Abstract
BACKGROUND AND OBJECTIVES: Asthma represents a heterogeneous chronic respiratory condition. Type 2 (T2) inflammation is the most crucial pathological event in asthma. In terms of whether T2 inflammation is dominant or not, asthma can be classified into T2-high and T2-low asthma. Currently, there exists a significant gap in our understanding of the heterogeneity of treatment-naive T2-high asthma patients. Moreover, no studies have examined the impacts of inhaled corticosteroids (ICS) on the airway microenvironment and metabolism of T2-high asthma during the early stage of treatment. This study, by employing multi-omic techniques, investigated the pathophysiological features and heterogeneity of untreated T2-high asthma, as well as the effects of ICS treatment. This study provided more in-depth insights into the pathophysiological mechanisms underlying T2-high asthma heterogeneity. METHODS: Thirty-one treatment-naive T2-high asthma patients and fourteen healthy individuals were enrolled in this study. On the basis of hierarchical clustering analysis of T2 inflammation markers, fractional exhaled nitric oxide (FeNO) level and blood eosinophil count (BEC), the T2-high asthma patients were divided into three subgroups in terms of FeNO levels (≤ 25 ppb, 26-50 ppb, and > 50 ppb). All asthma patients underwent asthma control scoring, pulmonary function tests, and FeNO measurement at baseline and during a regular 3-month follow-up. Induced sputum and plasma were collected. Other tests included 16S rRNA microbiome profiling of the induced sputum, Luminex xMAP immunoassays of cytokines, and plasma metabolomic analysis using Q-Exactive liquid chromatography-mass spectrometry (LC-MS/MS). Meanwhile, data from the healthy population were also harvested. RESULTS: T2-high asthma patients differed significantly from healthy controls in terms of airway inflammatory cytokines, airway microbial community structure, and plasma metabolic profiles. At baseline, T2-high asthma patients with different FeNO levels exhibited remarkable similarities in clinical symptoms, pulmonary function indices, airway cytokines, airway microbial diversity, and metabolites. After treatment with ICS, symptoms improved in T2-high asthma patients. The levels of FeNO, blood eosinophils, and total immunoglobulin E (tIgE) decreased significantly, while pulmonary function did not show substantial improvement. Some indices of airway cytokines underwent changes. No differences were found in airway microbial diversity; however, the abundance of Actinomyces increased. Moreover, the levels of glycerophospholipids and arachidonic acid metabolites decreased. Differentially expressed metabolites were enriched in arachidonic acid metabolism. The effect of ICS treatment varied among different T2-high asthma subgroups. CONCLUSIONS: The airway local microenvironment and systemic metabolic profiles of treatment-naive T2-high asthma patients were distinctly different from those of healthy individuals. Limited heterogeneity was observed among patients stratified in terms of T2-inflammatory burden. ICS altered the airway microenvironment and rectified the lipid/arachidonic acid metabolic dysregulation. However, ICS effects varied across various T2-high subgroups.