Lung dysbiosis disrupts an FFAR2-mediated innate immune circuit against Klebsiella pneumoniae

作者：Huang TC, Shao JS, Lai AC, Wu KC, Lin DF, Chang YJ · 发表于：Theranostics · 年份：2026 · DOI：10.7150/thno.131136 · 被引用次数：75 · 研究领域：Dysbiosis、Immunity, Innate、Lung、Klebsiella pneumoniae、Receptors, G-Protein-Coupled、Klebsiella Infections、Pneumonia, Bacterial、Animals、Mice、Bronchoalveolar Lavage Fluid、Mice, Inbred C57BL、Disease Models, Animal

RATIONALE: Pneumonia is a leading infectious disease, with Gram-negative bacteria such as K. pneumoniae posing serious clinical threats. Host defense against K. pneumoniae lung infection largely mediated by innate immune responses. Although gut microbiota has been shown to influence lung immunity via the gut-lung axis, the contribution of lung microbiota remains unclear. This study investigates the role of lung microbiota in K. pneumoniae lung infection, aiming to elucidate its functional significance in shaping pulmonary immune responses and susceptibility to bacterial pneumonia. METHODS: Using a vancomycin-induced lung dysbiosis mouse model, we profiled lung bacterial composition by 16S rRNA sequencing and quantified short-chain fatty acid (SCFA) levels in bronchoalveolar lavage fluid (BALF) using liquid chromatography-mass spectrometry (LC-MS). Mice were subsequently challenged with K. pneumoniae or LPS via intranasal administration to establish lung infection. We further performed bulk RNA sequencing and reanalyzed single-cell RNA sequencing datasets to dissect microbiota-immune interactions in the lung. Cellular assays, cytokine profiling, gene expression analysis, acetate supplementation, and conditional knockout mice were used to further elucidate the underlying mechanisms. RESULT: Here, we show that mice with lung dysbiosis are more susceptible to K. pneumoniae, exhibiting reduced IL-17A production and impaired IL-17A⁺ γδ T cell activation due to diminished IL-1β se...