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".

项目摘要 子宫内膜异位症，导致骨盆和下腹部疼痛，折磨15至49岁之间的十分之一女性 在美国的年龄。这些女性中有将近一半遭受慢性骨盆疼痛，许多人发现 可用的治疗方法（激素治疗和手术）具有负面影响，并且不能防止复发。 一个良好接受的理论是，当子宫内膜组织通过 逆行月经和植入骨盆器官和腹膜表面。但是，多达90％ 妇女经历月经经历，只有10％的妇女出现子宫内膜异位症，这表明 未知因素有助于子宫内膜异位症的发展。因此，识别这种因果因素是必不可少的 开发新工具来诊断和治疗这种痛苦的疾病。该提议将检验一个中心假设，即 而某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，而另一些则可以 通过发酵纤维产生短链脂肪酸（SCFA）来防止子宫内膜异位症。这个想法是建立的 在几个关键的初步和已发布数据上。首先，在子宫内膜异位症的合成注射模型中 微生物群的小鼠出现明显较小的子宫内膜损伤，腹膜较少 炎症比对照小鼠。但是，在口服的小鼠中用小鼠的粪便恢复了病变的大小 与子宫内膜异位症。其次，子宫内膜异位症的小鼠的腹膜液含有较少的SCFAS乙酸盐， 丙酸酯和丁酸酯比没有子宫内膜异位的小鼠的腹膜液比腹膜液。第三，丁酸抑制了这两者 小鼠的体内子宫内膜内膜病变的生长和从子宫内膜损伤衍生的人类细胞的体外生长。 最后，最近的报告表明，子宫内膜异位症的女性具有不同的肠道细菌组成 没有子宫内膜异位的妇女。这里提出的工作将基于这些强大的初步数据，并测试 通过追求以下特定目的假设：（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的影响 小鼠子宫内膜异位症的生长。在基础科学层面，该项目将识别肠道细菌和炎症 赋予对子宫内膜异位症的敏感性并确定SCFAS保护的机制的轮廓 反对子宫内膜异位症。具有翻译意义的意义，这项工作将确定促进或 预防生殖年龄妇女的子宫内膜异位症。这项工作将有助于推进其中之一 NICHD 2020年战略计划中指出的有抱负目标：“加速努力，以确定诊断， 预防和治疗子宫内膜异位症”。