Maternal stress and the gut microblome:impact on neurodevelopment

母亲压力和肠道微生物：对神经发育的影响

• 批准号: 9192362
• 负责人: Eldin Jasarevic
• 金额: $ 5.61万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-20 至 2018-06-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9192362
• 关键词: Accounting; Adult; Affect; Amino Acids; Anxiety; Appetite Regulation; Autistic Disorder; Behavior; Blood - brain barrier anatomy; Brain; Chronic; Collection; Data; Data Set; Development; Disease; Ecology; Environment; Etiology; Exhibits; Female; Fetus; Growth; Homeostasis; Hypothalamic structure; Incidence; Lactation; Lactobacillus; Lactobacillus casei rhamnosus; Life; Mediating; Mental Depression; Metabolic; Metabolism; Metagenomics; Modeling; Mothers; Neurodevelopmental Disorder; Newborn Infant; Nutrient; Nutritional; Nutritional status; Pathway interactions; Peripheral; Plasma; Pregnancy; Preparation; Probiotics; Production; Regulation; Risk; Role; Schizophrenia; Series; Sex Bias; Stress; Structure; Symptoms; System; Taxon; Technology; Time; Training; absorption; autism spectrum disorder; base; computerized tools; disorder risk; energy balance; fetal; gut microbiome; gut microbiota; insight; male; maternal stress; meetings; metabolic profile; metabolomics; microbial; microbial community; mouse model; neonatal brain; neurodevelopment; neuropsychiatric disorder; neuroregulation; novel; nutrient metabolism; offspring; postnatal; pregnant; prenatal; prenatal stress; programs; resilience; sex

PROJECT SUMMARY Early life perturbations, such as stress, are associated with long-term consequences on the developing brain, increasing subsequent risk of neuropsychiatric disorders that exhibit a sex bias in presentation, including schizophrenia, depression, and autism spectrum disorders. Despite advances in understanding the mechanistic roles of the maternal milieu in normal and pathological brain development, many question remain about how stress during pregnancy result in the development of offspring stress dysregulation, a pervasive symptom in neuropsychiatric disease. Recent studies indicate that maternal gut microbial communities are dynamically remodeled during pregnancy to maintain a continuous supply of nutrients to the developing fetus and prepare the mothers for the energetic demands of lactation. In our established mouse model of early prenatal stress (EPS), our preliminary studies show that newborns exposed to EPS exhibit sex-specific alterations in metabolic profiles related to energy balance and homeostasis, and, based on recent studies, may suggest that maternal changes in microbial-mediated nutrient availability may account for altered metabolite profiles in exposed offspring. Taken together, these results have led us to the hypothesis that brain development is altered by the impact of stress during pregnancy on the maternal gut microbiome and nutrient availability. Using cutting-edge `omics technologies, we aim to identify novel connections between maternal stress, the maternal gut microbiome and metabolism, and sex-specific brain development. The first aim of study will examine whether stress during pregnancy disrupts maternal gut microbiota and nutrient profiles critical for fetal brain development. This aim will utilize time-series profiling of the maternal gut microbiota, maternal peripheral metabolite and nutrient availability, and fetal brain metabolite profiles using combined metagenomics and metabolomics assessment, in addition to computational tools that integrate these datasets. As the effect of prenatal stress reprogramming on the developing brain may not emerge until later in development, the second aim will examine the lasting effect of stress on the maternal gut microbiota composition and nutrient availability on the brain development during the postnatal period. This aim will utilize time-series profiling of maternal gut microbiota, and metabolite profiles of the offspring hypothalamus using combined metagenomics and metabolomics assessment, in addition to computational tools that integrate these datasets. The final aim will determine causality of the maternal gut microbiome on brain development. Following colonization with probiotics during the window of stress exposure, then examine the impact on rescuing maternal gut microbiota composition, maternal nutrient availability, and sex-specific brain metabolite composition. Together, these studies will provide valuable insights into the mechanisms by which brain development is altered through the effect of stress on the maternal gut microbiome and nutrient availability necessary for normal neurodevelopment.

项目概要 早期生活的干扰，例如压力，与发育中的大脑的长期后果有关， 增加随后出现表现出性别偏见的神经精神疾病的风险，包括 精神分裂症、抑郁症和自闭症谱系障碍。尽管在理解方面取得了进展 母亲环境在正常和病理性大脑发育中的机械作用，仍然存在许多问题 关于怀孕期间的压力如何导致后代压力失调的发展，这是一种普遍存在的现象 神经精神疾病的症状。最近的研究表明，母体肠道微生物群落 在怀孕期间动态重塑，以维持对发育中的胎儿的持续营养供应 并让母亲为哺乳期的能量需求做好准备。在我们建立的早期小鼠模型中 产前应激 (EPS)，我们的初步研究表明，接触 EPS 的新生儿表现出性别特异性 与能量平衡和稳态相关的代谢特征的改变，并且根据最近的研究，可能 表明母体微生物介导的营养可用性的变化可能是代谢物改变的原因 暴露后代的概况。总而言之，这些结果使我们得出这样的假设：大脑 怀孕期间的压力对母体肠道微生物组和营养物质的影响会改变发育 可用性。利用尖端的“组学”技术，我们的目标是确定母亲之间的新联系 压力、母体肠道微生物组和新陈代谢以及性别特异性大脑发育。第一个目标是 研究将检查怀孕期间的压力是否会破坏母体肠道微生物群和营养成分 对胎儿大脑发育至关重要。这一目标将利用母体肠道微生物群的时间序列分析， 结合使用母体外周代谢和营养可用性以及胎儿脑代谢谱 宏基因组学和代谢组学评估，以及集成这些数据集的计算工具。 由于产前应激重编程对发育中大脑的影响可能要到后期才会显现出来。 发展，第二个目标将检查压力对母体肠道微生物群的持久影响 产后大脑发育的成分和营养可用性。这一目标将利用 使用母体肠道微生物群的时间序列分析和后代下丘脑的代谢物分析 结合宏基因组学和代谢组学评估，以及集成这些的计算工具 数据集。最终目标将确定母体肠道微生物群对大脑发育的因果关系。 在压力暴露期间用益生菌定植后，然后检查对 拯救母体肠道微生物群组成、母体营养可用性和性别特异性脑代谢物 作品。总之，这些研究将为大脑的机制提供有价值的见解。 压力对母体肠道微生物组和营养可用性的影响会改变发育 正常神经发育所必需的。