Genetic prediction of immune cells, inflammatory proteins, and metabolite-mediated association between gut microbiota and COPD: a Mendelian randomization study.

Observational studies have suggested a potential association between the gut microbiota and chronic obstructive pulmonary disease (COPD); however, the causal relationship between them, as well as the mediating roles of metabolites, inflammatory proteins, and immune cells, remain unclear. This study aims to elucidate the causal relationship between gut microbiota and COPD using genetic approaches and to explore the potential mediating roles of metabolites, inflammatory proteins, and immune cells. To investigate the causal association between gut microbiota and COPD, we first employed univariable Mendelian randomization (UVMR), using the inverse-variance weighted (IVW) method as the primary analytical approach. Robust IVW and penalized IVW methods were further applied to assess the stability of the findings. Subsequently, we performed a two-step multivariable Mendelian randomization (MVMR) analysis to evaluate the mediating effects of 233 metabolites, 91 inflammatory proteins, and 731 circulating immune cell types. Finally, horizontal pleiotropy was corrected using the MR-Egger intercept method, and potential outliers were identified and excluded through MR-PRESSO. The study adhered strictly to the STROBE-MR reporting guidelines. After adjusting for reverse causality, seven gut microbial taxa exhibited a significant causal relationship with COPD. In mediation analyses, CAG-475 was found to influence COPD risk through HLA DR⁺ CD4⁺ T cells (mediation proportion: 0.55%) and IL-10 (15.96%). The Desulfovibrionaceae family primarily mediated COPD risk via lipid metabolism pathways, with free cholesterol in large very-low-density lipoprotein (VLDL) particles accounting for 45.22% of the effect, along with six other lipid-related indicators. Lactobacillus B ruminis exerted its effects through immune markers such as CD19⁺ B cells and CD8dim T cells (mediation proportion: 0.42-0.85%). Conversely, no significant mediation pathways were identified for four microbial taxa, including CAG-485 sp002404675. This study represents the first genetic evidence supporting a causal framework linking gut microbiota to COPD through metabolic, immune, and inflammatory pathways. The findings highlight the critical roles of lipid metabolism dysregulation, immune markers, and inflammatory responses in COPD pathogenesis. However, further research is warranted to explore additional potential mediators and refine the proposed causal network.