Immune-Mediated Gut-Lung Axis in IPF: Bidirectional Mendelian Randomization and Mediation Analysis of Microbiota, Inflammatory Proteins, and Metabolites

INTRODUCTION: Immune dysregulation plays a critical role in idiopathic pulmonary fibrosis (IPF), but the mechanisms underlying this dysregulation remain unclear. METHODS: We performed bidirectional Mendelian randomization (MR) and mediation analysis using genome-wide association studies (GWAS) summary data from FinnGen (731 immune cell phenotypes, 473 gut microbiota, 91 inflammatory proteins, 179 plasma lipidome, 1,400 metabolites, and IPF cases). Sensitivity analyses ensured robustness. RESULTS: Nine immune cell phenotypes, nine gut microbiota taxa, three inflammatory proteins, one lipid species, and 29 metabolites showed significant causal associations with IPF. Regulatory T cells (Tregs) showed a dual role: protective subsets reduced IPF risk, while activated CD4+ Tregs increased susceptibility. Mediation analysis revealed that the effect of activated CD4+ Tregs was partially mediated by Phylum SAR324 (16.8%), TNFSF12 (10.8%), and CCL25 (4.94%). Immune cells, such as HLA-DR+ CD33- myeloid cells, modulated IPF via plasma metabolites (LIFR (22.1%) and decadienedioic acid (C10:2-DC) (8.38%)). Additionally, CD39+ CD4+ T cells demonstrated protective properties by suppressing the pro-fibrotic species CHKCI006 sp900018345 (14.8%), while CD39+ CD8br Tregs promoted the anti-fibrotic factor X-16935 (5.68%). DISCUSSION: These findings enhance our understanding of IPF pathogenesis, suggesting that modulating key metabolic pathways and immune regulatory nodes, such as Tregs, could represent promising therapeutic approaches. However, additional experimental studies are needed to validate these potential causal relationships. CONCLUSION: This MR study systematically maps multi-omics interactions in IPF, identifying novel mediators and therapeutic targets. Validating these mechanisms in experimental models could advance precision immunomodulatory strategies for IPF.