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. 2025 Aug;156(2):433-448.
doi: 10.1016/j.jaci.2025.03.018. Epub 2025 Apr 3.

Gene-by-environment interactions modulate the infant gut microbiota in asthma and atopy

Sara A Stickley  1 , Zhi Yi Fang  1 , Amirthagowri Ambalavanan  1 , Yang Zhang  2 , Amanda M Zacharias  1 , Charisse Petersen  3 , Darlene Dai  3 , Meghan B Azad  4 , Jeffrey R Brook  5 , Piushkumar J Mandhane  6 , Elinor Simons  7 , Theo J Moraes  8 , Michael G Surette  9 , Stuart E Turvey  3 , Padmaja Subbarao  8 , Qingling Duan  10
Affiliations
Free article

Gene-by-environment interactions modulate the infant gut microbiota in asthma and atopy

Sara A Stickley et al. J Allergy Clin Immunol. 2025 Aug.
Free article

Abstract

Background: Gut microbiota has been associated with health and susceptibility to childhood diseases, including asthma and allergies. However, the genomic factors contributing to interindividual variations in gut microbiota remain poorly understood.

Objective: We sought to integrate host genomics with early-life exposures to investigate main and interaction effects on gut microbiota during the first year of life. In addition, we identified gut microbes associated with childhood respiratory (asthma, wheeze) and atopic (atopic dermatitis, food/inhalant sensitization) outcomes.

Methods: We leveraged microbiome data from infant stool at ages 3 months (N = 779) and 1 year (N = 770) from the CHILD Cohort Study. We identified microbial taxa and co-occurring network clusters associated with asthma and atopy by age 5 years. Genome-wide association studies and gene-by-environment interaction analyses determined main and interaction effects of host genomics and early-life environmental exposures (eg, feeding practices, household pets, and birth characteristics) on gut microbial features.

Results: Shifts in microbial taxa and network clusters during the first year of life were associated with childhood respiratory and atopic outcomes (P < .05), some of which were sex-specific. In addition, some of these implicated microbes were associated with host genomics and early-life exposures. For example, Blautia obeum was associated with reduced food/inhalant sensitization and genetic variants near the MARCO gene (P = 9.4 × 10-11). Also, variants near the SMAD2 gene interact with breast-feeding to influence the green microbial network cluster (P = 8.3 × 10-10), associated with asthma.

Conclusions: Our study reports main and interaction effects of genomics and exposures on early-life gut microbiota, which may contribute to childhood asthma and atopy. Improved understanding of the factors contributing to gut dysbiosis will inform on early-life biomarkers and interventions.

Keywords: Gut microbiota; asthma; atopic dermatitis; atopic sensitization; gene-by-environment (G × E) interaction; genome-wide association study (GWAS); network analysis; sex-stratified; wheeze.

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Conflict of interest statement

Disclosure statement This study was funded by operating grants from Canadian Institutes of Health Research (grant nos MRT-168044 and PJT-178390). Disclosure of potential conflict of interest: M. B. Azad has consulted for DSM Nutritional Products (a food ingredient company), serves on the Scientific Advisory Board for Tiny Health (a microbiome testing company), and has received research funding (unrelated to this project) and speaking honoraria from Prolacta Biosciences (a human milk fortifier company). The rest of the authors declare that they have no relevant conflicts of interest. Data availability: The genome-wide association study summary statistics generated in this study have been deposited in the GWAS Catalogue database under accession number GCP ID GCP001221. Data from the CHILD Cohort Study are available from the CHILD database: https://childstudy.ca/childdb/.