Icariin Alleviates Bleomycin‐Induced Idiopathic Pulmonary Fibrosis in Mice by Modulating the Gut–Lung Axis and Serum Metabolism

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease of uncertain etiology with few specific and effective therapeutic agents approved for its treatment. We examined the underlying processes and the impact of icariin (ICA) on a bleomycin‐induced pulmonary fibrosis model. After giving ICA orally to the experimental mouse model for 4 weeks, the impact of the drug on pulmonary fibrosis was assessed by immunohistochemical analysis, Masson’s trichrome staining, and hematoxylin and eosin staining. 16S rRNA sequencing and 5R 16S rRNA sequencing were applied to investigate the compositions of the gut and lung microbiota, respectively. The alterations of serum metabolites were assessed using untargeted metabolomic technique. ICA treatment attenuated pulmonary fibrosis in the BLM‐induced mouse model. Meanwhile, ICA regulated the abundance and composition of pulmonary along with intestinal microbiota, especially Akkermansia and Lactobacillus . The strong connections between the intestinal and pulmonary microbiota supported the gut–lung axis. In addition, serum metabolic profiles and related metabolic pathways were influenced by ICA intervention. Spearman’s correlation analysis revealed that Akkermansia or Lactobacillus was significantly associated with various metabolites via corresponding metabolic pathways. ICA has a pulmonary‐protective effect against BLM‐induced pulmonary fibrosis, which appears to modulate serum metabolic profiles by affecting the Akkermansia- or Lactobacillus- involved gut–lung axis.