Untargeted metabolomics reveals unconjugated bilirubin and linked pathways in arachidonic acid metabolism and oxidative stress associated with early life recurrent wheeze
Turi KN, McKennan CG, Gebretsadik T, Snyder BM, Seroogy CM, Jackson DJ, Zoratti EM, Havstad S, Ober C, Lynch S, McCauley K, Yu C, Lemanske RF, Gern JE, and Hartert TV. Untargeted metabolomics reveals unconjugated bilirubin and linked pathways in arachidonic acid metabolism and oxidative stress associated with early life recurrent wheeze. American Journal of Respiratory and Critical Care Medicine 2020; 201(1).
American Journal of Respiratory and Critical Care Medicine
Rationale: Metabolomics can aide in understanding asthma pathogenesis by investigating important host-environment interactions in asthma development. This study aimed to identify the metabolome profile associated with infant wheeze as an early-life clinical phenotype associated with later childhood asthma.
Methods: A case-control study was conducted using the Environmental influences on Child Health Outcomes (ECHO) program funded Children's Respiratory and Environmental Workgroup (CREW) cohorts. The INSPIRE cohort was used for discovery phase; WISC and COAST cohorts were used for independent replication. Cases and controls were defined as those who wheezed and who did not wheeze during the first year of life respectively. Wheeze was defined by parental report in the prior 12 months for INSPIRE (categorical: 0, 1-3, or episodes) and WISC (yes/no), and by wheeze associated with respiratory infection in the prior 36 months for COAST (yes/no). Untargeted metabolomics was performed on blood collected from participants at age 1-year (INSPIRE, WISC, COAST) and 3-years (COAST) using mass spectrometry platforms. The metabolome and wheeze association was assessed by regressing the log-abundance of 1,057 metabolites (with ≤50% missing data) onto wheeze while adjusting for sex, age, daycare attendance, breastfeeding status and additional latent confounding factors. Inverse probability weighting was used to account for missing data from metabolites with >5% missing data.
Results: Among 338 participants in the discovery cohort, 18 annotated and non-annotated plasma metabolites were associated with first-year infant wheeze at a 20% false discovery rate. Citric acid, glyoxylate, and dicarboxylate were the dominant pathways among annotated and wheeze-associated metabolites. However, only unconjugated bilirubin (UCB) exhibited a dose-response relationship with first-year wheeze. Decreased plasma UCB levels were associated with increased wheezing episodes in INSPIRE. In 1-year INSPIRE plasma samples, UCB was 13% lower (β=0.87, 95%CI=0.74-1.02) and 21% lower (β=0.78, 95%CI=0.68-0.91) in those who wheezed 1-3 episodes and 4+ episodes compared to never wheezers, respectively. Results were replicated in WISC 1-year and COAST 3-year plasma samples. In addition, UCB abundance was negatively correlated with arachidonic acid and oxidative stress metabolite abundances.
Conclusion: Our results support a protective association between UCB and early-life wheeze. UCB's known antioxidant and anti-inflammatory properties and its relationship with other metabolites suggests the mechanism involves interaction with lipid mediators and oxidative metabolic pathways, which may provide opportunities to develop novel targeted prevention strategies for childhood asthma.