Gözde Gürdeniz1, Madeleine Ernst2, Daniela Rago1, Min Kim1, Julie Courraud2, Jakob Stokholm1, Klaus Bønnelykke1, Anders Björkbom2, Urvish Trivedi3, Søren J Sørensen3, Susanne Brix4, David Hougaard2, Morten Rasmussen1,5, Arieh S Cohen2, Hans Bisgaard1, Bo Chawes6. 1. COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark. 2. Section for Clinical Mass Spectrometry, Dept of Congenital Disorders, Danish Center for Neonatal Screening, Statens Serum Institut, Copenhagen, Denmark. 3. Dept of Biology, University of Copenhagen, Copenhagen, Denmark. 4. Dept of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark. 5. Section of Chemometrics and Analytical Technologies, Dept of Food Science, University of Copenhagen, Copenhagen, Denmark. 6. COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark chawes@copsac.com.
Abstract
BACKGROUND: Birth by caesarean section is linked to an increased risk of developing asthma, but the underlying mechanisms are unclear. OBJECTIVE: To elucidate the link between birth by caesarean section and asthma using newborn metabolomic profiles and integrating early-life gut microbiome data and cord blood immunology. METHODS: We investigated the influence of caesarean section on liquid chromatography mass spectrometry 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 caesarean section metabolic profile, gut microbiome data and frequency of cord blood regulatory T-cells (Tregs) at 1 week of age. RESULTS: In COPSAC2010, a partial least square discriminant analysis model showed that children born by caesarean section versus natural delivery had different metabolic profiles (area under the curve (AUC)=0.77, p=2.2×10-16), which was replicated in COPSAC2000 (AUC=0.66, p=1.2×10-5). The metabolic profile of caesarean section was significantly associated with an increased risk of asthma at school age in both COPSAC2010 (p=0.03) and COPSAC2000 (p=0.005). Caesarean section was associated with lower abundance of tryptophan, bile acid and phenylalanine metabolites, indicative of a perturbed gut microbiota. Furthermore, gut bacteria dominating after natural delivery, i.e. Bifidobacterium and Bacteroides were correlated with caesarean section-discriminative microbial metabolites, suggesting maternal microbial transmission during birth regulating the newborn's metabolism. Finally, the caesarean section metabolic profile was associated with frequency of cord blood Tregs. CONCLUSIONS: These findings propose that caesarean section programmes the risk of childhood asthma through perturbed immune responses and gut microbial colonisation patterns reflected in the blood metabolome at birth.
BACKGROUND: Birth by caesarean section is linked to an increased risk of developing asthma, but the underlying mechanisms are unclear. OBJECTIVE: To elucidate the link between birth by caesarean section and asthma using newborn metabolomic profiles and integrating early-life gut microbiome data and cord blood immunology. METHODS: We investigated the influence of caesarean section on liquid chromatography mass spectrometry 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 caesarean section metabolic profile, gut microbiome data and frequency of cord blood regulatory T-cells (Tregs) at 1 week of age. RESULTS: In COPSAC2010, a partial least square discriminant analysis model showed that children born by caesarean section versus natural delivery had different metabolic profiles (area under the curve (AUC)=0.77, p=2.2×10-16), which was replicated in COPSAC2000 (AUC=0.66, p=1.2×10-5). The metabolic profile of caesarean section was significantly associated with an increased risk of asthma at school age in both COPSAC2010 (p=0.03) and COPSAC2000 (p=0.005). Caesarean section was associated with lower abundance of tryptophan, bile acid and phenylalanine metabolites, indicative of a perturbed gut microbiota. Furthermore, gut bacteria dominating after natural delivery, i.e. Bifidobacterium and Bacteroides were correlated with caesarean section-discriminative microbial metabolites, suggesting maternal microbial transmission during birth regulating the newborn's metabolism. Finally, the caesarean section metabolic profile was associated with frequency of cord blood Tregs. CONCLUSIONS: These findings propose that caesarean section programmes the risk of childhood asthma through perturbed immune responses and gut microbial colonisation patterns reflected in the blood metabolome at birth.