Glycogen in bacterial Vaginosis & How Carbohydrates Shape the Vaginal Microbiome

细菌性阴道病中的糖原

• 批准号: 10250560
• 负责人: Warren G Lewis
• 金额: $ 39.49万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-07 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10250560
• 关键词: 16S ribosomal RNA sequencing; Acarbose; Affect; Amylases; Anaerobic Bacteria; Antibiotic Therapy; Antibiotics; Area; Bacteria; Bacterial Vaginosis; Behavior; Biochemical; Biochemistry; Carbohydrates; Carbon; Cleaved cell; Communities; Consumption; Data; Development; Discipline of obstetrics; Disease; Eating; Environment; Enzymes; Experimental Models; Galactose; Gardnerella; Gardnerella vaginalis; Genitourinary System Infection; Genomics; Glucans; Glucose; Glycogen; Goals; Growth; Health; Human; Individual; Investigation; Investigational Therapies; Lactobacillus; Lead; Length; Link; Liquid substance; Mannose; Measures; Mediator of activation protein; Metabolic; Metabolism; Methods; Microbiology; Mobiluncus; Modeling; Modernization; Outcome; Output; Physiology; Population; Pregnancy Complications; Premature Birth; Prevotella; Proteomics; Recurrence; Research; Resources; Risk; Role; Scientist; Shapes; Source; Specimen; Sucrose; Testing; Vagina; Woman; Women' s Health; bacterial community; bacterial metabolism; base; carbohydrate metabolism; enzyme activity; experience; feeding; glycogen metabolism; high risk; human model; improved; inhibitor/antagonist; insight; metabolic abnormality assessment; neglect; novel strategies; pathogen; preference; prevent; reproductive; success; sugar; tool; vaginal lactobacilli; vaginal microbiome; vaginal microbiota

SUMMARY Bacterial vaginosis (BV) is associated with higher risks of a dozen or more serious health complications. Unfortunately, antibiotic treatment is only effective for temporarily alleviation of BV. Microbiological and biochemical signatures of BV have been studied at length in relation to the `healthy' vaginal microbiome dominated by lactobacilli. However, little is known about the metabolism of many fastidious vaginal bacteria, how the metabolism of carbohydrates may drive bacterial growth, or how metabolic function of different bacteria may drive the compositions of bacterial communities and the physiology of the vagina. Such gaps in our understanding prevent the development of rational strategies to deter BV bacteria and encourage lactobacilli in the vagina. This proposal uses new experimental models of human vaginal community dynamics with the overarching goal of defining the carbohydrate preferences of vaginal bacteria. By measuring the growth and metabolic output of bacteria in mono-culture, and within ex vivo vaginal microbial communities, our broader objective is to develop conditions that specifically discourage BV bacteria and favor lactobacilli. In three specific aims, this proposal will use a combination of tools in microbiology and biochemistry together with genomics and proteomics to investigate the carbohydrate preferences of vaginal bacteria and potential mechanisms that can change in the composition and metabolism of vaginal communities. Glycogen is one example of an abundant potential source of carbohydrates in the vagina. As a polymer of glucose, glycogen is believed to be a carbon source for `healthy' lactobacilli. However, this interpretation has been based largely on correlative data rather than experimental investigation of the metabolic behaviors of vaginal bacteria. We present evidence that glycogen metabolism can fuel the outgrowth of specific BV bacteria and can lead to depletion of glycogen in culture. In Aim 1, we will examine which bacteria found in the vagina can employ amylases to metabolize glycogen, and we will define the relevant biochemical activities and identities of glycogen-cleaving enzymes. In Aim 2, we will investigate the larger role of glycogen metabolism for vaginal community dynamics, testing the hypothesis that glycogen supports the growth of bacteria in cultured BV communities, and that the inhibition of glycogen metabolism limits the expansion of BV-associated bacterial communities. Finally, in Aim 3, we will comprehensively investigate the carbohydrate preferences of vaginal bacteria, with particular emphasis on selectively promoting the growth and metabolism of lactobacilli. The successful completion of these aims will have an important positive impact on this field by establishing mechanistic insights about how BV bacteria utilize potential carbohydrate carbon sources available in the vagina. Furthermore, successful completion of these studies will lead to important insights about how to use the carbohydrate preferences of beneficial lactobacilli to promote their growth in the vagina, modulating carbohydrate metabolism for the treatment of BV.

概括 细菌性阴道病（BV）与十几个或更严重的健康并发症的较高风险有关。 不幸的是，抗生素治疗仅对暂时减轻BV有效。微生物学和 BV的生化特征已与“健康”阴道微生物组有关 由乳酸杆菌主导。但是，关于许多挑剔的阴道细菌的代谢知之甚少， 碳水化合物的新陈代谢如何促进细菌生长，或如何不同 细菌可能驱动细菌群落的组成和阴道的生理学。这样的差距 我们的理解阻止了制定理性策略来阻止BV细菌并鼓励 阴道中的乳杆菌。该建议使用人类阴道社区动态的新实验模型 以定义阴道细菌的碳水化合物偏好的总体目标。通过测量 单培养中细菌的生长和代谢输出，在体内阴道微生物群落中，我们 更广泛的目标是开发特异性劝阻BV细菌并有利于乳杆菌的疾病。在 三个具体目标，该提案将使用微生物学和生物化学方面的工具组合以及 基因组学和蛋白质组学研究阴道细菌的碳水化合物偏好和潜力 可以改变阴道群落组成和代谢的机制。糖原是一种 阴道中碳水化合物的大量潜在来源的例子。作为葡萄糖的聚合物，糖原是 被认为是“健康”乳酸杆菌的碳源。但是，这种解释主要基于 相关数据，而不是阴道细菌代谢行为的实验研究。我们 目前的证据表明，糖原代谢可以助长特定BV细菌的生长，并可能导致 糖原在培养中的耗竭。在AIM 1中，我们将检查阴道中发现哪些细菌可以使用 代谢糖原的淀粉酶，我们将定义相关的生化活性和身份 糖原裂解酶。在AIM 2中，我们将研究糖原代谢对阴道的较大作用 社区动力学，检验了糖原支持细菌在培养的BV中的生长的假设 社区，抑制糖原代谢限制了与BV相关细菌的扩张 社区。最后，在AIM 3中，我们将全面研究阴道的碳水化合物偏好 细菌，特别是选择性地促进乳酸杆菌的生长和代谢。这 这些目标的成功完成将通过建立对这一领域产生重要的积极影响 关于BV细菌如何利用潜在碳水化合物碳源可用的机械见解 阴道。此外，这些研究的成功完成将导致有关如何使用的重要见解 有益乳酸杆菌的碳水化合物偏好以促进其在阴道中的生长，调节 碳水化合物代谢用于治疗BV。