Oral supplementation of 6'-sialyllactose in early-life enhances cognitive function in mice via modulating gut microbiota and promoting brain myelination.

This study aimed to investigate the effects of early-life oral supplementation with 6'-sialyllactose (6'-SL) on neurobehavioral development in mice and the potential mechanisms involving the microbiota-gut-brain (MGB) axis. Neonatal mice received daily oral gavage of saline or 6'-SL from birth to postnatal day (PND) 21. Behavioral tests (Y-maze, open field, light-dark box, forced swim test) were conducted from PND 37-41. Fecal metagenomics and short-chain fatty acid (SCFA) levels were assessed, and brain gene expression was analyzed by RNA sequencing and reverse transcription quantitative real-time PCR (RT-qPCR) at PND 21 and PND 42. Our findings revealed that 6'-SL supplementation enhanced cognitive function in growing mice, as evidenced by improved performance in the Y-maze test. Early-life 6'-SL supplementation exerts profound and sustained regulatory effects on the gut microbiota and SCFA. At PND 21, 6'-SL enriched Akkermansia muciniphila and elevated acetate, isobutyrate, and isovalerate, while suppressing Enterococcus. At PND 42, Akkermansia muciniphila and Escherichia were further enriched, while Alistipes and Duncaniella were inhibited. Meanwhile, acetate, isobutyrate and propionate levels remained elevated. Notably, these changes were observed not only at the end of the intervention but also persisted at PND 42, indicating a sustained long-term effect of 6'-SL supplementation. In contrast, most myelin genes were altered only to a small extent at PND 21, compared with their marked upregulation in the PFC at PND 42 (Mbp, Mog, Olig1, Sox10, Egr2, Vegfa). Correlation analysis revealed that the abundance of Akkermansia muciniphila was positively correlated with isobutyrate levels, Escherichia showed a positive correlation with propionate levels, while Enterococcus was negatively correlated with acetic acid. These SCFA were positively associated with myelin gene expression. Further, these genes were positively associated with cognitive performance, suggesting their potential involvement in cognitive function. Thus, 6'-SL enhances spatial cognition in early-life mice through a mechanism involving gut microbiota and SCFA modulation, subsequent upregulation the transcription of prefrontal myelination-related gene. This study provides novel insights into the mechanisms by which 6'-SL regulates early brain development via the MGB axis and offers critical theoretical support for nutritional supplementation strategies in infancy.