Potential roles of gut microbiome and metabolomes in interstitial lung disease: evidence across preclinical and clinical research

Interstitial lung disease (ILD) is a heterogeneous condition that affects the lung parenchyma with varying degrees of inflammation and/or fibrosis. Several studies have suggested a potential link between the gut microbiome and the pathophysiology of lung diseases, including ILD. Accumulating evidence supports bidirectional gut-lung axis interactions potentially mediated by the microbiota. Alterations in the gut microbiome have been associated with the onset and severity of interstitial lung disease. This review aims to summarize findings from in vivo and clinical studies that have investigated the associations between the gut microbiome and ILD. Changes in the gut microbiome have been consistently found in various ILD subtypes, including idiopathic pulmonary fibrosis, radiation pneumonitis, silicosis, coal worker's pneumoconiosis, and connective tissue disease-related ILD. Preclinical studies demonstrate that gut dysbiosis is associated with altered immune responses, increased pro-inflammatory cytokines, and enhanced fibrotic pathways, with mechanistic evidence suggesting the involvement of specific microbial metabolites (short-chain fatty acids, bile acids, and immune mediators). Interventional studies in animal models suggest that fecal microbiota transplantation may attenuate pulmonary inflammation and fibrosis; however, clinical evidence remains limited. This review synthesizes findings across study types, highlights proposed mechanistic pathways, discusses contradictory results, and identifies critical knowledge gaps requiring future investigation to establish causality and inform potential therapeutic development.