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: 10595435
• 负责人: Ramakrishna Kommagani
• 金额: $ 38.9万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 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 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595435
• 关键词: Abdomen; Acetates; Affect; Age; Age-Years; Bacteria; Basic Science; Butyrates; Cell physiology; Cells; Consumption; Data; Development; Diagnosis; 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; diagnostic tool; 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".

项目概要 子宫内膜异位症会导致骨盆和下腹部疼痛，每 10 名 15 岁至 49 岁的女性中就有 1 人患有子宫内膜异位症 在美国的年龄。这些女性中近一半患有慢性盆腔疼痛，许多人发现 现有的治疗方法（激素疗法和手术）有副作用，并且不能防止复发。 一个广为接受的理论是，当子宫内膜组织通过腹膜腔进入腹膜腔时，就会发生子宫内膜异位症。 月经逆行并植入盆腔器官和腹膜表面。然而，尽管高达 90% 的女性经历月经逆行，只有 10% 的女性患有子宫内膜异位症，这表明 未知因素导致子宫内膜异位症的发生。因此，识别此类因果因素至关重要 开发新工具来诊断和治疗这种痛苦的疾病。该提案将检验中心假设： 有些肠道细菌通过诱导巨噬细胞介导的炎症来促进子宫内膜异位症，而另一些肠道细菌则通过诱导巨噬细胞介导的炎症来促进子宫内膜异位症。 通过发酵纤维产生短链脂肪酸（SCFA）来预防子宫内膜异位症。这个想法是建立起来的 初步和已发布数据的几项关键数据。首先，在子宫内膜异位症的同基因注射模型中， 微生物群耗尽的小鼠子宫内膜异位病变明显更小，腹膜也更少 炎症程度高于对照小鼠。然而，口服小鼠粪便后，病变大小得以恢复 患有子宫内膜异位症。其次，患有子宫内膜异位症的小鼠的腹腔液中含有较少的 SCFA 醋酸盐， 丙酸盐和丁酸盐的含量高于无子宫内膜异位症小鼠的腹腔液。第三，丁酸抑制 小鼠体内子宫内膜异位病变的生长和源自子宫内膜异位病变的人体细胞的体外生长。 最后，最近的报告表明，患有子宫内膜异位症的女性的肠道细菌组成与女性不同。 无子宫内膜异位症的女性。这里提出的工作将建立在这些强有力的初步数据的基础上，并测试 假设通过追求以下具体目标：（目标 1）确定肠道细菌的机制 促进子宫内膜异位症； （目标 2）确定短链脂肪酸 SCFA 影响子宫内膜异位症的机制； （目标 3）识别 人类肠道细菌与子宫内膜异位症相关，并确定肠道细菌对人类的影响 小鼠子宫内膜异位生长。在基础科学层面，该项目将识别肠道细菌和炎症 赋予对发生子宫内膜异位症的敏感性的概况，并确定 SCFA 的保护机制 对抗子宫内膜异位症。具有转化意义，这项工作将确定促进或促进的细菌候选者 预防育龄妇女子宫内膜异位症。总之，这项工作将有助于推进其中一项 NICHD 2020 战略计划中提出的理想目标：“加快努力明确诊断、 预防和治疗子宫内膜异位症”。