Dysbiotic gut fungi exacerbate Klebsiella peumoniae lung infection via Dectin-1-mediated alveolar macrophage hyperactivation.

Abstract

Escalating antibiotic resistance of Klebsiella pneumoniae underscores the urgent need for therapeutic strategies. Whereas 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 pneumonia by enhancing alveolar macrophage-driven inflammation via Dectin-1 signaling. Clinical analyses demonstrated that pneumonia patients receiving ineffective prehospital antibiotic therapy showed gut bacterial depletion accompanied by fungal overgrowth (primarily Candida spp.), with a positive correlation observed between fungal abundance and hospitalization duration. In murine models, antibiotic-induced gut microbiota disruption promoted fungal proliferation, subsequently upregulating Dectin-1 expression in alveolar macrophages. This activation triggered excessive IL-1β secretion and neutrophil recruitment, exacerbating lung injury and mortality. Our results demonstrated that both antifungal intervention and Dectin-1 knockout reversed these pathological effects, resulting in improved survival rates, reduced bacterial dissemination, and attenuated inflammatory cytokine levels. Mechanistically, gut fungi remotely potentiated pulmonary inflammation through the alveolar macrophage "Dectin-1/IL-1β/neutrophil axis", independent of pathogen clearance. Although recent studies have begun to uncover "mycobiome-lung" disease associations, our findings specifically demonstrate that fungal dysbiosis mediates the "gut-lung axis" during multidrug-resistant Klebsiella pneumoniae infections. This study provides mechanistic insights into microbial crosstalk and advances translational approaches for combating antibiotic-exacerbated pneumonias.