Gut Microbiota-Immune Interactions in Endometrial Cancer: Causal Mediation and Subtype-Specific Mechanisms

Purpose: In this study, we applied two-sample Mendelian randomization (MR) to explore the causal effects between gut microbiota (GM), immune cells, and endometrial cancer (EC) subtypes and to assess whether immune cells mediate the impact of GM on EC. Patients and Methods: Using two-sample Mendelian randomization and mediation analysis, we analyzed GWAS data: GM (Dutch Microbiome Project; N=7738), EC subtypes (IEU Open GWAS; N=331,588), and immune traits (N=3757). We assessed the effects of the causal gut microbiota on EC subtypes and immune trait mediation. Results: Subtype-specific causal relationships were identified. Overall EC: Four positive (e.g. genus Erysipelotrichaceae noname ) and three negative (e.g. species Bacteroides faecis ) microbial causal effects; three mediated by immune traits (e.g. Ruminococcus obeum via CD86+ myeloid DC AC). Endometrioid EC: Five negative (e.g. class Bacilli) and two positive (e.g. species Aspergillus senegalensis ) effects; three immune-mediated (e.g. Bacilli via IgD+ CD38br % lymphocytes). Non-endometrioid EC: Two positive (e.g. species Bacteroides stercoris ) and one negative (species Ruminococcus bromii ) effect; one mediated ( Ruminococcus bromii via CD8br NKT % lymphocytes). Conclusion: Immune traits significantly mediated causal pathways from GM to EC development. It also highlighted the distinct causal relationships and immune-mediated mechanisms across the three major EC subtypes (overall, endometrioid, and non-endometrioid). These subtype-specific insights into the gut-immune-cancer axis provide novel perspectives for developing therapeutic strategies targeting GM and the immune microenvironment in different EC subtypes.