Deep Multi-Omic Profiling Reveals Molecular Signatures that Underpin Preschool Wheeze and Asthma.

Abstract

Background: Wheezing in childhood is prevalent, with over half of all children experiencing at least one episode by age six. The pathophysiology of wheeze, especially why some children develop asthma while others do not, remains unclear.

Objective: This study addresses the knowledge gap by investigating the transition from preschool wheeze to asthma using multi-omic profiling.

Methods: Unsupervised, group-agnostic integrative multi-omic factor analysis was performed using host/bacterial (meta-)transcriptomic and bacterial shotgun metagenomic datasets from bronchial brush samples paired with metabolomic/lipidomic data from bronchoalveolar lavage samples acquired from children 1-17 years old.

Results: Two multi-omic factors were identified: one characterising preschool-aged recurrent wheeze and another capturing an inferred trajectory from health to wheeze and school-aged asthma. Recurrent wheeze was driven by Type 1-immune signatures, coupled with upregulation of immune-related and neutrophil-associated lipids and metabolites. Comparatively, progression towards asthma from ages 1-18 was dominated by changes related to airway epithelial cell gene expression, Type 2-immune responses, and constituents of the airway microbiome, such as increased Haemophilus influenzae.

Conclusion: These factors highlighted distinctions between an inflammation-related phenotype in preschool wheeze, and the predominance of airway epithelial-related changes linked with the inferred trajectory toward asthma. These findings provide insights into the differential mechanisms driving the progression from wheeze to asthma and may inform targeted therapeutic strategies.