Metabolomic Clusters and Their Association with Small Airway Disease in Asthma

Background: Asthma is a heterogeneous airway disease in which small airway dysfunction (SAD) plays a central role, but its biochemical basis are not yet fully understood. This study aimed to identify distinct serum metabolomic clusters in asthma and to evaluate their associations with physiologic and structural indicators of small airway involvement. Methods: Fifty-four adults with well-controlled asthma were enrolled. Serum metabolites were quantified using proton nuclear magnetic resonance spectroscopy and liquid chromatography-tandem mass spectrometry. Hierarchical clustering of 40 metabolites identified metabolic subgroups. SAD was assessed using impulse oscillometry and structural airway remodeling was quantified using chest computed tomography. Multivariable linear regression was used to assess associations between metabolite concentrations and small airway indices after adjustment for demographic and clinical factors. Results: Three metabolomic clusters were identified with distinct biochemical and clinical features. Cluster 1, enriched in lipid and fatty acid metabolites, showed higher airway resistance, thicker airway walls, and increased serum C-reactive protein levels, suggesting more pronounced small airway involvement. Cluster 2 was characterized by elevated levels of sugars and alkylamines while maintaining relatively preserved airway function. Cluster 3 had reduced concentrations of amino acids and tricarboxylic acid cycle metabolites, along with increased proportion of current smokers. Phenylalanine was inversely associated with airway resistance and a positive correlation with reactance, while methanol and dimethylamine showed opposite patterns. These relationships remained significant after multivariable adjustment, indicating independent metabolic correlates of small airway disease. Conclusion: Systemic metabolic profiles are associated with small airway inflammation and structural remodeling through bidirectional interactions between circulating metabolites and airway pathophysiology.