Background Observational studies have reported associations between inflammatory bowel diseases (IBDs) and prostate cancer. However, the causality remains controversial. We aimed to identify causal associations between IBD and prostate cancer.

Methods A two-sample Mendelian randomization (MR) analysis was conducted to estimate causal relationships between IBD, ulcerative colitis (UC), Crohn’s disease (CD), and prostate cancer. GWAS data from IIBDGC and FinnGen were used for three types of IBDs, and a fixed-effect meta-analysis combined MR results from two datasets. Multiple sensitivity tests, including reverse MR, colocalization, and Linkage Disequilibrium Score Regression analyses, were conducted to strengthen causal associations. A cross-sectional observational study, utilizing National Health and Nutrition Examination Survey (NHANES) data, was conducted to triangulate these associations. Furthermore, gut microbiome, immunome, and metabolome-wide analyses were conducted to explore mediation pathways.

Results The MR analysis showed that UC was associated with a decreased risk of prostate cancer (combined OR 0.97, 95% CI: 0.95 ~ 0.99, P=0.01), although IBD and CD did not present a significant association with prostate cancer. Sensitivity tests suggested that pleiotropy, reverse causation, linkage disequilibrium among shared variants, and genetic correlation would not bias the causal association between UC and prostate cancer. Triangulation by NHANSE also supported the identified association. Furthermore, a total of 212 gut microbiota, 41 cytokines, 731 immune cells, and 824 metabolites were included in the muti-omics analysis. Dozens of blood immune, metabolic features and gut microbiota were changed, induced by the exposure to UC. However, only immune characteristics mediated the protective effects of UC on prostate cancer, with a mediation proportion from 3.0% to 13.6%, while gut microbiota and blood metabolites did not. Among them, the enhanced CD4+ T and Treg cell subpopulations mediated the majority of the protective effects, particularly CD4 on central memory CD4+ T cell, with a mediation proportion of 13.6%.

Conclusions Our study identified the genetic association between UC and prostate cancer, highlighting the mediation roles of CD4+ T and Treg cell subpopulations. This underscored the importance of immunoregulation in the relationship between UC and prostate cancer, suggesting potential avenues for targeted therapeutic interventions.