Immune cells mediated the causal relationship between the gut microbiota and lung cancer: a Mendelian randomization study

Introduction The gut microbiota (GM) influences the occurrence and progression of lung cancer (LC), with potential involvement of immune cells (IC). We aimed to investigate the causal impact of GM on LC and identify potential immune cell mediators. Methods The utilized data for the Genome-Wide Association Studies (GWAS) were summarized as follows: gut microbiota data from the Dutch Microbiome Project (DMP) (N = 7, 738), lung cancer data from the Transdisciplinary Research in Cancer of the Lung (TRICL) and International Lung Cancer Consortium (ILCCO) (N case = 29, 266, N control = 56, 450) included four types of cancer: NSCLC, LUAD, LUSC, and SCLC, and immune cell data from European populations (N = 3, 757). We employed bi-directional two-sample univariable Mendelian randomization (UVMR), multivariable Mendelian randomization (MVMR), and mediation analysis to assess the causal relationship between GM and LC and potential immune cell mediators. Results Bi-directional UVMR analysis revealed that 24 gut microbiota species can affect LC, while LC can affect the abundance of 17 gut microbiota species. Mediation analysis demonstrated that six immune cells mediated the causal relationships of seven gut microbiota species on LC: “CCR7 on naive CD8+ T cell” mediated the causal relationship between sAlistipesₚutredinis and LUAD, with a mediation proportion of 9. 5% and P = 0. 018; “IgD− CD27− B cell %lymphocyte” mediated the causal relationships between gGordonibacter and sGordonibacterₚamelaeae with LUSC, with mediation proportions of 11. 8% and 11. 9%, respectively and P = 0. 029; “CD20− CD38− B cell %lymphocyte” mediated the causal relationship between sBacteroidesclarus and SCLC, with a mediation proportion of 13. 8% and P = 0. 005; “CD20 on IgD+ CD38− unswitched memory B cell” mediated the causal relationship between sStreptococcusₜhermophilus and SCLC, with a mediation proportion of 14. 1% and P = 0. 023; “HLA DR on CD14− CD16+ monocyte” mediated the causal relationship between sBifidobacteriumbifidum and SCLC, with a mediation proportion of 8. 7% and P = 0. 012; “CD45 on Granulocytic Myeloid-Derived Suppressor Cells” mediated the causal relationship between fLactobacillaceae and SCLC, with a mediation proportion of 4. 0% and P = 0. 021. Conclusion This Mendelian randomization study identified several specific gut microbiotas that exhibit causal relationships with lung cancer and potentially mediate immune cells.