观察性流行病学研究表明了肠道微生物群与乳腺癌之间的关联，但肠道微生物群是否因果性地影响乳腺癌的风险仍不清楚。我们采用双样本曼德利安随机化(Mendelian randomization, MR)分析来研究这种关联。我们使用MiBioGen研究中18340名个体的全基因组关联研究(GWAS)的肠道微生物群总结统计数据。总结统计的全乳腺癌风险和激素受体亚型特异性分析的GWAS统计资料来自于英国生物银行和FinnGen数据库，共计40万名个体。采用逆方差加权(inverse variance-weighted, IVW) MR方法来检查肠道微生物群与乳腺癌及其亚型之间的因果关系。我们还使用最大似然估计、MR-Egger和MR多态性残差总和离群值方法进行了敏感性分析。IVW估计结果显示，Genus_Sellimonas的增加与ER阳性乳腺癌的风险增加有因果关联(odds ratio (OR) = 1.09, p = 1.72E-04, false discovery rate (FDR) = 0.02)，而Genus_Adlercreutzia的增加对ER阳性乳腺癌具有保护作用(OR = 0.88, p = 6.62E-04, FDR = 0.04)。对于Her2阳性乳腺癌，Genus_Ruminococcus2的增加与风险降低有关(OR = 0.77, p = 4.91E-04, FDR = 0.04)，而Genus_Erysipelatoclostridium的增加与风险增加有关(OR = 1.25, p = 6.58E-04, FDR = 0.04)。未找到任何异质性或水平的多态性证据。我们的研究揭示了肠道微生物群—乳腺轴，为肠道微生物群在乳腺癌预防、诊断和治疗中的潜在作为候选靶点提供了重要数据。版权所有©2023年张氏，张氏，任氏，薛氏，王氏，王氏和吕氏。

Observational epidemiological studies suggested an association between the gut microbiota and breast cancer, but it remains unclear whether the gut microbiota causally influences the risk of breast cancer. We employed two-sample Mendelian randomization (MR) analysis to investigate this association.We used summary statistics of the gut microbiome from a genome-wide association study (GWAS) of 18,340 individuals in the MiBioGen study. GWAS summary statistics for overall breast cancer risk and hormone receptor subtype-specific analyses were obtained from the UK Biobank and FinnGen databases, totaling 400,000 individuals. The inverse variance-weighted (IVW) MR method was used to examine the causal relationship between the gut microbiome and breast cancer and its subtypes. Sensitivity analyses were conducted using maximum likelihood, MR-Egger, and MR pleiotropic residual sums and outliers methods.The IVW estimates indicated that an increased abundance of Genus_Sellimonas is causally associated with an increased risk of ER+ breast cancer [odds ratio (OR) = 1.09, p = 1.72E-04, false discovery rate (FDR) = 0.02], whereas an increased abundance of Genus_Adlercreutzia was protective against ER+ breast cancer (OR = 0.88, p = 6.62E-04, FDR = 0.04). For Her2+ breast cancer, an increased abundance of Genus_Ruminococcus2 was associated with a decreased risk (OR = 0.77, p = 4.91E-04, FDR = 0.04), whereas an increased abundance of Genus_Erysipelatoclostridium was associated with an increased risk (OR = 1.25, p = 6.58E-04, FDR = 0.04). No evidence of heterogeneity or horizontal pleiotropy was found.Our study revealed a gut microbiota-mammary axis, providing important data supporting the potential use of the gut microbiome as a candidate target for breast cancer prevention, diagnosis, and treatment.Copyright © 2023 Zhang, Zhang, Ren, Xue, Wang, Wang and Lv.