Abstract Background Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic lung disorder with unclear upstream triggers. Recent Mendelian randomization (MR) studies implicate gut microbiota (GM) as causal modulators of IPF through immune and metabolic pathways. However, no systematic synthesis has consolidated this emerging evidence. We aim to evaluate the causal relationship between GM and IPF using a systematic review (SR) of MR studies and identify potential mediating biological pathways. Methods We systematically searched PubMed, Embase and Web of Science database from inception to October 2025 for Mendelian randomization (MR) studies using keywords such as gut microbiota, IPF, and MR. Eligible studies included two-sample or multivariable MR analyses that evaluated gut microbial taxa or gut microbiota-related metabolic pathways as exposures and IPF as the outcome. Studies employing genome-wide association study summary statistics for both exposures and outcomes were included. Two reviewers independently extracted data from included studied. We performed pooled analysis using random effects model with REML estimator and used I2 statistics to assess heterogeneity based on gut microbiota family. Leave-one-out analysis assessed robustness. Results Across five MR studies, our pooled analysis shows that two taxa were associated with higher odds of IPF: Bacteriodiaece (OR 1.93, 95% CI 1.37-2.72; p 0.01; I2=0%) and Gastranaerophilales (OR 1.44; 95% CI 1.18-1.76; p 0.01;I2=0%), while other five taxa: Family XIII (OR 0.54; 95% CI 0.37-0.79; p 0.01; I2=60%), Oscillibacter (OR 0.57; 95% CI 0.47-0.70; p 0.01; I2=0%), Ruminococcus (OR 0.76; 95% CI 0.67-0.85; p 0.01; I2=0%), Selenomonadales (OR 0.55; 95% CI 0.41-0.74; p 0.01; I2=0%), Veillonella (OR 0.55; 95% CI 0.39-0.77; p 0.01; I2=0%), were associated with lower odds of IPF. The findings were robust in leave-one-out analysis. Conclusion This systematic review and pooled analysis of Mendelian randomization studies provides robust genetic evidence that distinct gut microbiota taxa exert causal effects—both risk-enhancing and protective—on susceptibility to idiopathic pulmonary fibrosis (IPF). Specifically, taxa such as Bacteroidaceae and Gastranaerophilales are associated with an increased risk of IPF, while other taxa including Family XIII, Oscillibacter, Ruminococcus, Selenomonadales, and Veillonella are linked to lower odds of IPF. These associations remained consistent across sensitivity analyses, strengthening the causal inference. Collectively, the findings support the hypothesis that the gut-lung axis, potentially mediated by immune and metabolic pathways, plays a significant role in IPF pathogenesis. Further mechanistic research is warranted to elucidate underlying biological pathways and assess the translational potential of modulating the gut microbiota for IPF prevention or therapy. This abstract is funded by: none
Sura et al. (Fri,) studied this question.