Evaluating the impact of human milk oligosaccharides on the vaginal microenvironment

项目摘要 人类微生物群的形成和成熟与终生健康结果有关，其最初的 母体阴道微生物区系对其构成有很大影响。对母体阴道的干扰 孕期或产期的微生物区系与多种健康疾病的风险增加有关 早产会在晚年发展为免疫或代谢性疾病。促进最优技术转移的因素 微生物对婴儿的影响是未知的，到目前为止，对这一关键过程的知识主要是描述性的或 相互关联的。我们试图通过应用模型开发方面的最新进展来克服这一障碍，特别是 利用灵芝动物、立体组织培养和复合微生物的培养 社区，为影响产妇阴道的宿主和微生物因素产生实验证据 怀孕期间的环境。有了这些模型，我们将测试一个假设，该假设提出了一个全新的 母体对初生婴儿微生物区系的影响机制。母乳喂养一直与 改善婴儿健康，降低感染疾病的风险，加速免疫和微生物成熟 在肠子里。人乳寡糖(HMOS)是母乳中含量第三丰富的成分， 作为微生物区系发育的益生素，并在肠道上皮形成免疫发展和耐受性。 最近，很明显，HMO在怀孕期间系统性地存在，这表明 对母体和胎儿生物学的影响比以前认识到的更广泛。临床研究表明， 母体血清HMO与阴道微生物组特征和HMO生产中的遗传变异有关 有阴道病原体定植和早产风险。这一提议的中心假设是医疗保健组织 调节孕期母体阴道微环境，促进益生菌生长 为婴儿肠道播种，并同时支持屏障功能和限制母亲炎症。我们将测试 这一假说是通过：1)表征HMOS在体外对人类阴道群落的生物活性 2)评价HMOS对阴道的免疫调节作用 用人阴道粘膜类有机物和灵知菌和无菌小鼠模型。这种研究方法 是申请人在微生物发病机制和动物模型方面的背景的补充合并 阴道定植和宿主-微生物组相互作用，以及BCM在以下领域的机构优势 人类微生物群的临床研究，人类器官的发展，以及微生物群的创新和 治疗学。这个高影响力的项目将评估HMO在阴道中活动的基本生物学和 提供一种治疗策略，以更好地利用HMOS在调节阴道微生物和免疫方面的潜力。 完成这个项目所需的丰富经验是很容易获得的， 申请者的经验和支持合作者，并将为新的发现、出版物、 以及一条激动人心的研究轨迹。

Project Summary Formation and maturation of the human microbiota is associated with lifelong health outcomes, and its initial composition is heavily influenced by the maternal vaginal microbiota. Perturbations to the maternal vaginal microbiota in pregnancy or intrapartum are associated with increased risk of multiple health disorders from preterm birth to developing immune or metabolic disease later in life. Factors that promote an optimal transfer of microbes to the infant are undefined, and to date, knowledge of this critical process is largely descriptive or correlative. We seek to overcome this barrier by applying recent advances in model development, particularly the use of gnotobiotic animals, three-dimensional tissue culture, and cultivation of complex microbial communities, to generate experimental evidence for host and microbial factors shaping the maternal vaginal environment during pregnancy. With these models in hand, we will test a hypothesis proposing an entirely novel mechanism of maternal influence on the initial infant microbiota. Breastfeeding is consistently associated with improved infant health, reduced risk of infectious disease, and accelerated immune and microbial maturation within the gut. Human milk oligosaccharides (HMOs), the third most abundant component of breastmilk, serve as prebiotics for the developing microbiota and shape immune development and tolerance at the gut epithelium. Quite recently, it has become apparent that HMOs are systemically present during pregnancy, suggesting a wider influence on maternal and fetal biology than previously appreciated. Clinical studies have correlated maternal serum HMOs with vaginal microbiome signatures and genetic variants in HMO production are linked with vaginal pathogen colonization and risk for preterm birth. The central hypothesis of this proposal is that HMOs modulate the maternal vaginal microenvironment in pregnancy to promote growth of beneficial microbes for seeding the infant gut and to concurrently support barrier function and limit maternal inflammation. We will test this hypothesis by: 1) Characterizing the biological activity of HMOs towards human vaginal communities in vitro and in humanized gnotobiotic mice, and 2) Evaluating immunomodulatory impacts of HMOs at the vaginal mucosa using human vaginal organoids and gnotobiotic and germ-free mouse models. This research approach is a complementary merger of the applicant’s background in microbial pathogenesis and animal models of vaginal colonization and host-microbiome interactions, and the institutional strengths of BCM in the areas of human microbiome clinical research, human organoid development, and microbiome innovation and therapeutics. This high impact project will apprise the basic biology of HMO activity in the vaginal tract and provide a therapeutic tactic to better harness the potential of HMOs in modulating vaginal microbes and immunity. The breadth of experience necessary to complete this project is readily available through the combination of the applicant’s experience and supporting collaborators, and will lay the foundation for new findings, publications, and an exciting research trajectory.