Gut microbiota influence on lung cancer risk through blood metabolite mediation: from a comprehensive Mendelian randomization analysis and genetic analysis.

Background: Gut microbiota (GM) and metabolic alterations play pivotal roles in lung cancer (LC) development and host genetic variations are known to contribute to LC susceptibility by modulating the GM. However, the causal links among GM, metabolite, host genes, and LC remain to be fully delineated. Method: Through bidirectional MR analyses, we examined the causal links between GM and LC, and utilized two-step mediation analysis to identify potential mediating blood metabolite. We employed diverse MR methods, including inverse-variance-weighted (IVW), weighted median, MR-Egger, weighted mode, and simple mode, to ensure a robust examination of the data. MR-Egger intercept test, Radial MR, MR-PRESSO, Cochran Q test and Leave-one-out (LOO) analysis were used for sensitivity analyses. Analyses were adjusted for smoking, alcohol intake frequency and air pollution. Linkage disequilibrium score regression and Steiger test were used to probe genetic causality. The study also explored the association between specific host genes and the abundance of gut microbes in LC patients. Results: The presence of Conclusion: These findings underscore the importance of GM in the development of LC, with metabolites partly mediating this effect, and provide dietary and lifestyle recommendations for high-risk lung cancer populations.