Evaluating the impact of human milk oligosaccharides on the vaginal microenvironment

评估母乳低聚糖对阴道微环境的影响

• 批准号: 10645794
• 负责人: Katy Patras
• 金额: $ 20.97万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645794
• 关键词: 3-Dimensional; Acceleration; Amniotic Fluid; Animal Model; Animals; Antibiotics; Area; Bacteria; Bacteroides; Biological; Biology; Birth; Breast Feeding; Cells; Clinical Research; Communicable Diseases; Communities; Complex; Development; Disease; Environment; Enzymes; Epithelial Cells; Epithelium; Event; Foundations; Germ-Free; Gnotobiotic; Growth; Hand; Health; Human; Human Activities; Human Biology; Human Microbiome; Human Milk; Immune; Immune System Diseases; Immune response; Immunity; In Vitro; Infant; Infant Development; Infant Health; Inflammation; Institution; Intervention; Knowledge; Lactation; Life; Link; Literature; Medical; Metabolic Diseases; Metabolism; Microbe; Modeling; Mothers; Mucous Membrane; Mus; Neonatal; Oligosaccharides; Organism; Organoids; Outcome; Pathogenesis; Pathway interactions; Plasma; Polysaccharides; Pregnancy; Premature Birth; Process; Production; Publications; Research; Risk; Role; Sampling; Shapes; Testing; Therapeutic; Urine; Vagina; Work; adverse pregnancy outcome; antimicrobial; bacterial community; bacterial fitness; beneficial microorganism; dysbiosis; experience; fetal; gastrointestinal epithelium; genetic variant; genome analysis; gut microbiota; host microbiome; human microbiota; immunoregulation; improved; in vivo; innovation; insight; intrapartum; maternal serum; microbial; microbial community; microbiome; microbiome signature; microbiota; model development; mouse model; novel; pathobiont; pathogen; prebiotics; prevent; reproductive tract; response; tissue culture; vaginal microbiome; vaginal microbiota; vaginal mucosa

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.

项目摘要 人类微生物群的形成和成熟与终身健康结果及其最初的健康结果有关 组成受母亲阴道菌群的影响很大。对母亲阴道的扰动 怀孕或产前的微生物群与来自多种健康疾病的风险增加有关 早年生长出来的早产或代谢疾病的早产。促进最佳转移的因素 婴儿的微生物是不确定的，迄今为止，此关键过程的知识在很大程度上具有描述性或 相关。我们试图通过应用模型开发的最新进展来克服这一障碍，特别是 使用gnotobiriotic动物，三维组织培养和复杂微生物的培养 社区，为构成母体阴道的宿主和微生物因子的实验证据 怀孕期间的环境。借助这些模型，我们将检验一个假设，提出了一个完全新颖的假设 对初始婴儿微生物群的物物影响机制。母乳喂养始终与 改善婴儿健康，降低感染疾病的风险以及加速免疫和微生物成熟 在肠内。人牛奶寡糖（HMOS）是母乳的第三大部分成分，服务 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在怀孕期间系统地存在，这表明 对孕产妇和胎儿生物学的影响广泛比以前所欣赏的。临床研究已经相关 具有阴道微生物组特征和HMO产生中的遗传变异的母体血清HMO与HMO的遗传变异 阴道病原体定植和早产风险。该提议的中心假设是HMOS 调节妊娠中母亲的阴道微环境，以促进有益微生物的生长 看到婴儿肠道并同时支持屏障功能并限制母体炎症。我们将测试 该假设通过：1）表征HMO在体外对人类阴道群落的生物学活性 在人源化的gnotobiotic小鼠中，以及2）评估HMO对阴道的免疫调节影响 使用人类阴道类器官和gnotobiotic和无菌小鼠模型的粘膜。这种研究方法 是申请人在微生物发病机理和动物模型中的背景的完整合并 阴道定植和宿主 - 微生物组相互作用，以及BCM在该地区的机构优势 人类微生物组临床研究，人体器官发育和微生物组创新和 疗法。这个高影响力项目将了解阴道界HMO活动的基本生物学，并 提供一种治疗策略，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的广度很容易通过结合 申请人的经验和支持合作者，并将为新发现，出版物， 以及令人兴奋的研究轨迹。