Introduction: Asthma is a heterogeneous disease where individuals with similar phenotypic features may have different underlying endotypes. While several Th2 mechanisms have been characterized, there is limited understanding of the mechanisms contributing to the non-Th2 component of asthma.
 
Aims and Objectives: To identify metabolites associated with blood neutrophils that may prove useful for stratifying asthmatics.
 
Methods: Using serum metabolomics we identified associations with asthma using matched asthma cases and controls (n=1040) from the Mass General Brigham Biobank. Top findings were replicated in an independent asthma validation cohort (n=610) from Partners HealthCare Biobank. Targeted assays were developed for sphingolipids, microbial metabolites and steroids to confirm top associations. Blood neutrophils were stratified into tertiles (T1:0-3.65; T3:>5.21).
 
Results: Metabolomics identified and replicated asthma associations with sphingolipid, microbial-related, and steroid metabolites. A pattern of dysregulation was observed between neutrophils and the ratio of sphingolipids to androgen, glucocorticoid, and progestogen metabolites (p-values: 5.65x10-9-2.17x10-2). Stratification of high vs. low neutrophils within asthma cases identified 127 significant ratios between sphingolipids and glucocorticoids (p-values: 2.63x10-5-5.0x10-3). Dihydroceramide and sphingosines were the main drivers in the numerator, and all measured glucocorticoids were associated with significance in the denominator. This ratio was consistent over the course of 2 years.
 
Conclusions: The ratio of dihydroceramide and sphingosines to glucocorticoids may prove useful in characterizing non-Th2 driven asthma.