5-methoxyindole-3-carboxaldehyde attenuates alveolar type II epithelial cell senescence induced by exposure to polystyrene microplastics in pulmonary fibrosis via PI3K/AKT/mTOR signaling pathway

Microplastics, as a novel type of environmental pollutant, have garnered increasing concern for their potential threat to human health. Pulmonary fibrosis, with high mortality and limited therapy, is exacerbated by airborne contaminants like microplastics. This research assessed the pathological role of polystyrene microplastic (PS-MPs) exposure in driving airway microbial dysbiosis and subsequent fibrotic lung remodeling. Mice were intranasally instilled with PS-MPs and treated with a mixture of antibiotics. Bronchoalveolar lavage fluid was collected from the mice, and the airway microbiota, along with their associated metabolic profiles, were characterized using 16S rRNA gene sequencing, non-targeted metabolomics, and network pharmacology. Exposure to PS-MPs significantly increased the abundance of Staphylococcus , Prevotella , and Weissella in the mouse airway and altered the structure of the lung microbiota. Microbiota derived metabolites, such as 5-methoxyindole-3-carboxaldehyde (5-MC), arachidonylamide, progesterone, and oleamide, were significantly negatively correlated with Staphylococcus , Prevotella , and Weissella , with 5-MC showing the largest fold change. Experimental data demonstrated that microbiota derived 5-MC attenuated particulate induced alveolar epithelial senescence via PI3K/AKT/mTOR pathway modulation, consequently reducing fibrotic pathology. This evidence establishes that PS-MPs initiate pulmonary fibrosis through dysbiosis-mediated metabolic disruption, whereas the microbial metabolite 5-MC counteracts PS-MPs triggered fibrosis by rescuing cellular aging processes. • PS-MPs induce airway dysbiosis with increased Staphylococcus and Prevotella . • Microbial metabolite 5-MC is significantly reduced after microplastic exposure. • 5-MC alleviates particulate induced lung fibrosis via PI3K/AKT/mTOR pathway. • Microbiota metabolite axis plays a key role in microplastic related pulmonary fibrosis.