Dysbiotic Gut Fungi Exacerbate Klebsiella pneumoniae Pneumonia via Dectin-1-Mediated Alveolar Macrophage Hyperactivation

The escalating antibiotic resistance of Klebsiella pneumoniae underscores the urgent need for novel therapeutic strategies. While gut bacterial dysbiosis exacerbates pulmonary infections, the role of gut fungi in modulating lung immunity remains understudied. Here, we demonstrate that antibiotic-induced gut fungal expansion aggravates K. pneumoniae pneumonia by enhancing alveolar macrophage (AM)-driven inflammation via Dectin-1 signaling. Clinical analyses revealed that antibiotic-treated pneumonia patients exhibited gut bacterial depletion, fungal overgrowth (predominantly Candida spp.), and a positive correlation between fungal abundance and hospitalization duration. In murine models, antibiotic disruption of gut bacteria promoted fungal proliferation, which upregulated Dectin-1 expression in AMs. This activation triggered excessive IL-1β secretion and neutrophil recruitment, exacerbating lung injury and mortality. Crucially, antifungal intervention or Dectin-1 knockout (D1KO) reversed these effects, improving survival, reducing bacterial dissemination, and attenuating inflammatory cytokine levels. Mechanistically, gut fungi remotely potentiated pulmonary inflammation through the AM Dectin-1/IL-1β/neutrophil axis, independent of pathogen clearance. Our findings unveil a previously unrecognized gut-lung interplay mediated by fungal dysbiosis and highlight dual targeting of bacteria and fungi as a promising strategy for multidrug-resistant K. pneumoniae infections. This study provides mechanistic insights into microbial crosstalk and advances translational approaches for combating antibiotic-exacerbated pneumonias.