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

项目总结 细菌性阴道病(BV)是一种以低水平乳酸菌为特征的阴道微生物群失调， 通常在健康女性的阴道中占主导地位，以及各种厌氧细菌的过度生长，最值得注意的是， 阴道加德纳氏菌(G.V.)BV影响了大约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)。目前的治疗方法 主要由口服或局部使用的抗生素组成的选择，最初是有效的；然而，经常 复发很普遍，会导致反复的BV感染和不良副作用。潜在的新疗法， 包括益生素、代谢产品(如乳酸)和益生菌(乳杆菌)正在研究其 将阴道微生物群重新平衡为“正常”乳杆菌的能力，并抵消G.V.然而， 这些和其他治疗BV的方法通常需要反复阴道给药，这可能会限制他们的 方便和适当的使用。可储存和释放乳酸和益生菌的新型递送工具 需要乳酸菌。然而，在我们对宿主、微生物和传递的理解上仍然存在着显著的差距 车辆相互作用，导致难以获得长期、有效的保护和 针对BV的治疗。 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 了解递送载体与宿主和阴道微生物的相互作用。为了实现这些目标，我们 将优化由顺层或双纺聚合物组成的新型输送平台的设计 提供益生菌的电纺纤维(EFS)，在体外测试其有效性，并评估其安全性和有效性 这些纤维在BV的小鼠模型中。这些研究将为改进治疗方法提供基础 结果，虽然为乳酸为基础的益生菌纤维对阴道微生物的影响提供了新的见解， 宿主炎症反应和BV疾病标记物和进展。虽然我们最初将应用这一交付 对于靶向BV致病机制的方法，我们预计研究结果将对 开发未来的多功能平台，以防止和治疗更广泛、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.