Causality of genetically determined gut microbiota on lung cancer: a Mendelian randomization study

Lung cancer (LC) is a growing global health concern, characterized by a persistent static 5-year survival rate and a worrisome increase in LC-related deaths. Despite substantial research, the connection between gut microbiota and LC remains a topic of ongoing debate. Conventional observational studies are susceptible to potential confounders and inverse causation. This study aims to investigate the potential causal association between gut microbiota and LC by using Mendelian randomization (MR).

There were 5,717,754 gut microbiota-related single-nucleotide polymorphisms (SNPs) identified from the MiBioGen consortium (18,340 participants from 24 cohorts) used as instrumental variables in our study. Gut microbiota composition was measured using 16S rRNA sequencing, and association estimates for 211 bacterial taxa were obtained after adjusting for age, gender, technical variables, and genetic principal components. Genetic statistics related to LC were obtained from the Integrative Epidemiology Unit (IEU) database, involving 11,348 cases and 15,861 controls. LC cases were diagnosed based on histopathological confirmation, which is the gold standard for LC diagnosis. The inverse variance-weighted method was applied to estimate the causation between gut microbiota composition and LC. Colocalization analysis was also performed within a 500 kb window of identified SNPs, with posterior probability (PP)4/(PP3 + PP4) >0.8 confirming colocalization signals.

There were 27,209 eligible studies involving 11,348 patients included. Inverse-variance weighted (IVW) analysis revealed significant associations for one taxonomic order, two families, and seven genera within the gut microbiota composition. Specifically, we observed significant associations with order Bifidobacteriales [odds ratio (OR) =0.81, 95% confidence interval (CI): 0.68-0.97, P=0.03], family Bifidobacteriaceae (OR =0.81, 95% CI: 0.69-0.97, P=0.03), family Peptococcaceae (OR =0.80, 95% CI: 0.67-0.96, P=0.02), genus Clostridium sensu stricto 1 (OR =0.75, 95% CI: 0.58-0.97, P=0.03), genus Collinsella (OR =0.78, 95% CI: 0.63-0.97, P=0.03), genus Coprococcus 3 (OR =1.37, 95% CI: 1.03-1.83, P=0.03), genus Erysipelatoclostridium (OR =1.20, 95% CI: 1.05-1.38, P=0.01), genus Holdemanella (OR =1.22, 95% CI: 1.06-1.40, P=0.01), genus Peptococcus (OR =1.15, 95% CI: 1.02-1.30, P=0.02), and genus Ruminiclostridium 6 (OR =0.83, 95% CI: 0.70-0.98, P=0.03). Notably, our reverse MR analysis did not reveal any causal influence of LC on the gut microbiota. No significant heterogeneity in instrumental variables or horizontal pleiotropy was found. Colocalization analysis highlighted key SNPs, suggesting shared genetic pathways contributing to LC. Multivariable MR (MVMR) was performed to evaluate the direct causal effects of gut microbiota on the risk of cancers. Colocalization analysis identified several key SNPs, such as rs12474093 and rs2213306, being linked to genes involved in immune modulation and cell proliferation, suggesting shared genetic pathways between gut microbiota and LC.

These findings suggest that targeting gut microbiota-associated pathways, such as short-chain fatty acid (SCFA) production, may offer novel strategies for LC prevention and treatment. Future research should explore the clinical implications of modulating gut microbiota to improve LC outcomes, particularly in high-risk populations.