Untargeted metabolomic profiling in children identifies novel pathways in asthma and atopy

Abstract

BackgroundAsthma and other atopic disorders can present with varying clinical phenotypes marked by differential metabolomic manifestations and enriched biological pathways. ObjectiveTo identify these unique metabolomic profiles in atopy and asthma. MethodsWe analyzed baseline non-fasted plasma samples from a large multi-site pediatric population of 470 children < 13 years from three different sites in the US and France. Atopy (At+) was defined as skin prick test ≥ 3 mm and/or specific IgE ≥ 0.35 kUi/L, and/or total IgE ≥ 173 IU/mL. Asthma (As+) was based on physician’s diagnosis. The cohort was divided into four groups of varying combinations of As and At and six pairwise analyses were conducted to best assess differential metabolomic profiles between groups. Results210 children were classified as At-As-, 42 as At+As-, 74 as At-As+ and 144 as At+As+. Untargeted global metabolomic profiles were generated through Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy. We applied two independent machine learning classifiers and shortlisted 362 metabolites as discriminant features. Our analysis showed the most diverse metabolomic profile in the At+As+ / At-As- comparison, followed by the At-As+ / At-As- comparison, indicating that asthma is the most discriminant condition associated with metabolomic changes. At+As+ metabolomic profiles were characterized by higher levels of bile acids, sphingolipids, and phospholipids, and lower levels of polyamine, tryptophan, and gamma-glutamyl amino-acids. ConclusionAt+As+ phenotype displays a distinct metabolomic profile suggesting underlying mechanisms such as modulation of host-pathogen and gut microbiota interactions, epigenetic changes in T-cell differentiation, and lower antioxidant properties of the airway epithelium.