Xu Yunyun, Zhu Yichen, Wu Xiaoyun, Peng Wan, Zhong Yanying, Cai Yujie, Chen Wenjing, Liu Lu, Tan BuZhen, Chen Tingtao
Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, China.
Microb Biotechnol. 2025 Aug;18(8):e70202. doi: 10.1111/1751-7915.70202.
Endometriosis (EMs) is a common inflammatory disorder in women of reproductive age, severely impacting patients' quality of life and fertility. Current hormonal therapies offer limited efficacy, and surgical interventions often fail to prevent recurrence. Recent studies suggest a close association between gut microbiota and the pathophysiology of EMs, though the precise mechanisms remain unclear. To investigate the influence of gut microbiota on EMs, this study established an EMs mouse model and performed faecal microbiota transplantation (FMT) using samples from healthy donors (AH group) and EMs patients (AE group) into the model mice. Results demonstrated that compared to the model group (M group), FMT from healthy donors (AH group) significantly reduced ectopic lesion volume (658.3 ± 116.1 vs. 167.2 ± 112.8 mm, p < 0.01) and weight (0.7420 ± 0.1233 vs. 0.1885 ± 0.1239 mg, p < 0.01). Conversely, FMT from EMs patients exacerbated disease progression. Mechanistic studies revealed that healthy donor FMT attenuated EMs by remodelling the gut microbial composition (enhancing α-diversity and Lactobacillus abundance while suppressing Bacteroidetes), significantly elevating acetate levels in faeces and ectopic lesions, activating the JAK1/STAT3 signalling pathway within lesions, and thereby driving macrophage polarisation toward the M1 phenotype (by increased iNOS/CD86 expression and decreased Arg1/CD206 expression). Simultaneously, healthy donor FMT enhanced intestinal barrier integrity by upregulating tight junction proteins (ZO-1, Occludin, Claudin-1/5) and reducing levels of intestinal permeability markers (DAO, IFABP). In contrast, AE group FMT disrupted gut microbial ecology, reduced acetate production, failed to activate the JAK1/STAT3 pathway, promoted M2 macrophage polarisation and impaired intestinal barrier function. Collectively, this study elucidates for the first time that acetate, as a key gut microbiota metabolite, exerts anti-EMs effects by activating the JAK1/STAT3 signalling pathway to drive macrophage reprogramming toward the M1 phenotype, thereby positioning gut microbiota reconstruction as a novel therapeutic strategy for endometriosis.
子宫内膜异位症（EMs）是育龄期女性常见的炎症性疾病，严重影响患者的生活质量和生育能力。目前的激素疗法疗效有限，手术干预往往无法预防复发。最近的研究表明肠道微生物群与EMs的病理生理学密切相关，但其确切机制尚不清楚。为了研究肠道微生物群对EMs的影响，本研究建立了EMs小鼠模型，并将来自健康供体（AH组）和EMs患者（AE组）的样本进行粪便微生物群移植（FMT）到模型小鼠体内。结果表明，与模型组（M组）相比，来自健康供体的FMT（AH组）显著降低了异位病变体积（658.3±116.1 vs. 167.2±112.8mm，p<0.01）和重量（0.7420±0.1233 vs. 0.1885±0.1239mg，p<0.01）。相反，来自EMs患者的FMT加剧了疾病进展。机制研究表明，健康供体FMT通过重塑肠道微生物组成（提高α多样性和乳酸杆菌丰度，同时抑制拟杆菌）来减轻EMs，显著提高粪便和异位病变中的乙酸水平，激活病变内的JAK1/STAT3信号通路，从而驱动巨噬细胞向M1表型极化（通过增加iNOS/CD86表达和降低Arg1/CD206表达）。同时，健康供体FMT通过上调紧密连接蛋白（ZO-1、闭合蛋白、Claudin-1/5）和降低肠道通透性标志物（DAO、IFABP）水平来增强肠道屏障完整性。相比之下，AE组FMT破坏了肠道微生物生态，减少了乙酸产生，未能激活JAK1/STAT3通路，促进M2巨噬细胞极化并损害肠道屏障功能。总的来说，本研究首次阐明，乙酸作为肠道微生物群的关键代谢产物，通过激活JAK1/STAT3信号通路来驱动巨噬细胞重编程为M1表型，从而发挥抗EMs作用，从而将肠道微生物群重建定位为子宫内膜异位症的一种新的治疗策略。
