Causal relationship between oral microbiome, circulating inflammatory proteins and lung cancer: A Mendelian...

Recent research showed that oral microbiomes (OMs), as the main source of lung microbiomes, were associated with lung cancer (LC), but the causal relationship and mechanisms remain unclear. This study aimed to explore the immune mechanisms of LC through the "OM - inflammatory proteins - LC" axis. Instrumental variables covering 43 oral microbial taxa, 91 circulating inflammatory proteins, and LC subtypes were obtained from large-scale genome-wide association study summary data of European origin. We employed Mendelian randomization (MR) analysis to validate causal links between the OM and LC and to assess the mediation effects of inflammatory proteins. The primary statistical method was the inverse variance weighted method, supplemented by leave-one-out analysis, MR-Egger regression, and Cochran's Q test to assess heterogeneity and pleiotropy. Finally, we calculated the effect size of inflammatory proteins as mediators. The results suggested that 9 oral microbial taxa and 20 inflammatory proteins were significantly associated with LC and its subtypes. Key findings included: Genus Rothia increased the risk of squamous cell carcinoma. At the species level, Haemophilus parainfluenzae protected against lung adenocarcinoma, whereas Megasphaera micronuciformis prevented small cell LC. Among the inflammatory proteins, the protein S100-A12 elevated adenocarcinoma risk, and STAM binding protein increased the risk of squamous cell carcinoma. Protective proteins included artemin (squamous cell carcinoma), cystatin D (adenocarcinoma), and interleukin 18 (both subtypes mentioned above). M. micronuciformis and overall LC had a causal relationship in which cystatin D played a mediating role. This study reveals a potential causal link between the OM, circulating inflammatory proteins, and LC. The protective effect of M. micronuciformis was mediated by cystatin D, highlighting a novel immune pathway. These findings provide biomarkers for early detection of LC and therapeutic targets for LC intervention.