Causal relationship between gut microbiota and lung squamous cell carcinoma: a bidirectional two-sample Mendelian randomization study

Abstract Purpose This study aims to explore the potential causal relationship between gut microbiota and lung squamous cell carcinoma (LUSC). Methods A bidirectional two-sample Mendelian randomization analysis was conducted using genome-wide association study (GWAS) data from gut microbiota and LUSC. Gut microbiota served as the exposure factor, with instrumental variables selected from a GWAS involving 18 340 participants. LUSC data were drawn from a European cohort including 29 266 LUSC cases and 56 450 controls. Inverse-variance weighted (IVW) method was used as the primary method, with the Benjamini-Hochberg method applied to adjust for multiple comparisons. An independent dataset (ieu-a-967, containing 3275 LUSC cases and 15 038 controls) was used for replication analysis to ensure robustness. Results IVW analysis found that Butyricicoccus (OR = 0.79, 95% CI: 0.63–0.99, P = .042) and Coprobacter (OR = 0.85, 95% CI: 0.74–0.97, P = .018) were significantly protective against LUSC. In contrast, Victivallis (OR = 1.11, 95% CI: 1.00–1.23, P = .045) and Ruminococcus (OR = 1.28, 95% CI: 1.03–1.60, P = .028) increased LUSC risk. Replication analysis in the independent dataset confirmed significant associations for Ruminococcus and Coprobacter. No reverse causality or pleiotropy was detected. Conclusion This study provides evidence of a causal relationship between specific gut microbiota and LUSC risk, highlighting new microbial targets for potential prevention and treatment strategies in lung cancer. Key messages What is already known on this topic? Previous studies have suggested potential links between gut microbiota composition and the development of various cancers, including lung cancer. However, the exact causal relationship between specific gut microbiota and lung squamous cell carcinoma (LUSC) has remained unclear. Traditional observational studies have struggled to determine the direction of causality due to confounding factors, making further investigation necessary through more robust methods such as Mendelian randomization (MR). What this study adds? This bidirectional MR study provides novel genetic evidence indicating that certain gut microbiotas are causally associated with LUSC risk. Specifically, Butyricicoccus appears to reduce the risk of LUSC, while Victivallis increases the risk. These findings highlight the role of the gut-lung axis in LUSC and open up new avenues for exploring gut microbiota as potential modulators of lung cancer risk. How this study might affect research, practice, or policy? The implications of this study may significantly influence future research into cancer prevention strategies by targeting gut microbiota. Additionally, it could inform clinical practices aimed at modulating gut microbiota to lower the risk of LUSC, potentially influencing dietary or probiotic interventions to reduce cancer susceptibility. Furthermore, these results might shape public health policies that focus on the gut-lung axis as a novel avenue for cancer prevention and management.