Vaginal microbiota transfer ameliorates cesarean-associated neurodevelopmental deficits in mice via N-bc2S1P synthesis on neonatal skin.

Cesarean section (CS) bypasses neonatal exposure to maternal vaginal microbiota, leaving the metabolic contribution of skin microbiota to neurodevelopment unclear. In CS neonates receiving vaginal microbiota transfer, skin multi-omics at 24 h identified restoration of β-carboline-sphingosine-1-phosphate (N-bc2S1P), whose levels correlated with ASQ-3 scores at 3 and 6 months. In mice, N-bc2S1P assembled on neonatal skin by Lactobacillus crispatus and Bacteroides fragilis reaches the brain and selectively triggers β-arrestin1-biased S1PR2 signaling in forebrain excitatory neurons. This pathway promotes AP-1/CBP recruitment, increases H3K27 acetylation at Notch loci, and transiently ameliorates CS-associated early-life neurodevelopmental impairments. Because N-bc2S1P is rapidly cleared, we engineered the skin commensal Staphylococcus epidermidis to co-synthesize β-carboline and S1P, sustaining cutaneous N-bc2S1P production, prolonging brain exposure, and improving neurodevelopmental outcomes. These findings identify a microbe-derived, arrestin-biased S1PR2 agonist and show that engineered skin commensals extend transient maternal microbial signals into more durable neurodevelopmental benefit in mice.