Exhaled breath condensate metabolomics reveals conserved networks and bidirectional crosstalk in asthma and CRSwNP

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) and asthma frequently coexist. However, the metabolic inter-play between those diseases is poorly understood. We aimed to perform metabolomic profiling of exhaled breath condensate (EBC) from CRSwNP and asthma patients and investigate possible interaction pathways. METHODOLOGY: EBC samples from the upper and lower airways of patients with CRSwNP, asthma, and control subjects were analyzed using untargeted metabolomics. Metabolite consistency and conserved modules between the upper and lower airways were quantified. WGCNA, trend cluste-ring analysis, and a pathway enrichment analysis of differential metabolite expression were performed. RESULTS: A total of 252 metabolites were identified, with a strong correlation between the upper and lower airway profiles. WGCNA analysis showed that each module of the upper or lower airway was conserved, with at least 1 module included in the consensus network. The key enriched pathways for lower airway metabolites showed a continuous increasing or decreasing trend in the control, CRSwNP, and asthma groups, and mainly involved the impact of CRSwNP on asthma. The main enriched pathways for upper airway differential metabolites in the control, asthma, and CRSwNP groups were related to the impact of asthma on nasal polyps. N-(8Z,11Z,14Z-eicosatrienoyl) ethanolamine was significantly down-regulated in the EBC of CRSwNP and asthma patients, and was negatively correlated with the risk for CRSwNP and asthma onset. Leukotriene F4 (LTF4) was up-regulated in the EBC of CRSwNP and asthma patients, and was positively correlated with the risk for CRSwNP onset. CONCLUSION: Non-invasive EBC metabolomics revealed conserved metabolic networks and bidirectional perturbations between CRSwNP and asthma, providing new evidence for the "unified airway" hypothesis.