Vaginal microbiota transfer ameliorates cesarean-associated neurodevelopmental deficits in mice via N-bc2S1P...

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.