Gut microbiota influences lung cancer risk through circulating cytokines—Insights from a Mendelian randomization study

Lung cancer is the leading cause of cancer-related deaths worldwide. Gut microbiota and circulating cytokines may play important roles in the development and progression of lung cancer, but their causality has not been clarified. In this study, we comprehensively assessed the causal associations between 473 types of gut microbiota and 91 types of circulating cytokines with 3 types of lung cancers, including squamous cell carcinoma, adenocarcinoma, and small cell lung cancer, by using Mendelian randomization analysis in conjunction with the most recent genome-wide association studies data and lung cancer cohort data. The mediating role of circulating cytokines in the relationship between gut microbiota and lung cancer was further explored using mediation analyses. Mediation analysis identified 6 important circulating cytokines that intricately regulate the development and progression of 3 types of lung cancer. Lung squamous carcinoma was more susceptible to circulating cytokines than lung adenocarcinoma and small cell lung cancer. In this study, we constructed a causal network of "gut microbiota-circulating cytokines-lung cancer" at a multi-omics level, and revealed the causal relationship between specific gut microbiota and circulating cytokines in the development and progression of lung cancer, which will provide new targets and strategies for the prevention and treatment of lung cancer in the future.