Vaginal microbiota transplant to promote Lactobacillus-dominant cervicovaginal communities

阴道微生物群移植促进以乳杆菌为主的宫颈阴道群落

基本信息

批准号：
10366355
负责人：
Caroline M Mitchell
金额：
$ 83.96万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10366355
关键词：
16S ribosomal RNA sequencing Adverse event Anaerobic Bacteria Animal Model Antibiotic Therapy Antibiotics Area Bacterial Vaginosis Biological Response Modifier Therapy Cervical dysplasia Characteristics Chemicals Clinical Clostridium difficile Collection Communities Complex Data Databases Development Donor person Dose Engraftment Enrollment Experimental Models Formulation Future Genes Genetic Genital Genitalia Goals HIV Health Human Human Papillomavirus In Vitro Individual Infection Inflammation Intervention Intervention Studies Kinetics Lactobacillus Light Link Metabolic Metronidazole Mucosal Immune Responses Mucositis Oral Organism Outcome Placebos Premature Birth Premenopause Prevalence Prevention Probiotics Public Health Randomized Randomized Clinical Trials Recording of previous events Recurrence Relapse Reproductive Health Risk Safety Saline Shotguns Spontaneous abortion Testing Transplant Recipients Transplantation Treatment Efficacy Vagina Woman Women&apos s Health adverse event monitoring adverse pregnancy outcome arm candidate selection cervicovaginal comparative genomics deep sequencing design dysbiosis efficacy evaluation fecal transplantation follow-up genital microbiome genome sequencing gut microbiota immune activation improved in vivo infection risk inflammatory marker insight interest metabolic profile metabolomics metagenomic sequencing microbial microbial colonization microbial community microbiome microbiota microbiota transplantation multi-component intervention novel novel strategies post intervention prebiotics primary outcome randomized trial recruit restoration safety testing scale up secondary outcome success therapy design treatment strategy vaginal fluid vaginal lactobacilli vaginal microbiome vaginal microbiota whole genome

项目摘要

PROJECT SUMMARY Vaginal colonization with a Lactobacillus-dominant microbial community is associated with lower risk for preterm birth, HIV acquisition, HPV persistence and cervical dysplasia. A diverse, Lactobacillus-deficient vaginal microbiota such as that seen in bacterial vaginosis (BV) is associated with mucosal inflammation, which is likely the mechanistic link to the adverse health outcomes seen with dysbiosis. Antibiotic treatment for BV achieves short term cure, but recurrence is common. Probiotic treatment to restore healthy lactobacilli is only moderately successful, even with daily treatment. These results emphasize the need for novel strategies to manipulate the genital microbiome and produce sustainable shifts away from dysbiosis. We propose a randomized clinical trial of vaginal microbiota transplant (VMT) with extensive characterization of donors, transplant material, recipients and engraftment, to identify determinants of vaginal microbial colonization and stability. Our team has already obtained an IND, successfully recruited donors, and generated preliminary data demonstrating stability of Lactobacillus in donated material. In Aim 1 we will enroll up to 25 healthy donors and 126 recipients with a history of recurrent BV and an abnormal Nugent score. Recipients receive 1 week of oral metronidazole and are randomized to VMT or saline placebo, two doses given on non-consecutive days in a single week. The primary outcome is prevalence of a Lactobacillus-dominant vaginal microbiota by 16S rRNA sequencing 1 month after intervention. Secondary outcomes include adverse events, Lactobacillus dominance over the entire 6 month follow up, and prevalence of BV by Nugent score at 1, 3 & 6 months. In Aim 2 we will characterize the impact of vaginal fluid transplantation on recipient microbiome (Aim 2.1) and mucosal inflammation (Aim 2.2). For Aim 2.1 we will use 16S rRNA sequencing, qPCR and shotgun metagenomic sequencing (SMS) to define the kinetics of Lactobacillus colonization and community diversity over the 6 months following study intervention. In Aim 2.2 we will assess the impact of VMT vs. placebo on soluble markers of inflammation in vaginal fluid and endocervical immune cell activation. In Aim 3 we will identify genetic characteristics of both successful donations and Lactobacillus isolates cultivated from successful VMT donors and recipients (Aim 3.1). We will compare isolates in vitro to test functional metrics for future selection of strains for novel products (Aim 3.2). We will also compare metabolic profiles of successful vs. unsuccessful donations (Aim 3.3). The resulting isolate collection and database of genes and metabolites associated with achieving Lactobacillus dominance will provide a basis for design of a novel live biotherapeutic for prevention of BV and its associated sequelae. Execution of these three aims will also provide novel insights into determinants of vaginal Lactobacillus colonization and the causal relationship between Lactobacillus and protection from BV, moving the field forward whether or not our trial demonstrates a clinical benefit for VMT. Data obtained will provide guidance on what features are important for designing a synthetic intervention, which would be easier to scale up for widespread use than VMT.

项目摘要具有乳酸杆菌的阴道定殖与乳酸杆菌的微生物群落与早产的风险较低有关出生，艾滋病毒收购，HPV持久性和宫颈发育不良。多样的，乳杆菌缺乏阴道诸如细菌性阴道病（BV）中发现的微生物群与粘膜炎症有关，这很可能是与营养不良的不良健康结局的机械联系。 BV的抗生素治疗短期治疗，但复发很常见。益生菌治疗以恢复健康的乳酸杆菌仅适度即使日常治疗成功。这些结果强调需要采取新颖策略来操纵生殖器微生物组并产生可持续性从营养不良转移。我们提出了一个随机临床阴道菌群移植（VMT）的试验，具有供体，移植物质的广泛表征，接受者和植入，以确定阴道微生物定植和稳定性的决定因素。我们的团队有已经获得了IND，成功招募的捐助者，并产生了证明稳定性的初步数据乳酸杆菌的捐赠材料。在AIM 1中，我们最多将注册25位健康捐助者和126名接受者复发性BV的历史和异常的Nugent评分。接收者接受1周的口服甲硝唑，为随机分配给VMT或盐水安慰剂，在一周内不连续的几天服用两次剂量。主要结果是16s rRNA测序1个月后，乳酸杆菌含量为主导的阴道微生物群的患病率干涉。次要结果包括不良事件，在整个6个月内乳酸杆菌的优势跟进，在1、3和6个月内按Nugent分数对BV的患病率。在AIM 2中，我们将表征对受体微生物组（AIM 2.1）和粘膜炎症（AIM 2.2）的阴道流体移植。对于目标2.1 我们将使用16S rRNA测序，QPCR和shot弹枪元基因组测序（SMS）来定义研究干预后的6个月内，乳杆菌定植和社区多样性。在AIM 2.2我们将评估VMT与安慰剂对阴道液和宫颈炎症可溶性标记的影响免疫细胞激活。在AIM 3中，我们将确定成功捐赠和从成功的VMT供体和受体中种植的乳杆菌分离物（AIM 3.1）。我们将比较分离株在体外测试功能指标，以未来选择新产品的菌株（AIM 3.2）。我们还将比较成功与失败捐赠的代谢概况（AIM 3.3）。由此产生的分离株收集和与实现乳杆菌优势相关的基因和代谢产物数据库将为用于预防BV及其相关后遗症的新型Live Biothapeic的设计。这三个执行目的还将为阴道乳酸杆菌定植和因果关系提供新的见解乳酸杆菌与BV保护之间的关系，无论我们的审判是否向前推进现场证明了VMT的临床益处。获得的数据将提供有关哪些功能对哪些功能很重要的指导设计合成干预措施，比VMT更容易扩展以供广泛使用。