Matsuda Shigeru, Kuwabara Yoshimitsu, Taketomi Yoshitaka, Nagasaki Yuki, Sugita Yosuke, Suzuki Shunji, Manabe Ichiro, Murakami Makoto, Oishi Yumiko
Department of Obstetrics and Gynecology, Nippon Medical School, Tokyo, Japan.
Laboratory of Microenvironmental and Metabolic Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Front Immunol. 2025 Jun 5;16:1547949. doi: 10.3389/fimmu.2025.1547949. eCollection 2025.
Chronic endometritis (CE) is an inflammatory disease of the uterus that is associated with infertility and poor reproductive outcomes. Although most cases of CE are attributed to bacterial infections, antibiotic treatment is sometimes ineffective, and the mechanisms underlying the development and persistence of inflammation in CE are poorly understood. In the present study, we established a novel mouse model of CE that causes fetal death without affecting implantation and demonstrated that dysregulation of lipid metabolism contributes to its pathology. A deficiency in SREBP1, a key regulator of lipid metabolism, prolonged endometrial inflammation with CD138 plasma cell accumulation and induced miscarriage in LPS-induced endometritis, thereby mimicking CE. Lipidomic analyses showed that deficiency significantly reduced phospholipids containing eicosapentaenoic acid (EPA) within uterine tissue. Dietary supplementation of EPA increased endometrial levels of EPA-containing phospholipids and ameliorated inflammation and miscarriage in CE mice. These results suggest that dysregulation of lipid metabolism, particularly reductions in polyunsaturated fatty acids in endometrial phospholipids, promotes inflammation and miscarriage in CE. Importantly, EPA-containing phospholipids were also decreased in endometrial tissue from human CE patients. Thus, dysregulated lipid metabolism appears to play a pivotal role in the development of CE and provides novel therapeutic targets.
慢性子宫内膜炎（CE）是一种子宫炎症性疾病，与不孕症和不良生殖结局相关。尽管大多数CE病例归因于细菌感染，但抗生素治疗有时无效，且CE炎症发生和持续存在的潜在机制尚不清楚。在本研究中，我们建立了一种新型CE小鼠模型，该模型可导致胎儿死亡而不影响着床，并证明脂质代谢失调促成其病理过程。脂质代谢关键调节因子SREBP1的缺乏会延长子宫内膜炎症并伴有CD138浆细胞积聚，并在脂多糖诱导的子宫内膜炎中导致流产，从而模拟了CE。脂质组学分析表明，该缺乏显著降低了子宫组织中含二十碳五烯酸（EPA）的磷脂。饮食中补充EPA可提高CE小鼠子宫内膜中含EPA磷脂的水平，并改善炎症和流产情况。这些结果表明，脂质代谢失调，尤其是子宫内膜磷脂中多不饱和脂肪酸的减少，会促进CE中的炎症和流产。重要的是，人类CE患者的子宫内膜组织中含EPA的磷脂也减少。因此，脂质代谢失调似乎在CE的发展中起关键作用，并提供了新的治疗靶点。
