Intestinal dysbiosis associates with silica-induced pulmonary fibrosis in mice via arginine and tryptophan pathways.

BACKGROUND

Pulmonary fibrosis (PF) is a life-threatening interstitial lung disease with a lack of effective therapeutic approaches. Silicosis is a subtype of PF that is specifically caused by the inhalation of crystalline silica particles. In recent years, the gut-lung axis has been shown to be involved in the occurrence and progression of various respiratory diseases. However, the involvement and specific mechanism of action of the gut microbiome in silica-induced PF remain to be elucidated. Therefore, we established a silica-induced PF murine model using an inhalation exposure system, and combined gut metagenomic and untargeted metabolomics data to correlate microbial and metabolic changes with profibrotic cytokine levels.

RESULTS

In mice exposed to silica dust for 64 days and 128 days, Akkermansia muciniphila and Staphylococcus lentus were significantly enriched, whereas the abundance of Lactobacillus murinus was notably reduced. Relevant network analysis revealed that these gut microbiota changes were highly correlated with metabolic disorders of tryptophan and arginine. Moreover, changes in the gut microbiome composition corresponded with the fluctuations in the levels of profibrotic cytokines, including transforming growth factor-beta, tumor necrosis factor-alpha, fibroblast growth factor, and hydroxyproline.

CONCLUSION

We successfully established a murine model of PF induced by silica inhalation. Our results suggest that Lactobacillus murinus, Akkermansia muciniphila, and Staphylococcus lentus are key microorganisms involved in the development of silica-induced PF, while the arginine and tryptophan metabolic pathways serve as key regulatory pathways in the gut-lung axis contributing to disease development.