The upper airways present a barrier to inhaled allergens and microbes, which alter immune responses and subsequent risk for diseases, such as allergic rhinitis (AR).
Objective
We tested the hypothesis that early-life microbial exposures leave a lasting signature in DNA methylation that ultimately influences the development of AR in children.
Methods
We studied upper airway microbiota at 1 week, 1 month, and 3 months of life, and measured DNA methylation and gene expression profiles in upper airway mucosal cells and assessed AR at age 6 years in children in the Copenhagen Prospective Studies on Asthma in Childhood birth cohort.
Results
We identified 956 AR-associated differentially methylated CpGs in upper airway mucosal cells at age 6 years, 792 of which formed 3 modules of correlated differentially methylated CpGs. The eigenvector of 1 module was correlated with the expression of genes enriched for lysosome and bacterial invasion of epithelial cell pathways. Early-life microbial diversity was lower at 1 week (richness P = .0079) in children with AR at age 6 years, and reduced diversity at 1 week was also correlated with the same module’s eigenvector (ρ = −0.25; P = 3.3 × 10−5). We show that the effect of microbiota richness at 1 week on risk for AR at age 6 years was mediated in part by the epigenetic signature of this module.
Conclusions
Our results suggest that upper airway microbial composition in infancy contributes to the development of AR during childhood, and this trajectory is mediated, at least in part, through altered DNA methylation patterns in upper airway mucosal cells.
Key words
Allergic rhinitis
microbiota
DNA methylation
gene expression
early life
upper airways
Abbreviations used
AR
Allergic rhinitis
AS
Allergic sensitization
COPSAC
Copenhagen Prospective Studies on Asthma in Childhood
DMC
Differentially methylated CpG
DNAm
DNA methylation
FDR
False-discovery rate
QC
Quality control
RA
Relative abundance
WGCNA
Weighted gene coexpression network analysis
Cited by (0)
This work was supported by the National Institutes of Health (NIH) (grant no. HL129735 to H.B. and C.O.). Copenhagen Prospective Studies on Asthma in Childhood is funded by private and public research funds (complete list on www.copsac.com), including the Lundbeck Foundation (grant no. R16-A1694), the Danish Ministry of Health (grant no. 903516), the Danish Council for Strategic Research (grant no. 0603-00280B), the Danish Council for Independent Research (grant nos. 10-082884 and 271-08-0815), and the Capital Region Research Foundation. A.M. is supported by Bourse de formation postdoctorale – Fonds de recherche du Québec - Santé. D.V. was supported in part by the NIH (grant nos. AI133765 and AI144722). U.T. and S.J.S. are supported by the Novo Nordisk Fonden.
Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.
