P0074Association between smoking status and gut microbiota Ruminococcus gnavus: a Mendelian randomization analysis

Background Smoking alters gut microbiota and has been implicated in IBD pathogenesis. Ruminococcus genus, particularly R. gnavus, shows increased abundance in IBD patients, but the causal relationship with smoking remains unclear. This study aimed to estimate the causal relationship between smoking status and the Ruminococcus genus, particularly R. gnavus, using the Mendelian randomization (MR)approach to control for confounding factors inherent in observational studies. Methods Two-sample MR analyses were performed using IEU-GWAS database from European ancestry individuals. Exposure data included current smokers (n = 91,353-337,030), former smokers (n = 83,133-424,960), and never smokers as controls (n = 359,706). Outcome data comprised overall Ruminococcus genus and R. gnavus-specific data from gut microbiome GWAS studies (n = 5,959-14,306). Primary analysis employed inverse variance weighted (IVW) method with sensitivity analyses. Each smoking status group was analyzed separately. Results Former smokers showed a significant increase in R. gnavus abundance (OR = 1.542, 95%CI: 1.223-1.945, p = 0.0002). Current smokers showed an increasing trend in overall Ruminococcus abundance (OR = 39.509, 95% CI: 0.880-1774.3, p = 0.056), but the wide confidence intervals indicated unstable estimates. No significant association with R. gnavus was detected in current smokers. Never smokers showed no significant associations. Other Ruminococcus species showed inconsistent results, with data unavailable for some. Sensitivity analyses supported primary findings. In part of the Ruminococcus data, we estimated a causal relationship with ulcerative colitis, with a p-value in the 0.02 range, indicating statistical significance. However, the number of available variants was very limited — only one SNP barely met the threshold — so we could not perform sensitivity analyses. Therefore, further studies with larger datasets are needed to confirm this finding. Conclusion Significant association between former smoking and increased R. gnavus abundance was demonstrated, but a direct causal relationship with current smoking could not be established. Study limitations include limited GWAS data for direct assessment of current smoking-R. gnavus relationship, lack of multiple testing correction, and need for replication in independent cohorts. Ulcerative colitis association analysis was constrained by insufficient SNPs preventing sensitivity analyses. Consistent findings in former smokers suggest post-cessation microbiome changes may contribute to IBD pathogenesis. Smoking effects on gut microbiota appear species-specific, and establishing definitive causal relationships requires larger datasets and independent cohort validation. Conflict of interest: Dr. Fuchigami, Ayako: No conflict of interest