Mechanistic insights into endometriosis: roles of Streptococcus agalactiae and L-carnitine in lesion development and angiogenesis.

IF 9.2 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE
Yuan Zhuang, Ting Lyu, Yang Chen, Wei Li, Lei Tang, Shi-Ping Xian, Peng-Fei Yang, Lijie Wang, Qian-Qian Zhang, Chaoming Mei, Yu-Jing Lin, Zhixiang Yan, Zhanyu Li, Jian-Zhong He, Fa-Min Zeng
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引用次数: 0

Abstract

Retrograde menstruation is a widely recognized etiological factor for endometriosis (EMs); however, it is not the sole cause, as not all affected women develop EMs. Emerging evidence suggests a significant association between the vaginal microbiota and EMs. Nonetheless, the precise mechanisms by which microbial communities influence the pathophysiology and progression of EMs remain unclear. In this study, the cervical mucus from patients with EMs showed significantly greater microbial abundance compared with that of controls, with Streptococcus agalactiae (S. agalactiae) exhibiting the most substantial increase as determined by 16S rRNA gene sequencing. In a murine model, elevated S. agalactiae levels significantly increased the lesion number and colonization, whereas antibiotic treatment reduced lesion formation. Metabolomic analyses showed elevated L-carnitine levels in the cervical secretions and serum of patients with EMs, a finding corroborated in murine tissues. Exogenous L-carnitine administration similarly increased the number and weight of endometriotic lesions. Meanwhile, the inhibition of L-carnitine synthesis suppressed lesion formation induced by S. agalactiae. In vitro, both S. agalactiae and L-carnitine promoted EMs cell proliferation, migration, and invasion. L-carnitine synthesis inhibition attenuated cell motility stimulated by S. agalactiae. Mechanistically, S. agalactiae enhanced angiogenesis through L-carnitine by upregulating vascular endothelial growth factor expression and increasing human umbilical vein endothelial cell motility. These findings identify S. agalactiae as a key cervical microbiome component in EMs development and reveal a microbiota-metabolite-angiogenesis axis that may offer novel therapeutic targets.

子宫内膜异位症的机制:无乳链球菌和左旋肉碱在病变发展和血管生成中的作用。
月经逆行是子宫内膜异位症(EMs)的一个公认的病因;然而,这并不是唯一的原因,因为并不是所有受影响的女性都会患上多发性硬化症。新出现的证据表明阴道微生物群与EMs之间存在显著关联。尽管如此,微生物群落影响em病理生理和进展的确切机制仍不清楚。在本研究中,EMs患者的宫颈粘液中微生物丰度明显高于对照组,其中16S rRNA基因测序结果显示,无乳链球菌(S. agalactiae)增幅最大。在小鼠模型中,升高的无乳链球菌水平显著增加了病变数量和定植,而抗生素治疗减少了病变形成。代谢组学分析显示,EMs患者的宫颈分泌物和血清中左旋肉碱水平升高,这一发现在小鼠组织中得到了证实。外源性左旋肉碱同样增加了子宫内膜异位症病变的数量和重量。同时,抑制左旋肉碱合成可抑制无乳链球菌诱导的损伤形成。在体外,无乳链球菌和左旋肉碱均能促进EMs细胞的增殖、迁移和侵袭。抑制左旋肉碱合成可减弱无乳链球菌刺激的细胞运动。机制上,无乳链球菌通过左旋肉碱上调血管内皮生长因子的表达,增加人脐静脉内皮细胞的活动性,从而促进血管生成。这些发现确定了S. agalactiae是EMs发展中的关键宫颈微生物组成分,并揭示了微生物-代谢-血管生成轴可能提供新的治疗靶点。
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来源期刊
Angiogenesis
Angiogenesis PERIPHERAL VASCULAR DISEASE-
CiteScore
21.90
自引率
8.20%
发文量
37
审稿时长
6-12 weeks
期刊介绍: Angiogenesis, a renowned international journal, seeks to publish high-quality original articles and reviews on the cellular and molecular mechanisms governing angiogenesis in both normal and pathological conditions. By serving as a primary platform for swift communication within the field of angiogenesis research, this multidisciplinary journal showcases pioneering experimental studies utilizing molecular techniques, in vitro methods, animal models, and clinical investigations into angiogenic diseases. Furthermore, Angiogenesis sheds light on cutting-edge therapeutic strategies for promoting or inhibiting angiogenesis, while also highlighting fresh markers and techniques for disease diagnosis and prognosis.
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