Abstract
BACKGROUND: Multiple risk factors for asthma severity have been identified by epidemiological studies. Yet, the pathophysiological mechanisms driving the severity of clinical asthma manifestations remain incompletely understood. In asthmatic children, Notch4 expression on circulating Treg cells and levels of circulating GDF15 have been shown to be increased as a function of disease severity, suggesting a contribution of Treg dysfunction to disease phenotype. METHODS: 126 children with asthma (intermittent = 40; mild persistent = 43; moderate persistent = 29, and severe persistent = 14) and 83 non-asthmatic controls were recruited in the Allergy clinic at Boston Children's Hospital and from asthma cohorts. Untargeted metabolomic analysis and cytokine profiling were performed in plasma and results correlated with disease severity, Notch4 expression, and presence of other atopic comorbidities. RESULTS: Children with moderate/severe asthma had higher levels of select lipids (triglycerides, ceramides) and carboxylic acids (lactic acid, aconitic acid) and lower levels of amino acids (sarcosine and arginine) and of IFNλ 2/3 compared to children with intermittent/mild asthma. Treg Notch4 expression and GDF15 levels, which increase with disease severity, correlated positively with lactic acid and xanthine levels and inversely with sarcosine and arginine. The concomitant presence of food allergy was associated with alterations in microbiome-related metabolites and allergic rhinitis with marked triglyceride dysregulation. CONCLUSIONS: Untargeted metabolomic profiling identified both shared and unique pathways associated with known asthma severity contributors, Notch4 dysregulation and GDF15 elevation, suggesting that different mechanisms may both converge or independently contribute to determining clinical manifestations of asthma severity in asthmatic children.