High-resolution metabolomics to identify urine biomarkers in corticosteroid-resistant asthmatic children

Abstract

Corticosteroid (CS) treatment has been established as the first anti-inflammatory treatment for adults and children with asthma. However, a subset of patients fails to respond to combined systemic and inhaled CS treatment. This study was aimed at further understanding CS resistance among children with severe asthma. High-resolution metabolomics was performed on urine samples from CS-respondent (n=15) and CS-nonrespondent (n=15) children to determine possible urine biomarkers related to CS resistance. The metabolic phenotypes of CS responders and CS nonresponders were analyzed using bioinformatics including Manhattan plot with false- discovery rate, hierarchical cluster analysis, Kyoto Encyclopedia Genes and Genomes, and Mummichog pathway analysis. The 2-way hierarchical cluster analysis study determined 30 metabolites showing significantly different levels between CS responders and CS nonresponders. The importantmetabolites annotated were 3,6-dihydronicotinic acid (126.05m/z, RT: 106, [M+H]+), 3-methoxy-4-hydroxyphenyl(ethylene)glycol (185.05m/z, RT: 155, [M+H]+), 3,4-dihydroxy-phenylalanine (198.07m/z, RT: 446, [M+H]+), γ-glutamylcysteine (236.06m/z, RT: 528, [M+S(34)+H]+), Cys-Gly, (253.06m/z, RT: 528, [M-NH3+H]+), and reduced Flavin mononucleotide (517.0794m/z, RT: 533, [M+NaCl]+). Tyrosine metabolism, degradation of aromatic compounds, and glutathione metabolism are suggested to be significant pathways relating to CS resistance. High-resolution metabolomics is a promising approach in asthma research. Five candidate markers were identified to be related to CS-resistant children with severe asthma. These compounds, upon validation, may contribute further in the understanding of CS resistance among children with severe asthma through the use of urine.