Neonatal metabolome of caesarean section and risk of childhood asthma

Gözde Gürdeniz; Madeleine Ernst; Daniela Rago; Min Kim; Julie Courraud; Jakob Stokholm; Klaus Bønnelykke; Anders Björkbom; Urvish Trivedi; Søren J Sørensen; Susanne Brix; David Hougaard; Morten Rasmussen; Arieh S Cohen; Hans Bisgaard; Bo Chawes

doi:10.1183/13993003.02406-2021

Neonatal metabolome of caesarean section and risk of childhood asthma

Eur Respir J. 2022 Jun 23;59(6):2102406. doi: 10.1183/13993003.02406-2021. Print 2022 Jun.

Authors

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 Rasmussen^{1

5}, Arieh S Cohen², Hans Bisgaard¹, Bo Chawes⁶

Affiliations

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.

PMID: 34887324
DOI: 10.1183/13993003.02406-2021

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Asthma* / etiology
Cesarean Section / adverse effects
Child
Female
Gastrointestinal Microbiome*
Humans
Infant, Newborn
Metabolome
Pregnancy
Prospective Studies