金黄色葡萄球菌来源的黄嘌呤通过促进Th17细胞分化和IL-17A产生加重过敏性鼻炎诱导的嗅觉功能障碍

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中文摘要

目的： 过敏性鼻炎（AR）常伴有嗅觉功能障碍（OD），但微生物代谢物在这一过程中的作用仍不清楚。本研究旨在探讨金黄色葡萄球菌（Sa）来源的代谢物黄嘌呤如何通过促进Th17细胞分化和IL-17A产生加重AR诱导的OD。
方法： 对AR患者和AR小鼠模型进行多组学分析，包括代谢组学、蛋白质组学和16S rRNA基因测序。培养Sa，并使用非靶向代谢组学检测其上清液中的关键代谢物。对AR小鼠进行Sa上清液或黄嘌呤鼻腔激发，并与慢性AR伴OD小鼠进行比较。在经Sa上清液或黄嘌呤刺激的AR小鼠中评估抗IL-17A中和抗体的治疗潜力。
结果： 嘌呤代谢显著富集，AR患者和小鼠模型中黄嘌呤水平升高，尤其是伴有OD者。AR小鼠的气道微生物失调以葡萄球菌丰度增加为特征，且AR患者中Sa感染通路富集。Sa上清液的非靶向代谢组学显示黄嘌呤水平升高和嘌呤代谢富集。Sa上清液或黄嘌呤鼻腔激发显著加重OD。机制上，黄嘌呤促进Th17细胞分化和IL-17A产生。值得注意的是，IL-17A中和有效缓解了黄嘌呤加重的OD，表明IL-17A通路在此过程中发挥关键作用。
结论： Sa来源的黄嘌呤通过驱动Th17细胞分化和IL-17A产生加重AR诱导的OD。这些发现突出表明黄嘌呤-IL-17A通路是改善AR嗅觉功能的潜在治疗靶点。

英文摘要

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.