Lung microbiota coordinates alveolar macrophage and γδ T cell activation against Klebsiella pneumoniae via SCFA-FFAR2 axis

This effect is dependent on decreased IL-1β secretion from alveolar macrophages (AMs), accompanied by restrained NF-κB and GPR signaling. Additionally, lung dysbiosis reduces microbiota-derived SCFAs in the lung, while FFAR2, their major receptor, is predominantly expressed on AMs.

Furthermore, acetate activation of FFAR2 on AMs enhances NF-κB phosphorylation, inflammasome activation, and IL-1β production, promoting IL-17A+ γδ T cell activation. Moreover, acetate supplementation rescued lung dysbiosis-suppressed immune responses and host defense in a FFAR2-dependent manner on AMs. In conclusion, lung microbiota-derived SCFAs coordinate the activation of AMs and γδ T cells through FFAR2, suggesting that lung dysbiosis compromises the protective role of commensal bacteria in modulating innate immune network against K. pneumoniae infections.