Dysbiosis, Recurrent Bacterial Vaginosis and the Vaginal Microbiome

项目摘要/摘要： 以细菌性阴道病(BV)临床综合征为代表的被破坏或“不良”的阴道微生物区系， 可能导致严重的复发症状，尽管接受抗生素治疗，以及严重的生殖 后果包括早产和性传播感染的获得和传播。 新的分子技术使人们能够更深入地了解蛋白质的复杂结构 阴道微生物群落，而新生的代谢组学领域的研究表明， 这些微生物区系的产出可能是生物失调发病机制中的一个关键因素。激素避孕法(HC) 流行病学研究表明，在某些情况下，但不是所有情况下，BV事件和复发的风险会降低 女人。初步数据表明，HC稳定了微生物区系，并使其远离低乳酸菌， 混合厌氧菌--BV的优势群落。因此，它可能会成为一种 在选定的患者中改善生物失调和治疗复发的BV。然而，尽管50多年来 广泛使用，我们对HC对阴道团结构的影响的理解 无症状的妇女是不完整的，HC对这些地区阴道群落功能的影响 女性并不为人所知。此外，HC对小鼠阴道微生物区系结构和功能的影响 患有复发性BV的妇女尚不清楚。本提案试图通过3个目标来阐明这些问题：1) 评价HC对无症状妇女阴道微生物区系结构的影响 乳杆菌(特别是乳杆菌)和其他选定的厌氧菌的绝对细菌计数 阴道微生物群落，2)确定HC对小鼠阴道微生物区系功能的影响 无症状妇女，通过产生乳酸异构体和生物胺来衡量，以及3)至 评价HC对小鼠阴道微生物区系结构和功能的影响 女性复发性炎。目标1和目标2将嵌套在现有的队列研究中，即荷尔蒙 避孕纵向研究。对于目标3，PI将招募一小部分飞行员队列，以进行关于 女性复发性BV从HC开始。通过正式的教学和来自团队的结构化指导 它由泌尿生殖系统感染、元基因组学和高级分析方面的专家组成，PI将 培养独特的分析技能，包括R统计包、纵向数据分析、 多层次建模、主成分分析和层次聚类分析，以及经验 在患者招募和临床研究方面。这将使她能够实现成为一名 独立的临床研究人员，将利用元基因组学和代谢组学的强大新工具 设计和领导干预措施，以改善妇女的临床结果。

Project Summary/Abstract: Disrupted or “dysbiotic” vaginal microbiota, as epitomized by the clinical syndrome of bacterial vaginosis (BV), can result in severe recurrent symptoms despite antibiotic therapy, as well as serious reproductive consequences including preterm labor and the acquisition and transmission of sexually transmitted infections. New molecular techniques are enabling a more sophisticated understanding of the complex structure of vaginal microbial communities, while studies from the nascent field of metabolomics suggest that the functional output of these microbiota may be a key factor in the pathogenesis of dysbiosis. Hormonal contraception (HC) has been shown in epidemiologic studies to decrease the risk of incident and recurrent BV in some, but not all women. Preliminary data suggests that HC stabilizes and shifts the microbiota away from the low-lactobacilli, mixed anaerobe-predominant communities characteristic of BV. As such, it may hold promise as a way to ameliorate dysbiosis and treat recurrent BV in selected patients. However, despite over 50 years of widespread use, our understanding of the impact of HC on the structure of vaginal communities in asymptomatic women is incomplete, and the impact of HC on the function of vaginal communities in these women is not known. Additionally, the impact of HC on the structure and function of the vaginal microbiota in women with recurrent BV is unknown. This proposal seeks to elucidate these questions through 3 aims: 1) To evaluate the impact of HC on the structure of the vaginal microbiota in asymptomatic women as measured by absolute bacterial counts of Lactobacillus species, (in particular L. iners), and other selected anaerobes in vaginal microbial communities, 2) To determine the impact of HC on the function of the vaginal microbiota in asymptomatic women as measured by the production of lactic acid isomers and biogenic amines, and 3) To evaluate the impact of HC on the structure and function of the vaginal microbiota in a small pilot cohort of women with recurrent BV. Aims 1 and 2 will be nested within an existing cohort study, the Hormonal Contraception Longitudinal Study. For aim 3, the PI will recruit a small pilot cohort for an observational study of women with recurrent BV starting on HC. Through formal didactics and structured mentorship from a team which comprises experts in genitourinary infections, metagenomics, and advanced analytics, the PI will develop a unique analytic skill set, including knowledge of the R statistical package, longitudinal data analysis, multi-level modeling, principle component analysis and hierarchical clustering analysis, as well as experience in patient recruitment and clinical research. This will enable her to achieve the long-term goal of becoming an independent clinical investigator who will utilize the powerful new tools of metagenomics and metabolomics to design and lead interventions to improve clinical outcomes in women.