Role of the Gut Microbiota in Endometriosis

肠道微生物群在子宫内膜异位症中的作用

• 批准号: 10212008
• 负责人: Ramakrishna Kommagani
• 金额: $ 38.01万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2021-12-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10212008
• 关键词: Abdomen; Acetates; Affect; Age; Age-Years; Bacteria; Basic Science; Butyrates; Cell physiology; Cells; Consumption; Data; Development; Diagnosis; Diagnostic; Diagnostic tests; Diet; Dietary Fiber; Disease; Endometrial; Estrogens; Feces; Fermentation; Fiber; Future; Genetic Transcription; Goals; Greater sac of peritoneum; Growth; Growth Factor; Human; Immune; Implant; In Vitro; Inflammation; Inflammatory; Injections; Interleukin-1 beta; Lesion; Mammals; Mediating; Metabolic; Modeling; Mus; National Institute of Child Health and Human Development; Operative Surgical Procedures; Oral; Organ; Pain; Pelvis; Peritoneal; Peritoneal Fluid; Peritoneal Macrophages; Probiotics; Propionates; Publishing; Recurrence; Reporting; Retrograde Menstruation; Role; Sampling; Strategic Planning; Surface; Testing; Text; Tissues; United States; Volatile Fatty Acids; Woman; Work; chronic pelvic pain; cytokine; dietary supplements; endometriosis; experience; gut bacteria; gut microbiome; gut microbiota; hormone therapy; in vivo; macrophage; microbiota; prevent; release factor; reproductive; side effect; theories; tool; treatment strategy

PROJECT SUMMARY Endometriosis, which causes pain in the pelvis and lower abdomen, afflicts 1 in 10 women between 15 and 49 years of age in the United States. Nearly half of these women experience chronic pelvic pain, and many find that available treatments (hormone therapy and surgery) have negative side effects and do not prevent recurrences. A well-accepted theory is that endometriosis occurs when endometrial tissue enters the peritoneal cavity via retrograde menstruation and implants onto pelvic organs and peritoneal surfaces. However, whereas up to 90% of women experience retrograde menstruation, only 10% of women develop endometriosis, suggesting that unknown factors contribute to development of endometriosis. Thus, identifying such causal factors is essential to develop new tools to diagnose and treat this painful disease. This proposal will test the central hypothesis that whereas some gut bacteria promote endometriosis by inducing macrophage-mediated inflammation, others protect against endometriosis by fermenting fiber to produce short chain fatty acids (SCFAs). This idea is built on several key pieces of preliminary and published data. First, in a syngeneic injection model of endometriosis, microbiota-depleted mice developed significantly smaller endometriotic lesions and had less peritoneal inflammation than control mice. However, lesion size was restored in mice orally gavaged with feces from mice with endometriosis. Second, the peritoneal fluid of mice with endometriosis contained less of the SCFAs acetate, propionate, and butyrate than peritoneal fluid from mice without endometriosis. Third, butyrate inhibited both in vivo endometriotic lesion growth in mice and in vitro growth of human cells derived from endometriotic lesions. Finally, recent reports indicate that women with endometriosis have different gut bacteria compositions than women without endometriosis. The work proposed here will build on these strong preliminary data and test the hypothesis by pursuing the following specific aims: (Aim 1) Determine the mechanism by which gut bacteria promote endometriosis; (Aim 2) Determine the mechanism by which SCFAs affect endometriosis; (Aim 3) Identify human gut bacteria associated with endometriosis, and determine the effect of gut bacteria on human endometriosis growth in mice. At the level of basic science, this project will identify gut bacteria and inflammatory profiles that confer sensitivity to developing endometriosis and identify mechanisms by which SCFAs protect against endometriosis. Of translational significance, this work will identify bacterial candidates that promote or protect against endometriosis in reproductive-age women. Together, this work will help advance one of the Aspirational Goals stated in the NICHD 2020 Strategic Plan: to "accelerate efforts to definitively diagnose, prevent, and treat endometriosis".

项目总结 子宫内膜异位症会导致骨盆和下腹部疼痛，15岁至49岁的女性中每10人中就有1人患有此病。 在美国的年龄。其中近一半的女性经历了慢性盆腔疼痛，许多人发现 现有的治疗方法(激素治疗和手术)有负面副作用，不能防止复发。 一个广为接受的理论是，子宫内膜异位症发生时，子宫内膜组织通过 逆行月经并植入盆腔器官和腹膜表面。然而，尽管高达90% 在经历逆行月经的女性中，只有10%的女性患上子宫内膜异位症，这表明 子宫内膜异位症的发生与未知因素有关。因此，确定这些因果因素是至关重要的。 开发新的工具来诊断和治疗这种痛苦的疾病。这一提议将检验核心假设，即 而一些肠道细菌通过诱导巨噬细胞介导的炎症促进子宫内膜异位症，而另一些 通过发酵纤维产生短链脂肪酸(SCFAs)来预防子宫内膜异位症。这个想法是建立在 关于几个关键的初步和公布的数据。首先，在子宫内膜异位症的同基因注射模型中， 微生物区系耗竭的小鼠的子宫内膜异位症病变明显较小，腹膜病变较少 比对照组小鼠更容易发炎。然而，口服小鼠粪便的小鼠的病变大小得以恢复。 患有子宫内膜异位症。第二，子宫内膜异位症小鼠腹腔液中含有较少的单链脂肪酸醋酸酯， 丙酸和丁酸盐，而不是来自非子宫内膜异位症小鼠的腹腔液。第三，丁酸被抑制在 小鼠子宫内膜异位病变体内生长和人子宫内膜异位病变来源细胞的体外生长。 最后，最近的报告表明，患有子宫内膜异位症的妇女的肠道细菌组成与 未患子宫内膜异位症的女性。这里提出的工作将建立在这些强大的初步数据基础上，并测试 通过追求以下特定目标来提出假说：(目标1)确定肠道细菌 促进子宫内膜异位症；(目标2)确定单链脂肪酸影响子宫内膜异位症的机制；(目标3)确定 人类肠道细菌与子宫内膜异位症的关系，并确定肠道细菌对人类的影响 小鼠子宫内膜异位症的生长。在基础科学的层面上，这个项目将确定肠道细菌和炎症 增加对子宫内膜异位症发生的敏感性并确定超临界脂肪酸保护机制的概况 抗子宫内膜异位症。具有翻译意义，这项工作将识别促进或 预防育龄妇女子宫内膜异位症。共同努力，这项工作将有助于推动 NICHD 2020年战略计划中规定的理想目标：“加快努力，明确诊断， 预防和治疗子宫内膜异位症“。