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: 9574492
• 负责人: Eldin Jasarevic
• 金额: $ 5.25万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 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/9574492
• 关键词: Adult; Affect; Amino Acids; Anxiety; Appetite Regulation; Autistic Disorder; Behavior; Blood - brain barrier anatomy; Brain; Brain region; Chronic; Collection; Data; Data Set; Development; Disease; Ecology; Environment; Etiology; Exhibits; Female; Fetus; Growth; Homeostasis; Human Milk; 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; Pathologic; Pathway interactions; Peripheral; Plasma; Pregnancy; Preparation; Probiotics; Production; Regulation; Risk; Role; Schizophrenia; Series; Sex Bias; Stress; Structure; Symbiosis; Symptoms; System; Technology; Time; Training; absorption; autism spectrum disorder; base; computerized tools; disorder risk; energy balance; fetal; gut microbiome; gut microbiota; insight; male; maternal stress; metabolic profile; metabolomics; microbial; microbial community; mouse model; neonatal brain; neonate; neurodevelopment; neuropsychiatric disorder; neuroregulation; novel; nutrient metabolism; offspring; postnatal; pregnant; prenatal; prenatal stress; public health relevance; resilience; sex; suckling

 DESCRIPTION (provided by applicant): 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, maternal breast milk composition, 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.

 描述（由适用提供）：早期生命扰动（例如压力）与对发展中的大脑的长期后果有关，增加了神经精神疾病的风险，这些风险在表现中暴露了性别偏见，包括精神分裂症，抑郁症和自闭症谱系障碍。尽管了解母体环境在正常和病理大脑发育中的机理作用方面的进步，但许多问题仍然存在许多问题，即怀孕期间的压力如何导致后代应激失调的发展，这是神经精神病中普遍存在的症状。最近的研究表明，在怀孕期间，对生物肠道微生物群落进行了动态重塑，以维持向发育中的胎儿的持续养分供应，并为母亲准备哺乳的能量需求。在我们既定的早期产前压力（EPS）的老鼠模型中，我们的初步研究表明，暴露于EPS的新生儿表现出与能量平衡和稳态相关的代谢特征的特定性别变化，并且基于最近的研究，可能表明，微生物介导的营养可用性可能会导致变化的代替代质体的变化。综上所述，这些结果使我们提出了这样的假设：妊娠期间的压力对孕妇肠道微生物组和营养可用性的影响改变了大脑的发育。我们使用尖端的``OMICS技术''我们旨在确定母校压力，母体肠道微生物组和代谢以及性别特定的大脑发育之间的新联系。研究的第一个目的是检查怀孕期间的压力是否会破坏孕产妇肠道菌群和对胎儿脑发育至关重要的营养特征。此目标将利用母体肠道菌群的时间序列分析，外周周代谢物和营养物的可用性以及胎儿脑代谢物概况 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组合。由于产前应力重编程对发育中的大脑的影响可能直到发育后期才出现，因此，第二个目标将检查压力对产后时期孕产妇肠道菌群组成和养分的持久影响。此目标将利用母体肠道菌群的时间序列分析，母乳组成以及后代下丘脑的代谢物概况，除了将集成这些数据集集成的计算工具外，还使用宏基因组学和代谢组学评估。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。在压力暴露的窗口中与益生菌定殖后，然后检查对拯救材料肠道菌群组成的影响，产妇营养物的可用性和性别特异性的脑代谢产物组成。总之，这些研究将通过压力对正常神经发育所需的母体肠道微生物组和营养利益的影响来改变大脑发育的机制有价值的见解。