肠道真菌群改变参与肺孢子菌肺炎的发病机制
Gut mycobiota alteration contributes to the pathogenesis of Pneumocystis pneumonia.
摘要(中文译文)
肺孢子菌是一种机会性真菌病原体，可在免疫功能低下宿主中引起危及生命的肺炎，且在HIV阴性个体中的发病率不断上升。尽管肠道真菌群已被认为是远端免疫的关键调节因素，但其在HIV阴性肺孢子菌肺炎（PCP）中的作用仍完全未被探索。我们建立了小鼠肺孢子菌感染模型，并进行了全长内转录间隔区（ITS）测序，以表征五周内肠道真菌群落的纵向变化。对血浆样本进行了非靶向代谢组学分析，以识别系统性代谢改变。为探究因果关系，使用氟康唑清除肠道真菌群落，并在无菌小鼠中进行粪菌移植（FMT），以评估肠道真菌在调节肺部免疫应答中的功能作用。尽管肠道真菌群的α多样性保持不变，但β多样性分析显示，感染后第3周（w3）开始出现显著的结构改变，与肺部真菌负荷峰值相吻合。线性判别分析效应量鉴定出淡紫紫孢菌和疣状篮状菌为富集的机会性分类群。非靶向代谢组学显示w3时出现显著的代谢重编程，甘氨酸、丝氨酸和苏氨酸代谢以及三羧酸循环均发生显著扰动。氟康唑介导的肠道真菌清除显著增加了肺部肺孢子菌负荷并加重了肺部炎症，同时伴有肺部Th1细胞应答降低。关键的是，将氟康唑处理供体的粪菌移植至无菌小鼠后重现了加重表型，证实肠道真菌失调足以损害Th1介导的抗真菌免疫并加重疾病严重程度。本研究首次确立肠道真菌失调通过肠-肺轴主动促进HIV阴性PCP的发病机制。我们的发现揭示共生肠道真菌支持对控制PCP至关重要的肺部Th1免疫应答，其破坏会加重疾病。这些结果为肠道真菌群作为PCP潜在治疗靶点提供了新见解，并提示在易感人群中应避免不加选择地使用抗真菌药物。
Abstract
Pneumocystis is an opportunistic fungal pathogen that causes life-threatening pneumonia in immunocompromised hosts, with increasing incidence in HIV-negative individuals. Although the gut mycobiota has emerged as a critical regulator of distal immunity, its role in HIV-negative Pneumocystis pneumonia (PCP) remains entirely unexplored. We established a murine model of Pneumocystis murina infection and performed full-length internal transcribed spacer (ITS) sequencing to characterize longitudinal changes in gut fungal communities over five weeks. Untargeted metabolomics was conducted on plasma samples to identify systemic metabolic alterations. To investigate causality, gut fungal communities were depleted using fluconazole, and fecal microbiota transplantation (FMT) was performed in germ-free mice to assess the functional role of gut fungi in modulating pulmonary immune responses. While α diversity of the gut mycobiota remained unchanged, β diversity analysis revealed significant structural alterations beginning week 3 (w3) post-infection, coinciding with peak pulmonary fungal burden. Linear discriminant analysis effect size identified Purpureocillium lilacinum and Talaromyces verruculosus as enriched opportunistic taxa. Untargeted metabolomics demonstrated marked metabolic reprogramming at w3, with significant perturbations in glycine, serine, and threonine metabolism, as well as the tricarboxylic acid cycle. Fluconazole-mediated depletion of gut fungi significantly increased pulmonary Pneumocystis burden and exacerbated lung inflammation, accompanied by reduced pulmonary Th1 cell responses. Critically, FMT from fluconazole-treated donors into germ-free mice recapitulated the exacerbated phenotype, confirming that gut fungal dysbiosis is sufficient to impair Th1-mediated antifungal immunity and worsen disease severity. This study establishes, for the first time, that gut fungal dysbiosis actively contributes to the pathogenesis of HIV-negative PCP via the gut-lung axis. Our findings reveal that commensal gut fungi support pulmonary Th1 immune responses essential for controlling PCP, and their disruption exacerbates disease. These results provide new insights into the gut mycobiota as a potential therapeutic target in PCP and caution against indiscriminate antifungal use in susceptible populations.
如何引用
AMA
Yuxi Chen, Hanyujie Kang, Baolu Yang, Lin Feng, Renyang Tong, Zhiling Zhao, et al. Gut mycobiota alteration contributes to the pathogenesis of Pneumocystis pneumonia.. Journal of translational medicine. 2026; doi:10.1186/s12967-026-08153-7.
APA
Yuxi Chen, Hanyujie Kang, Baolu Yang, Lin Feng, Renyang Tong, Zhiling Zhao, et al (2026). Gut mycobiota alteration contributes to the pathogenesis of Pneumocystis pneumonia.. Journal of translational medicine. https://doi.org/10.1186/s12967-026-08153-7
GB/T 7714
Yuxi Chen, Hanyujie Kang, Baolu Yang, Lin Feng, Renyang Tong, Zhiling Zhao, et al. Gut mycobiota alteration contributes to the pathogenesis of Pneumocystis pneumonia.[J]. Journal of translational medicine, 2026 doi:10.1186/s12967-026-08153-7.
在 PubMed增强版 阅读全文
翻译全文 · AI 文献问答 · PDF 原文下载 · 引用导出