Lung dysbiosis disrupts an FFAR2-mediated innate immune circuit against.

Abstract

RATIONALE: Pneumonia is a leading infectious disease, with Gram-negative bacteria such asposing serious clinical threats. Host defense againstlung 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 inlung 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 withor 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, exhibiting reduced IL-17A production and impaired IL-17A⁺ γδ T cell activation due to diminished IL-1β secretion from alveolar macrophages (AMs) with restrained NF-κB and GPR signaling. Additionally, lung dysbiosis decreases SCFA levels in the lung, while FFAR2, a primary SCFA receptor, is predominantly expressed in AMs. Acetate, the major ligand for FFAR2, enhances IL-1β production in AMs and restores dysbiosis-suppressed immune responses in an FFAR2-dependent manner. Moreover,mice display compromised resistance to, and FFAR2 is likewise enriched in human AMs, underscoring translational relevance. CONCLUSION: Lung microbiota coordinates AM and γδ T cell activation againstvia SCFA-FFAR2 axis, a protective network disrupted by lung dysbiosis. These findings highlight the therapeutic potential of SCFA-FFAR2 targeting.