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.

项目摘要 早期生活（例如压力）与对发展中的大脑的长期后果有关， 增加随后出现性偏见的神经精神疾病的风险，包括 精神分裂症，抑郁和自闭症谱系障碍。尽管在理解 母体环境在正常和病理大脑发育中的机械作用，许多问题仍然存在 关于怀孕期间的压力如何导致后代应力失调的发展，这是一种普遍的 神经精神病的症状。最近的研究表明，母体肠道微生物群落是 怀孕期间动态重塑，以维持发育中的胎儿的持续养分 并为母亲准备哺乳的精力需求。在我们既定的鼠标早期模型中 产前压力（EPS），我们的初步研究表明，暴露于EPS的新生儿表现出特定的性别 与能量平衡和稳态有关的代谢谱的改变，并且基于最近的研究，可能 表明微生物介导的营养利用率的孕产妇变化可能是代谢物改变的 暴露后代的概况。综上所述，这些结果使我们提出了一个假设，即大脑 妊娠期间压力对母体肠道微生物组和营养的影响改变了发展 可用性。使用尖端``omics技术，旨在确定母亲之间的新颖联系 压力，母体肠道微生物组和代谢以及性别特定的大脑发育。第一个目的 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特征 对于胎儿脑发育至关重要。这个目标将利用母体肠道微生物群的时间序列分析， 孕产妇外周代谢物和养分可用性，以及胎儿脑代谢物轮廓 除了整合这些数据集的计算工具外，宏基因组学和代谢组学评估。 由于产前应力重编程对发育大脑的影响可能不会出现，直到后来 开发，第二个目标将检查压力对母体肠道菌群的持久影响 产后大脑发育的成分和营养可用性。这个目标将利用 使用下丘脑的母体肠道微生物群的时间序列分析和代谢物谱。 除了整合这些集成的计算工具外，宏基因组学和代谢组学评估 数据集。最终目标将确定孕产妇肠道微生物组在大脑发育中的因果关系。 在压力暴露窗口期间用益生菌定殖后，然后检查对 营救母体肠道菌群组成，产妇营养可用性和性别特异性脑代谢物 作品。这些研究将共同​​提供有关大脑的机制的宝贵见解 通过压力对孕产妇肠道微生物组和营养可用性的影响改变了发展 正常神经发育所必需的。