Staphylococcus aureus ‐derived xanthine exacerbates allergic rhinitis‐induced olfactory dysfunction through promoting Th17 cell differentiation and IL ‐ 17A production

Abstract Objectives Allergic rhinitis (AR) is frequently accompanied by olfactory dysfunction (OD), yet the role of microbial metabolites in this process remains poorly elucidated. This study aimed to investigate how xanthine, a metabolite derived from Staphylococcus aureus ( Sa ), exacerbates AR‐induced OD by promoting Th17 cell differentiation and IL‐17A production. Methods Multi‐omics analyses, comprising metabolomics, proteomics and 16S rRNA gene sequencing, were performed on AR patients and mouse models with AR. Sa was cultured and key metabolites in its supernatant were detected using untargeted metabolomics. AR mice were nasally challenged with Sa supernatant or xanthine, and comparisons were made with mice with chronic AR and OD. The therapeutic potential of an anti‐IL‐17A neutralising antibody was assessed in AR mice stimulated with Sa supernatant or xanthine. Results Purine metabolism was significantly enriched, and xanthine levels were elevated in AR patients and mouse models, particularly those with OD. Airway microbial dysbiosis in AR mice was characterised by increased Staphylococcus abundance, and the Sa infection pathway was enriched in patients with AR. Untargeted metabolomics of Sa supernatant revealed increased xanthine levels and enrichment of purine metabolism. Nasal challenge with Sa supernatant or xanthine significantly exacerbated OD. Mechanistically, xanthine promoted Th17 cell differentiation and IL‐17A production. Notably, IL‐17A neutralisation effectively alleviated xanthine‐exacerbated OD, indicating a pivotal role for the IL‐17A pathway in this process. Conclusion Sa ‐derived xanthine aggravates AR‐induced OD by driving Th17 cell differentiation and IL‐17A production. These findings highlight the xanthine–IL‐17A pathway as a potential therapeutic target for improving olfactory function in AR.