Role of gut microbiota and immune response in breast cancer progression.

Breast cancer is one of the most prevalent cancers among women and is associated with high mortality rates. Emerging evidence suggests a link between gut microbiota and the development of various tumors, particularly those involving immune-mediated mechanisms. However, the potential relationship between gut microbiota and breast cancer-and whether this relationship is mediated by immune cells-remains unclear. This Mendelian randomization (MR) study utilized summary statistics from genome-wide association studies of 412 gut microbiota, 731 immune cell traits, and breast cancer (including its subtypes). Two-sample MR analyses were conducted to assess potential causal relationships between gut microbiota and breast cancer. To further validate the findings, Bayesian weighted MR was applied. Robustness was ensured through sensitivity, specificity, and pleiotropy analyses. A reverse MR analysis was also performed to assess the potential for reverse causality. Finally, mediation analysis was employed to investigate whether immune cells mediate the pathway from gut microbiota to breast cancer. The MR analysis identified 15 gut microbiota and related metabolic pathways significantly associated with breast cancer, with nine showing positive associations and six showing negative associations. The reverse MR analysis did not support a causal effect of breast cancer on gut microbiota. Mediation analysis revealed that DP (CD4⁺CD8⁺) % leukocyte mediated the pathway between gut microbiota (PWY-6263: superpathway of menaquinol-8 biosynthesis II) and breast cancer. These findings suggest a causal relationship between gut microbiota and breast cancer, with a small portion of this effect mediated by immune cells. This study underscores the potential role of gut microbiota and immune modulation in the pathogenesis of breast cancer.