肠道菌群失调通过β-葡糖醛酸酶调控巨噬细胞极化介导子宫内膜异位症免疫失衡的新机制

子宫内膜异位症（EMs）是常见的妇科疾病，严重危害女性身体健康和生活质量。巨噬细胞介导的免疫失衡是其发展的关键催化因素，但调控机制未明。具有免疫调节功能的肠道菌群很可能是挖掘EMs免疫失衡机制的关键突破口。我们前期发现：EMs患者肠道菌群失调导致革兰阴性杆菌异常增多，其代谢物β-葡糖醛酸酶（β-G）升高伴随EMs病灶巨噬细胞M1向M2型的极化，也与腹腔液LPS及血液雌激素水平相关。据此我们提出假说：肠道菌群失调通过β-G调控巨噬细胞的极化介导免疫失衡，促进EMs的发生发展。本项目拟采用分子细胞学方法结合实验动物模型，首先探讨β-G通过上调雌激素水平及与LPS相互作用调控巨噬细胞极化的机制，进而验证β-G可促进子宫内膜间质细胞的增殖和迁移；最后在动物模型验证使用粪便移植和β-G抑制剂可抑制EMs发展。本项目揭示EMs免疫失衡的新机制，为EMs的精准治疗提供新的理论依据和新靶点。

Endometriosis (EMs) is a common gynecological disease which seriously endangers women’s health and quality of life. Macrophage-induced immune imbalance is the key catalytic factor for the development of EMs, but the specific mechanism is still unclear. Intestinal flora, which possesses immunomodulatory function, is likely to be the key breakthrough for investigating the immune imbalance mechanism of EMs. The results of our precious study show that intestinal dysbiosis induces an abnormal increase of gram-negative bacilli in patients with EMs. β-glucuronidase (β-G), the metabolite of gram-negative bacilli, is increased in stool and serum levels, which is associated with the macrophage polarization from M1 to M2 in endometriotic lesions. In addition, the level of β-G is also positively correlated with LPS level of peritoneal fluid and serum estrogen level. Accordingly, we assume that intestinal dysbiosis regulates macrophage polarization through β-G, mediating the immune imbalance of EMs and as a result, promoting the occurrence and development of EMs. This study plans to confirm our hypothesis using molecular cytology methods combined with experimental animal model. First, we explore the mechanism that β-G regulates macrophage polarization through up regulating estrogen and interacting with LPS. Then we verify that β-G can promote the proliferation and migration of endometrial stromal cells at the level of cytology. Finally, we verify the efficacy of fecal transplantation and the use of β-G inhibitor on inhibiting the development of EMs. This study will reveal new mechanism underlying the immune imbalance of EMs, and provide new theoretical basis and new targets for the precise treatment of EMs.