BACKGROUND Endometriosis is a chronic, burdensome condition that is historically understudied. Consequently, there is a lack of understanding of the etiology of the disease and its associated symptoms, including infertility and chronic pelvic pain (CPP). Endometriosis development is influenced by estrogen metabolism and inflammation, which are modulated by several factors including the microbiome and the estrobolome (the collection of genes encoding estrogen-metabolizing enzymes in the gut microbiome). Therefore, there is increasing interest in understanding the role of microbiota in endometriosis etiology. OBJECTIVE AND RATIONALE To date, there is no cure for endometriosis and treatment options often are ineffective. This manuscript will review the potential relationship between the microbiome and endometriosis, infertility and CPP and highlight the available data on the microbiome in relation to endometriosis and its related symptoms. The overarching goal of this manuscript is to inform future microbiome research that will lead to a deeper understanding of the etiology of the disease and possible diagnostic modalities and treatments. The potential impact of the microbiome on estrogen regulation modulated by the estrobolome, as well as inflammation and other endometriosis-promoting mechanisms within the genital tract, will be reviewed. The methodological limitations of microbiome-related studies will be critically assessed to provide improved guidelines for future microbiome and clinical studies. SEARCH METHODS PubMed databases were searched using the following keywords: endometriosis AND microbiome, infertility AND microbiome, pelvic pain AND microbiome, IVF (in-vitro fertilization) AND microbiome, endometriosis AND infertility. Clinical and preclinical animal trials that were eligible for review, and related to microbiome and endometriosis, infertility or CPP were included. All available manuscripts were published in 2002–2021. OUTCOMES In total, 28 clinical and 6 animal studies were included in the review. In both human and animal studies, bacteria were enriched in endometriosis groups, although there was no clear consensus on specific microbiota compositions that were associated with endometriosis, and no studies included infertility or CPP with endometriosis. However, bacterial vaginosis-associated bacteria and Lactobacillus depletion in the cervicovaginal microbiome were associated with endometriosis and infertility in the majority (23/28) of studies. Interpretation of endometrial studies is limited owing to a variety of methodological factors, discussed in this review. In addition, metadata outlining antibiotic usage, age, race/ethnicity, menopausal status and timing of sample collection in relation to diagnosis of endometriosis was not consistently reported. Animal studies (6/6) support a bidirectional relationship between the gut microbiota and endometriosis onset and progression. WIDER IMPLICATIONS There is evidence that a dysbiotic gut or genital microbiota is associated with multiple gynecologic conditions, with mounting data supporting an association between the microbiome and endometriosis and infertility. These microbiomes likely play a role in the gut-brain axis, which further supports a putative association with the spectrum of symptoms associated with endometriosis, including infertility and CPP. Collectively, this review highlights the demand for more rigorous and transparent methodology and controls, consistency across the field, and inclusion of key demographic and clinical characteristics of disease and comparison participants. Rigorous study designs will allow for a better understanding of the potential role of the microbiome in endometriosis etiology and the relationship to other disorders of the female reproductive tract.

中文翻译：

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肠道和生殖器微生物群以及雌激素在子宫内膜异位症、不孕症和慢性盆腔痛中的作用

背景技术子宫内膜异位症是一种慢性的、繁重的疾病，历史上未被充分研究。因此，对该疾病的病因及其相关症状缺乏了解，包括不孕症和慢性盆腔痛 (CPP)。子宫内膜异位症的发展受雌激素代谢和炎症的影响，这些因素受多种因素的调节，包括微生物组和雌激素组（肠道微生物组中编码雌激素代谢酶的基因的集合）。因此，人们对了解微生物群在子宫内膜异位症病因中的作用越来越感兴趣。目标和理由 迄今为止，没有治愈子宫内膜异位症的方法，治疗方案通常无效。这篇手稿将回顾微生物组与子宫内膜异位症之间的潜在关系，不孕症和 CPP，并强调与子宫内膜异位症及其相关症状相关的微生物组的可用数据。这份手稿的首要目标是为未来的微生物组研究提供信息，从而更深入地了解疾病的病因以及可能的诊断方式和治疗方法。将回顾微生物组对雌激素组调节的雌激素调节的潜在影响，以及生殖道内的炎症和其他促进子宫内膜异位症的机制。将严格评估微生物组相关研究的方法学局限性，为未来的微生物组和临床研究提供改进的指南。搜索方法 使用以下关键字搜索 PubMed 数据库：子宫内膜异位症和微生物组、不孕症和微生物组、盆腔疼痛和微生物组、IVF（体外受精）和微生物组、子宫内膜异位症和不孕症。纳入了符合审查条件的、与微生物组和子宫内膜异位症、不孕症或 CPP 相关的临床和临床前动物试验。所有可用手稿均于 2002-2021 年出版。结果 总共有 28 项临床研究和 6 项动物研究被纳入审查。在人类和动物研究中，细菌在子宫内膜异位症组中富集，尽管对于与子宫内膜异位症相关的特定微生物群组成没有明确的共识，也没有研究包括不孕症或子宫内膜异位症的 CPP。然而，在大多数 (23/28) 研究中，宫颈阴道微生物组中的细菌性阴道病相关细菌和乳酸杆菌消耗与子宫内膜异位症和不孕症有关。由于本综述讨论的各种方法学因素，对子宫内膜研究的解释受到限制。此外，概述抗生素使用、年龄、种族/民族、绝经状态和与子宫内膜异位症诊断相关的样本采集时间的元数据并未得到一致报告。动物研究 (6/6) 支持肠道微生物群与子宫内膜异位症发病和进展之间的双向关系。更广泛的影响 有证据表明，失调的肠道或生殖器微生物群与多种妇科疾病有关，越来越多的数据支持微生物群与子宫内膜异位症和不孕症之间的关联。这些微生物组可能在肠-脑轴中发挥作用，这进一步支持了与子宫内膜异位症相关症状谱的假定关联，包括不孕症和CPP。总的来说，这篇综述强调了对更严格和透明的方法和控制、整个领域的一致性以及纳入疾病和比较参与者的关键人口统计学和临床​​特征的需求。严谨的研究设计将有助于更好地了解微生物组在子宫内膜异位症病因学中的潜在作用以及与女性生殖道其他疾病的关系。