Immune regulation by the gut microbiome at the maternal-fetal interface

母胎界面肠道微生物组的免疫调节

• 批准号: 10536170
• 负责人: Melody Y Zeng
• 金额: $ 43.73万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-07 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10536170
• 关键词: ARG2 gene; Affect; Antibiotics; Antibodies; Bacteria; Caring; Cells; Child; Coupled; Development; Diet; Down-Regulation; Exhibits; Fetal Development; Fetal Growth; Fetal Liver; Fetal Resorption; Fetal Tissues; Fetus; Future; Genes; Genetic; Germ-Free; Goals; Health; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunoglobulin G; Incidence; Infection; Interferon Activation; Interferon Type II; Interferons; Intestines; Investigation; Lead; Malignant Neoplasms; Maternal-Fetal Exchange; Methodology; Mus; Myeloid-derived suppressor cells; Neonatal; Neutropenia; Newborn Infant; Pathway interactions; Pharmaceutical Preparations; Placenta; Placentation; Pre-Eclampsia; Predisposition; Pregnancy; Pregnancy Complications; Pregnancy Rate; Pregnant Women; Premature Birth; Regulation; Role; Shapes; Signal Transduction; Spiral Artery of the Endometrium; Spontaneous abortion; System; T-Lymphocyte; Techniques; Therapeutic Intervention; Tissues; United States; Uterus; fetal; genetic signature; gut bacteria; gut inflammation; gut microbiome; immunoregulation; imprint; in utero; interdisciplinary approach; murine colitis; neutrophil; novel; offspring; postnatal; pregnant; prenatal; progenitor; recruit; response; transcriptome; transcriptomics; trend

Despite advances in prenatal and maternal care, the incidence of pregnancy complications and preterm births remains high in the United States. Maternal immune tolerance toward the fetus is critical to promote fetal growth, but the regulatory mechanisms underlying fetal immune cell development remain largely undefined. Interferons are key regulators for placentation, but excessive interferon responses contribute to fetal resorption. In addition, maternal neutropenia is frequently associated with pregnancy complications such as preeclampsia, which has been demonstrated to affect the fetus and newborn adversely. Our understanding of the functions of neutrophils at the maternal-fetal interface, beyond their conventional role in infection, is still very limited. The gut microbiome undergoes drastic changes during pregnancy. However, the role of maternal gut microbiome immune tolerance and fetal immune regulation remains poorly understood. We have developed novel techniques to isolate and characterize placental immune cells in pregnant mice. Built upon our novel discovery of the maternal MDSC- IFNγ axis at the maternal-fetal interface that is orchestrated by the gut microbiome, the current proposal aims to define the role of maternal gut microbiome-driven MDSC-IFNγ axis in fetal and neonatal immune development. Leveraging the methodologies established in our lab to isolate and profile the transcriptome of immune cells, we will use an unbiased and comprehensive approach to fully appreciate functional changes in the fetal immune landscape due to perturbations of the gut microbiome. The transcriptomic studies will be coupled with ex vivo functional studies of tissue immune cells isolated from the placentas and fetal/neonatal intestines, as well as investigation of specific gut bacteria and metabolites that drive the immune cell changes at the maternal-fetal interface. First, we will employ an unbiased approach to profile the transcriptome of the fetal immune cells in the fetal liver and intestine to determine the role of the maternal MDSC-IFNγ axis in the regulation of immune cell development in these fetal tissues. Secondly, we will investigate how lacking maternal MDSCs during gestation impacts the postnatal immune development in the intestine, and investigate immune imprinting of T cells by in utero excessive IFNγ signaling and assess how it impacts the susceptibility to gut inflammation in the offspring. Upon completion, these studies will have defined the role of maternal gut microbiome, via regulation of the MDSC-IFNγ axis, shapes the fetal immune landscape and neonatal immune development in the intestine. Our studies will identify specific fetal immune subsets that are susceptible to perturbed MDSC-IFNγ axis that could be potential therapeutic/interventive targets. The findings from our studies will provide the framework for future studies of targeted manipulation of the gut microbiome to modulate these immune pathways to promote fetal immune cell development.

尽管在产前和产妇护理方面取得了进展， 在美国仍然很高。母体对胎儿的免疫耐受对促进胎儿生长至关重要， 但胎儿免疫细胞发育的调节机制在很大程度上仍不清楚。干扰素 是胎盘形成的关键调节因子，但过度的干扰素反应有助于胎儿吸收。此外，本发明还提供了一种方法， 母体中性粒细胞减少症经常与妊娠并发症如先兆子痫有关， 已被证明对胎儿和新生儿有不良影响。我们对中性粒细胞功能的理解 在母体-胎儿界面，超出了它们在感染中的传统作用，仍然非常有限。肠道微生物组 在怀孕期间会发生剧烈的变化。然而，母体肠道微生物组免疫耐受的作用 胎儿免疫调节仍然知之甚少。我们开发了新的技术来分离和 表征妊娠小鼠中的胎盘免疫细胞。基于我们对母体MDSC的新发现- IFNγ轴在母体-胎儿界面由肠道微生物组协调，目前的建议旨在 确定母体肠道微生物组驱动的MDSC-IFNγ轴在胎儿和新生儿免疫发育中的作用。 利用我们实验室建立的分离和分析免疫细胞转录组的方法，我们 将使用公正和全面的方法来充分了解胎儿免疫功能的变化， 由于肠道微生物组的扰动，转录组学研究将与离体研究相结合。 从胎盘和胎儿/新生儿肠道分离的组织免疫细胞的功能研究，以及 研究特定的肠道细菌和代谢产物，驱动母胎免疫细胞的变化 接口.首先，我们将采用一种无偏的方法来分析胎儿免疫细胞的转录组， 胎儿肝脏和肠道，以确定母体MDSC-IFNγ轴在免疫细胞调节中的作用 在这些胎儿组织中的发育。其次，我们将研究在妊娠期缺乏母体MDSC 影响出生后肠道免疫发育，并通过免疫印迹研究T细胞的免疫印迹。 子宫过度IFNγ信号传导，并评估其如何影响后代对肠道炎症的易感性。 完成后，这些研究将通过调节肠道微生物组来确定母体肠道微生物组的作用。 MDSC-IFNγ轴，塑造了胎儿肠道免疫景观和新生儿肠道免疫发育。我们 研究将确定对MDSC-IFNγ轴干扰敏感的特定胎儿免疫亚群， 是潜在的治疗/干预目标。我们的研究结果将为未来的研究提供框架。 靶向操纵肠道微生物组以调节这些免疫途径以促进胎儿发育的研究 免疫细胞发育。