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身健康结果相关，其最初的 阴道微生物群的组成受到母体阴道微生物群的严重影响。母体阴道扰动 怀孕或分娩期间的微生物群与多种健康疾病的风险增加有关， 早产到以后的免疫或代谢疾病。促进最佳转移的因素 微生物对婴儿的影响尚不明确，迄今为止，对这一关键过程的了解主要是描述性的， 相关的我们试图通过应用模型开发的最新进展来克服这一障碍， 利用知生动物、三维组织培养和复合微生物培养 社区，以产生宿主和微生物因素塑造母体阴道的实验证据 怀孕期间的环境。有了这些模型，我们将测试一个假设，提出一个全新的 母亲对婴儿最初微生物群的影响机制。母乳喂养一直与 改善婴儿健康，降低传染病风险，加速免疫和微生物成熟 在肠道内。人乳低聚糖（HMO）是母乳中含量第三丰富的成分， 作为发育中的微生物群的益生元，并在肠道上皮形成免疫发育和耐受性。 最近，很明显，HMO在怀孕期间全身存在，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 阴道病原体定植和早产风险。这一提议的核心假设是， 调节怀孕期间母体阴道微环境，促进有益微生物的生长， 接种婴儿肠道并同时支持屏障功能和限制母体炎症。我们将测试 该假设通过：1）表征HMO对体外人阴道群落的生物活性 和在人源化gnotobiotic小鼠中，和2）评价HMO在阴道中的免疫调节作用， 使用人阴道类器官和无菌和无菌小鼠模型，这种研究方法 是申请人在微生物发病机理和动物模型方面的背景的互补合并。 阴道定植和宿主-微生物组相互作用，以及微生物管理局在以下领域的机构优势： 人类微生物组临床研究、人类类器官发育和微生物组创新， 治疗学这个高影响力的项目将告知HMO在阴道活动的基本生物学， 提供了一种治疗策略，以更好地利用HMO在调节阴道微生物和免疫力方面的潜力。 完成该项目所需的经验广度可以通过以下方式轻松获得： 申请人的经验和支持合作者，并将奠定新的发现，出版物， and an exciting令人兴奋research研究trajectory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.