Gut microbiota dysbiosis and metabolic abnormalities promote oxidative stress and fibrosis in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease marked by declining pulmonary function and excessive fibrosis. Recent studies suggest that gut microbiota and their metabolites influence systemic inflammation and fibrotic processes via the gut-lung axis. We conducted a comprehensive analysis involving pulmonary function tests, gut microbiota profiling, fecal metabolomics, and serum oxidative stress marker measurements in IPF patients and matched healthy controls. Additionally, a bleomycin-induced rat model of IPF were used to assess the effects of tryptophan-glycine (Trp-Gly) supplementation and Ruminococcus torques(R.torques) administration. IPF patients showed significant reductions in lung function (FVC%, FEV1%, TLC%, DLCO%) and distinct gut microbial alterations, including increased Ruminococcus abundance. Metabolomics revealed depletion of Trp-Gly and disrupted amino acid metabolism associated with microbial changes. Serum levels of inducible nitric oxide synthase (iNOS) were elevated, correlating negatively with Trp-Gly and positively with kynurenine, suggesting enhanced oxidative stress. In the animal model, Trp-Gly treatment mitigated fibrosis, oxidative stress, and TGF-β/Smad3 signaling activation, whereas R.torques aggravated these pathological features. Our findings uncover a microbiota-metabolite-oxidative stress axis implicating Ruminococcus-driven metabolic dysregulation in IPF pathogenesis. Targeting this axis provides promising avenues for novel diagnostic and therapeutic strategies in IPF.