomes. Magnetic resonance imaging (MRI) findings further suggested HMO-specific associations with cortical maturation, white-matter connectivity, and myelination. Current evidence supports a potential role for HMOs in early neurodevelopment; however, causal effects remain unconfirmed. Larger, diverse longitudinal studies and randomized controlled trials using standardized neurodevelopmental outcomes are needed to determine optimal HMO compositions, doses, and periods of exposure.