The maternal microbiome in childhood growth and immunity during undernutrition

营养不良期间儿童生长和免疫中的母体微生物组

基本信息

批准号：
10452697
负责人：
Carrie Adeline Cowardin
金额：
$ 34.83万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-16 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10452697
关键词：
16S ribosomal RNA sequencing Address Adoptive Transfer Adult Age Animals B-Lymphocytes Behavior Control Birth Bone Growth Breeding Cell physiology Cells Cessation of life Characteristics Chemicals Child Child Health Childbirth Childhood Cognitive Cognitive deficits Communicable Diseases Communities Complication Data Defect Development Environment Flow Cytometry Fostering Gene Expression Profiling Germ-Free Gnotobiotic Goals Growth Health Heterozygote Homozygote Housing Human Immune Immune response Immune system Immunity Immunotherapeutic agent Infant Health Infrastructure Intervention Investigation Lead Life Lymphoid Lymphopoiesis Malnutrition Maternal Health Mediating Metabolic Metabolic Diseases Microbe Modeling Mothers Mus Neonatal Partner in relationship Pathway interactions Phenotype Physiological Play Pregnancy Probiotics Productivity Rag1 Mouse Research Risk Role Sampling Shapes Signal Pathway Signal Transduction Sorting - Cell Movement Syndrome Systems Biology T cell response T cell therapy T-Lymphocyte Techniques Testing Therapeutic Intervention Time Universities Virginia Vulnerable Populations Weight Work adaptive immunity bone chemokine cognitive function disorder risk experience experimental study fetal global health gut microbes gut microbiome gut microbiota immune activation immune function improved innovation insight intergenerational machine learning algorithm maternal microbiome maternal microbiota member microbial microbial community microbiome microbiota mouse model novel strategies offspring postnatal postnatal period prenatal progenitor pup random forest targeted treatment therapeutic target tomography transmission process

项目摘要

Globally, undernutrition contributes to 44% of childhood deaths under the age of five 1. Stunting, or reduced linear growth, is a major complication of undernutrition that is associated with increased risk of metabolic and infectious disease, reduced educational attainment and poor cognitive function later in life 3. Stunted mothers are more likely to experience complications during childbirth, and to give birth to stunted children 5. In turn, many children that are born stunted do not recover despite current therapeutic interventions 4. Therefore, stunting is often referred to as an intergenerational syndrome, and new approaches are desperately needed to improve childhood growth in vulnerable populations. The maternal immune system plays a major role in shaping offspring physical, cognitive and immune development. The gut microbiota likewise influences both local and systemic immunity, raising the possibility that the maternal microbiome could influence fetal and childhood development. We hypothesize that maternal gut microbial composition shapes the fetal immune environment to control offspring growth and immune development during undernutrition. We propose to use a mouse model of intergenerational undernutrition to identify specific immune and microbial targets for therapeutic intervention. Our preliminary data demonstrate that breeding mice colonized with microbiota from healthy or severely stunted donors produce offspring with divergent weight, bone, and immune developmental phenotypes that persist into maturity. We will use this model to isolate the role of the maternal gut microbiome from the neonatal microbiome, giving critical insight into the window of potential intervention. We will also identify specific subsets of microbes that are capable of influencing offspring growth and immune development and characterize microbial metabolic products associated with these changes. Finally, we will identify maternal immune cells and signaling pathways that respond to these microbial communities to control healthy growth and immune development in offspring. These experiments will identify specific microbial species as well as host immune pathways to target therapeutically and define the appropriate developmental stage in which to intervene. The Cowardin lab is located within the Child Health Research Center at the University of Virginia, and as a member of the Trans- University Miocrobiome Initiative, is uniquely suited to pursuing these studies. The lab has both the infrastructure and expertise required for successful completion of these goals. Ultimately, this proposal will lead to potential probiotic and immunotherapeutic treatments to disrupt the transmission of stunting from mother to child.

在全球范围内，营养不良导致 44% 的 5 岁以下儿童死亡1。发育迟缓或线性生长减慢是营养不良的一个主要并发症，与代谢和传染病风险增加、受教育程度降低以及日后认知功能差有关3. 发育迟缓的母亲更有可能在分娩过程中出现并发症，并生出发育迟缓的儿童 5. 反过来，尽管目前采取了治疗干预措施，但许多出生时发育迟缓的儿童仍无法康复4. 因此，发育迟缓通常被称为代际综合症，迫切需要新的方法来改善弱势群体的儿童生长。母体免疫系统在塑造后代身体、认知和免疫发育方面发挥着重要作用。肠道微生物群同样影响局部和全身免疫，增加了母体微生物群影响胎儿和儿童发育的可能性。我们假设母体肠道微生物组成塑造胎儿免疫环境，以控制营养不良期间后代的生长和免疫发育。我们建议使用代际营养不良的小鼠模型来确定治疗干预的特定免疫和微生物靶标。我们的初步数据表明，被来自健康或严重发育不良供体的微生物群定殖的繁殖小鼠产生的后代具有不同的体重、骨骼和免疫发育表型，并且这些后代持续到成熟。我们将使用该模型将母体肠道微生物组与新生儿微生物组的作用分开，从而对潜在干预窗口提供重要的见解。我们还将确定能够影响后代生长和免疫发育的特定微生物子集，并表征与这些变化相关的微生物代谢产物。最后，我们将确定对这些微生物群落做出反应的母体免疫细胞和信号通路，以控制后代的健康生长和免疫发育。这些实验将识别特定的微生物种类以及宿主免疫途径以进行治疗，并确定进行干预的适当发育阶段。 Cowardin 实验室位于弗吉尼亚大学儿童健康研究中心内，作为跨大学微生物组计划的成员，非常适合开展这些研究。该实验室拥有成功完成这些目标所需的基础设施和专业知识。最终，该提案将带来潜在的益生菌和免疫治疗方法，以阻止发育迟缓从母亲到孩子的传播。