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.
Abstract
Birth by caesarean section influences the risk of asthma, partially by gut microbial colonisation and perturbed immune responses reflected by dysregulations in bile acid and tryptophan metabolism during early life https://bit.ly/3mFuqt0
Footnotes
Author contributions: G. Gürdeniz, B. Chawes, H. Bisgaard and D. Rago developed the concept and designed the overall study approach. A.S. Cohen, A. Björkbom and D. Hougaard organised and conducted mass spectrometric analysis. M. Ernst and J. Courraud interpreted mass spectra. S.J. Sørensen and U. Trivedi performed the gut microbiome analysis. S. Brix provided cord blood immune data. D. Rago, M. Kim, M. Ernst, A.S. Cohen, M. Rasmussen, J. Stokholm, K. Bønnelykke, H. Bisgaard and G. Gürdeniz interpreted the data. G. Gürdeniz, B. Chawes, H. Bisgaard and M. Ernst wrote the manuscript.
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Governance: We are aware of and comply with recognised codes of good research practice, including the Danish Code of Conduct for Research Integrity. We comply with national and international rules on the safety and rights of patients and healthy subjects, including Good Clinical Practice (GCP) as defined in the European Union's Directive on Good Clinical Practice, the International Conference on Harmonisation's (ICH) good clinical practice guidelines and the Helsinki Declaration. Privacy is important to us which is why we follow national and international legislation on General Data Protection Regulation (GDPR), the Danish Act on Processing of Personal Data and the practice of the Danish Data Inspectorate.
Conflict of interest: All authors declare no potential, perceived, or real conflict of interest regarding the content of this manuscript. The funding agencies did not have any role in design and conduct of the study; collection, management, and interpretation of the data; or preparation, review, or approval of the manuscript. No pharmaceutical company was involved in the study.
Support statement: All funding received by COPSAC is listed on www.copsac.com. The Lundbeck Foundation (grant number R16-A1694); the Ministry of Health (grant number 903516); Danish Council for Strategic Research (grant number 0603-00280B); and The Capital Region Research Foundation have provided core support to the COPSAC research centre. This research is also supported by Danish National Biobank resource and the Novo Nordisk Foundation. Furthermore, this project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement number 946228). Funding information for this article has been deposited with the Crossref Funder Registry.
- Received September 3, 2021.
- Accepted October 27, 2021.
- Copyright ©The authors 2022. For reproduction rights and permissions contact permissions{at}ersnet.org
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