Immune cells mediate the causal relationship between the gut microbiota and different types of endometrial cancer: A bidirectional two-sample, two-step Mendelian randomization study

Background Endometrial cancer (EC), one of the most common gynecological cancers classified as either type I or II, is an immunogenic cancer whose tumor microenvironment and immune cell infiltration significantly regulate its prognosis. The gut microbiome affects the occurrence and development of endometrial cancer, and its changes can influence immune conditions. However, whether the gut microbiome regulates different types of endometrial cancer progression through immune cells remains unclear. Method The data used for genome-wide association studies (GWAS) included gut microbiome data from the Dutch Microbiome Project (DMP) (N = 7,738), endometrial cancer data from the IEU Open GWAS project: endometrial cancer (N = 240,027), endometrial cancer with endometrioid histology (N = 54,884), non-endometrioid histology (N = 36,677), and immune cell trait data from European populations (N = 3,757). Using two-sample Mendelian randomization, we investigated the causal relationship between gut microbiota and the three endometrial cancer types. Subsequently, two-step Mendelian randomization and mediation analyses were performed to explore the mediating role of immune traits in the relationship between the gut microbiome and three types of endometrial cancer. Result According to the traditional definition of endometrial cancer and gut microbiome analysis, there are four positive causal effects, three adverse causal effects, and three established mediating effects combined with immune cell traits. Five negative and two positive relationships of the gut microbiome on endometrial cancer with endometrioid histology, together with three immune trait-mediated effects. Analysis of endometrial cancer with non-endometrioid histology showed two positive and one negative causalities, with identified one intermediate causality. Conclusion Our findings emphasize the elusive relationship between gut microbiota, immune cell traits, and various types of endometrial cancer. The distinct connections and mediating effects provide novel perspectives for the distinct therapies targeting the gut microbiota and the immune microenvironment of endometrial cancer with different subtypes.