BACKGROUND: Birth by cesarean section (CS) is linked to an increased risk of developing asthma, but the underlying mechanisms are unclear.

OBJECTIVE: To elucidate the link between birth by CS and asthma using newborn metabolomic profiles and integrating early life gut microbiome data and cord blood immunology.

METHODS: We investigated the influence of CS on liquid chromatography mass spectrometry (LC-MS) metabolomic profiles of dried blood spots from newborns of the two independent Copenhagen Prospective Studies on Asthma in Childhood cohorts, i.e. COPSAC2010 (n=677) and COPSAC2000 (n=387). We assessed the associations between the CS metabolic profile, age one-week gut microbiome data and frequency of cord blood Tregs.

RESULTS: In COPSAC2010, a partial least square-discriminant analysis (PLS-DA) model showed that children born by CS versus natural delivery had different metabolic profiles (AUC=0.77, p=2.2e-16), which was replicated in COPSAC2000 (AUC=0.66, p=1.2e-5). The metabolic profile of CS was significantly associated with an increased risk of asthma at school-age in both COPSAC2010 (p=0.03) and COPSAC2000 (p=0.005). CS was associated with lower abundance of tryptophan, bile acid and phenylalanine metabolites, indicative of a perturbed gut microbiota. Further, gut bacteria dominating after natural delivery, i.e. Bifidobacterium and Bacteroides were correlated with CS-discriminative microbial metabolites, suggesting maternal microbial transmission during birth regulating the newborn's metabolism. Finally, the CS metabolic profile was associated with frequency of cord blood Tregs.

CONCLUSIONS: These findings propose that CS is programming the risk of childhood asthma through perturbed immune responses and gut microbial colonization patterns reflected in the blood metabolome at birth.