Zhang Xiaofang, Ma Na, Jin Conghui, Cao Xiaoli
Department of Infection Management, Affiliated Cancer Hospital of Nantong University, Nantong Cancer Hospital Nantong, Jiangsu Province, China.
Department of Clinical Medicine, Medical School, Nantong University, Nantong, Jiangsu Province, China.
Biomol Biomed. 2025 Apr 14. doi: 10.17305/bb.2025.12003.
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.
乳腺癌是女性中最常见的癌症之一，且死亡率很高。新出现的证据表明肠道微生物群与各种肿瘤的发生发展之间存在联系，尤其是那些涉及免疫介导机制的肿瘤。然而，肠道微生物群与乳腺癌之间的潜在关系，以及这种关系是否由免疫细胞介导，仍不清楚。这项孟德尔随机化（MR）研究利用了来自412种肠道微生物群、731种免疫细胞特征和乳腺癌（包括其亚型）的全基因组关联研究的汇总统计数据。进行了两样本MR分析，以评估肠道微生物群与乳腺癌之间的潜在因果关系。为了进一步验证研究结果，应用了贝叶斯加权MR。通过敏感性、特异性和多效性分析确保了稳健性。还进行了反向MR分析，以评估反向因果关系的可能性。最后，采用中介分析来研究免疫细胞是否介导了从肠道微生物群到乳腺癌的途径。MR分析确定了15种肠道微生物群和相关代谢途径与乳腺癌显著相关，其中9种呈正相关，6种呈负相关。反向MR分析不支持乳腺癌对肠道微生物群的因果效应。中介分析显示，DP（CD4⁺CD8⁺）%白细胞介导了肠道微生物群（PWY-6263：甲基萘醌-8生物合成II的超级途径）与乳腺癌之间的途径。这些发现表明肠道微生物群与乳腺癌之间存在因果关系，其中一小部分效应由免疫细胞介导。这项研究强调了肠道微生物群和免疫调节在乳腺癌发病机制中的潜在作用。
