Role of Pulmonary Microbiota Dysbiosis-Mediated Epithelial–Mesenchymal Transition in Silicosis Fibrosis

Abstract Silicosis is a life-threatening occupational disease characterized by irreversible pulmonary fibrosis. While lung microbiota dysbiosis is implicated in its pathogenesis, the molecular mechanisms linking microbial alterations to fibrotic progression remain incompletely understood. Building upon our previous findings of silica-induced lung microbiota dysbiosis, this study investigated whether the lung microbiota drives silicosis fibrosis via epithelial–mesenchymal transition (EMT). This study reveals that antibiotic intervention significantly attenuates pulmonary fibrosis and EMT in silica-induced silicosis mouse model. Mechanistically, in vivo and in vitro results revealed that silica and lung microbiota-derived lipopolysaccharide (LPS) synergistically drive alveolar epithelial cells toward an EMT phenotype. This process is mediated by the sustained upregulation of the transcription factor Snail, which acts as a master regulator to amplify EMT signaling. Subsequently, these EMT-transformed cells orchestrate fibroblast activation and collagen deposition through paracrine communication. Crucially, silencing Snail or depleting the microbiota effectively reversed these pathological changes and inhibited fibroblast activation. These findings establish a critical “lung microbiota–Snail–EMT–fibroblast” axis in the pathogenesis of silicosis. This study provides compelling evidence that the lung microbiota is an active driver rather than a passive bystander in fibrosis, suggesting that targeting this signaling axis offers a promising therapeutic strategy for silicosis.