Maternal stress and the gut microblome:impact on neurodevelopment

 描述（由申请人提供）：早期生活干扰，如压力，与发育中大脑的长期后果有关，增加了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。尽管在理解母亲环境在正常和病理性大脑发育中的机械作用方面取得了进展，但仍存在许多问题，即妊娠期间的压力如何导致后代压力失调的发展，这是神经精神疾病的一种普遍症状。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，以保持对发育中的胎儿的持续营养供应，并为母亲哺乳的能量需求做好准备。在我们建立的早期产前应激（EPS）小鼠模型中，我们的初步研究表明，暴露于EPS的新生儿在与能量平衡和稳态相关的代谢谱中表现出性别特异性改变，并且根据最近的研究，可能表明母体微生物介导的营养物质可用性的变化可能是暴露后代代谢谱改变的原因。综上所述，这些结果使我们提出了一个假设，即怀孕期间压力对母体肠道微生物组和营养物质可用性的影响会改变大脑发育。利用尖端的“组学”技术，我们的目标是确定母体压力，母体肠道微生物组和代谢以及性别特异性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母体肠道微生物群和对胎儿大脑发育至关重要的营养成分。这一目标将利用母体肠道微生物群、母体外周代谢物和营养可用性以及胎儿脑代谢物谱的时间序列谱， 结合宏基因组学和代谢组学评估，以及整合这些数据集的计算工具。由于产前压力重编程对发育中大脑的影响可能要到发育后期才出现，第二个目标将研究压力对母体肠道微生物群组成的持久影响以及出生后大脑发育的营养可用性。这一目标将利用母体肠道微生物群，母体母乳成分和后代下丘脑代谢产物谱的时间序列分析，使用组合宏基因组学和代谢组学评估，以及整合这些数据集的计算工具。最终目标将确定母体肠道微生物组对大脑发育的因果关系。在应激暴露窗口期间用益生菌定殖后，然后检查对挽救母体肠道微生物群组成、母体营养物质可用性和性别特异性脑代谢物组成的影响。总之，这些研究将提供有价值的见解，通过压力对母体肠道微生物组和正常神经发育所需的营养物质的影响来改变大脑发育的机制。

 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.