Genetic Insights into the Gut-Lung Axis: Mendelian Randomization Analysis on Gut Microbiota, Lung Function, and COPD

Zi-Xuan Cheng,1 Jian-Lan Hua,1 Zhi-Jun Jie,2 Xing-Jing Li,3 Jing Zhang1 1Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, the Fifth People’s Hospital of Shanghai, Fudan University, Shanghai, People’s Republic of China; 3Department of Respiratory Medicine, Zhongshan Hospital Wusong Branch, Fudan University, Shanghai, People’s Republic of ChinaCorrespondence: Jing Zhang, Email jingatlas@hotmail.comBackground: Chronic obstructive pulmonary disease (COPD) is a respiratory disorder with a complex etiology involving genetic and environmental factors. The dysbiosis of gut microbiota has been implicated in COPD. Mendelian Randomization (MR) provides a tool to investigate causal links using genetic variants as instrumental variables. This study aims to employ MR analysis to explore the causal relationship between gut microbiota, lung function, and COPD.Methods: We utilized genome-wide association study (GWAS) data from MiBioGen, UK Biobank and FinnGen, which were related to gut microbial taxa, lung function parameters including forced vital capacity in one second (FEV1), forced vital capacity (FVC), and percentage of predicted FEV1 (FEV1%pred), as well as GWAS data for COPD. MR analysis was conducted to assess the causal effects of gut microbiota on lung function and the risk of COPD. Sensitivity analysis was utilized to examine the stability of the causal relationships. Multiple testing and reverse analysis were employed to evaluate the robustness of these relationships.Results: Using the IVW method, 64 causal correlations were identified. Through conducting sensitivity analysis, multiple testing, and reverse analysis, we identified 14 robust and stable causal relationships. The bacterial taxa that showed a positive association with lung function included Desulfovibrionaceae, Erysipelotrichales, Desulfovibrionales, Clostridiales, Clostridia, Deltaproteobacteria and Erysipelotrichia, while Selenomonadales and Negativicutes showed a negative association with lung function. The abundance of Holdemanella were positively correlated with the risk of COPD, while FamilyXIII exhibited a negative correlation with the risk of COPD.Conclusion: Several microbial taxa were discovered to have a positive causal correlation with lung function, offering potential insights into the development of probiotics. The presence of microbial taxa negatively correlated with lung function and positively correlated with COPD emphasized the potential impact of gut microbiota dysbiosis on respiratory health.Keywords: COPD, lung function, gut-lung axis, gut microbiota, Mendelian randomization analysis