A shared metabolic-immune axis links local and systemic inflammation in chronic rhinosinusitis with comorbid asthma

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) comorbid with asthma (CRSwA) represents a severe "unified airway" phenotype, yet the metabolic mechanisms linking upper and lower airway inflammation remain unclear. This study aimed to identify shared metabolic signatures connecting local pathology with systemic circulation by comparing the metabolic profiles of nasal polyp tissue and serum. Methods: We performed an integrated analysis using non-targeted metabolomics and transcriptomics on paired nasal polyp tissue and serum samples from 22 CRSwA patients and 40 non-asthmatic CRSwNP patients to identify differential metabolites and explore their association with the immune microenvironment. Results: CRSwA patients exhibited distinct metabolic signatures dominated by lipids and their derivatives in both tissue and serum. An analysis of the metabolome shared between compartments revealed a weak but significant positive correlation in metabolic fold changes, suggesting a subtle systemic link to the local inflammation. This shared metabolic profile was strongly associated with a local Th2-polarized immune microenvironment. This shared profile was strongly associated with a local Th2-polarized immune microenvironment, where key metabolites (e.g., Resolvin D2, Lipoxin A4) correlated significantly with the abundance of M2 macrophages and eosinophils. Furthermore, a logistic regression model based on serum metabolites effectively distinguished CRSwA from non-asthmatic CRSwNP (AUC = 0.8322). Conclusion: Our study reveals a highly conserved "metabolic-immune axis" that connects local tissue inflammation with systemic circulation, positioning metabolic dysregulation as a central hub in the unified airway disease model for CRSwA. These findings offer new perspectives for developing serum-based diagnostic markers and metabolically-targeted therapies for this challenging clinical condition.