Neonatal metabolome of cesarean section and risk of childhood asthma

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