Understanding the Host-Microbiome-Therapeutic Triad: Implications for Designing Alternative Intravaginal Delivery Platforms to Treat Bacterial Vaginosis

项目摘要 细菌性阴道病（BV）是阴道微生物组的生态失调，其特征在于低水平的乳酸杆菌， 通常在健康女性的阴道中占主导地位，并且各种厌氧菌的过度生长，最值得注意的是， 葡萄加德纳菌（G. v.）BV影响约30%的美国女性，并与不良反应风险增加有关。 妊娠结局、术后感染和性传播感染（STI）。当前治疗 主要由口服或局部应用的抗生素组成的选择最初是有效的;然而， 复发是普遍的，导致复发性BV感染和不良副作用。潜在的新疗法， 包括益生元，代谢产物（例如，乳酸）和益生菌（乳酸杆菌）正在研究其 使阴道微生物组向“正常”乳酸杆菌重新平衡并平衡G. V的能力。然而， 这些和其他BV治疗方法通常需要重复阴道给药，这可能限制其治疗效果。 方便和适当的使用。新的运载工具，可以储存和释放乳酸和益生菌 需要乳酸杆菌。然而，在我们对宿主、微生物和递送的理解方面仍然存在重大差距 车辆相互作用，导致难以获得长期有效的保护方法， 治疗BV。 在这个项目中，我们寻求开发新的治疗方法来改变BV的发病机制，同时推进治疗。 了解运载工具与宿主和阴道微生物的相互作用。为了实现这些目标，我们 将优化由顺序分层或双纺丝聚合物组成的新型递送平台的设计， 电纺纤维（EF），提供益生菌，测试其体外功效，并评估安全性和有效性 这些纤维在BV的小鼠模型中。这些研究将为改善治疗提供基础。 结果，同时提供了新的见解，乳酸为基础的，益生菌纤维对阴道微生物的影响， 宿主炎症反应和BV疾病标志物和进展。虽然我们最初将应用此交付 作为一种靶向BV发病机制的方法，我们设想研究结果将对 开发未来的多用途平台，以预防和治疗更广泛，更复杂的相互作用， 女性生殖道中的细菌和病毒病原体。

PROJECT SUMMARY Bacterial vaginosis (BV) is a dysbiosis of the vaginal microbiome characterized by low levels of lactobacilli, which typically dominate the vagina in healthy women, and overgrowth of diverse anaerobic bacteria, most notably, Gardnerella vaginalis (G.v.). BV affects ~30% of U.S. women and is associated with increased risk of adverse pregnancy outcomes, postsurgical infections, and sexually transmitted infections (STIs). Current treatment options, primarily comprised of orally- or topically-applied antibiotics, are initially efficacious; however, frequent relapse is prevalent, contributing to recurrent BV infections and adverse side effects. Potential new therapies, including prebiotics, metabolic products (e.g., lactic acid), and probiotics (lactobacilli) are being studied for their abilities to re-balance the vaginal microbiome toward “normal” Lactobacilli and counterbalance G.v. However, these and other methods of BV treatment often require repeated vaginal administrations, which can limit their convenience and appropriate use. New delivery vehicles that can store and release lactic acid and probiotic lactobacilli are needed. However, significant gaps remain in our understanding of host, microbe, and delivery vehicle interactions, contributing to the difficulty in attaining a long-term, effective method of protection and treatment against BV. In this project, we seek to develop new therapies to alter BV pathogenesis, while advancing the understanding of delivery vehicle interactions with the host and vaginal microbes. To achieve these goals, we will optimize the design of a novel delivery platform composed of sequentially-layered or dual-spun polymeric electrospun fibers (EFs) that deliver probiotics, test their efficacy in vitro, and assess the safety and effectiveness of these fibers in a murine model of BV. These studies will provide the foundation for improved therapeutic outcomes, while providing new insight into the effects of lactic acid-based, probiotic fibers on vaginal microbes, host inflammatory response, and BV disease markers and progression. While we will initially apply this delivery approach to target BV pathogenesis, we envision the research outcomes will have a significant impact on the development of future multipurpose platforms to prevent and treat broader, more complex interactions between bacterial and viral pathogens in the female reproductive tract.