The Time-Dependent Dynamics of Gut Microbiota and the Interaction With Host Metabolism in Mouse Pulmonary Fibrosis Models

Abstract Background: Pulmonary fibrosis (PF) is a chronic progressive disease whose pathogenesis is thought to be associated with activation of the immune system and consequent metabolic changes. Recent studies suggested that gut microbes are closely related with host's immune response and metabolic changes in fibrotic hosts. However, the dynamic changes of the gut microbiome and the interaction profiles with host metabolism during the development of pulmonary fibrosis remain inconclusive. Results: We collected serum and fecal samples from bleomycin-induced fibrotic mice at 0, 7, 14, and 28 days and performed UPLC-MS analysis on serum metabolites and metagenomic sequencing on fecal samples. It is found that the serum metabolic profile and gut microbiome were significantly altered in mice during the progression of fibrosis. Among the serum metabolites, the levels of three major types of lipids, i.e., glycerolipids, glycerophospholipids, and fatty acids exhibit significant time-dependent changes. The glycerolipid TG and multiple glycerophospholipids (3 PG, 6 PE, and 1 PC) decreased in the early stage of fibrosis and increased in the late stage. The other two types of glycerolipids MG and DG and the fatty acids Cartinine and Punicic acid decreased through the development of fibrosis. In the meantime, we detected significantly elevated abundance of gut microbiome taxa, including Prevotella sp. from Bacteroidetes, Lactobacillus from Firmicutes, and Bifidobacterium from Actinobacteria in mice with pulmonary fibrosis. When compared to the dynamic profiles of serum metabolites, the abundances of gut microbiome show a high level of correlation with that of serum metabolites. The taxa from Bacteroides, such as Butyricimonas_synergistica and Muribaculaceae, show positive correlation with the cluster of glycerophospholipids, while taxa from Firmicutes, such as Clostridioides difficile and Enterococcus faecium exhibit negative correlation. Further functional classification suggested that those taxa are involved in multiple functional modules, such as Transporters, Secretion system, and Metabolism. Conclusions: The results reveal the synergistic changes between the gut microbiome and host metabolism and the dynamic responses of gut microbiome to host fibrosis during the progression of fibrosis.