Bridging the gaps: the gut-lung axis and microbial metabolites in the pathogenesis and treatment of pulmonary fibrosis

Pulmonary fibrosis (PF) is a chronic interstitial lung disease characterized by structural damage to the lung parenchyma, excessive deposition of extracellular matrix (ECM), and irreversible decline in lung function. Current pharmacological treatments cannot effectively reverse fibrosis, highlighting an urgent need for novel therapeutic targets. Recently, the gut-lung axis and its bidirectional communication have received increasing attention for their roles in PF progression. Metabolites derived from gut microbiota, including short-chain fatty acids (SCFAs), bile acids, tryptophan metabolites, lipopolysaccharides (LPS), and trimethylamine N-oxide, regulate immune responses, modulate signaling pathways, influence epigenetic modifications, and maintain intestinal barrier integrity, thereby exerting bidirectional effects on PF. Protective metabolites primarily inhibit fibroblast activation and collagen deposition, whereas pathological metabolites promote fibrosis by inducing inflammatory responses and oxidative stress. Potential therapeutic strategies targeting the gut-lung axis include fecal microbiota transplantation (FMT), probiotic and dietary interventions, and Traditional Chinese Medicine (TCM). However, clinical applications face challenges such as donor standardization, immunological safety, and consistency of therapeutic efficacy. Critical limitations remain, including reliance on acute-injury animal models that inadequately represent the chronic, irreversible nature of human PF. Translating findings across distinct PF subtypes requires caution, as their genetic architectures, immune landscapes, and microbiome interactions may differ considerably. Additionally, the causal relationship between microbial dysbiosis and fibrosis remains unclear, and clinical translation currently lacks stratified intervention strategies based on biomarkers. Future research should prioritize large-scale longitudinal cohort studies, integrated multi-omics analyses, organoid models, and gut-lung chip platforms to identify key effector molecules and therapeutic targets, ultimately facilitating precise clinical interventions targeting the gut-lung axis.