Nutrition and Inflammation in Pregnancy: Impacts on Early Human Brain Development

项目摘要 在资源匮乏的环境中，出生后1000天内的营养不良和感染是普遍存在的， 可能对儿童的认知和心理发展产生终身影响的风险因素。迅速 发育中的胎儿大脑增加了营养和代谢需求， 炎症。蛋白质、能量和铁是早期大脑发育所需的关键营养素;然而， 在撒哈拉以南非洲的育龄妇女中，10%体重不足，20%缺铁 贫血妊娠感染在非洲也很常见，三分之一的妇女患有地质蠕虫病。 感染，导致缺铁和炎症。铁调素是铁稳态的调节剂， 然而，关于妊娠期hepcidin以及如何优化胎儿生长的研究有限。 铁的生物利用度在炎症的背景下。了解营养之间的复杂关系， 炎症和神经发育是一个主要的研究空白。理解的主要方法 产前大脑发育的机制主要来自动物和观察研究。 在这里，我们提出了一个前所未有的机会，利用正在进行的，独立资助的随机 对照试验（RCT）检查因果关系，并严格调查生物学途径， 产前营养和炎症影响人类胎儿大脑发育， 埃塞俄比亚农村的风险人口。在母体试验中，妊娠早期的女性随机接受：1） 标准产前护理，2）一揽子强化营养支持（铁-叶酸、碘盐、强化 平衡能量蛋白（BEP）补充剂），3）一揽子感染管理（驱虫，治疗 尿路感染），或4）两种包装。拟议的项目将支持先进的，多模式的，婴儿 6岁时的神经发育评估（EEG/VEP、头颅超声、神经检查、诱发模仿任务） 和24个月大，并分析母体和新生儿脐带血的炎症生物标志物（C- 反应蛋白，α-1酸性糖蛋白，白细胞介素（IL）-6），神经营养因子（IL-6可溶性受体），铁 储存（血清铁蛋白、可溶性转铁蛋白受体、全身铁）和铁调素。我们的具体目标是：（1） 确定干预措施对后代神经发育的影响，（2）调查干预措施对后代神经发育的影响。 对母亲-新生儿铁和炎症生物标志物的干预，以及（3）检查母亲-新生儿铁和炎症生物标志物的作用。 新生儿铁状况和炎症对儿童神经发育的影响。利用埃塞俄比亚正在进行的一项随机对照试验， 将确定铁、BEP和炎症对儿童神经行为高级测量的影响 并将加深对生物途径和干预目标的理解。我们将 阐明妊娠期铁和炎症的复杂动力学及其对神经网络的影响， 大脑结构和儿童期的行为。我们的工作将有助于优化产前干预策略， 改善全球高疾病负担和脆弱人群的早期人类大脑发育。

PROJECT SUMMARY In low-resource settings, undernutrition and infections during the first 1000 days of life are prevalent, modifiable risk factors that may have lifelong effects on a child’s cognitive and psychological development. The rapidly developing fetal brain has increased nutritional and metabolic demands and is highly susceptible to the effects of inflammation. Protein, energy, and iron are key nutrients required for early brain development; yet, among women of reproductive age in Sub-Saharan Africa, 10% are underweight and 20% have iron deficiency anemia. Pregnancy infections are also common in Africa, where one in three women have a geo-helminthic infection, contributing to iron deficiency and inflammation. Hepcidin, a regulator of iron homeostasis, is stimulated by inflammation, yet there is limited research on hepcidin in pregnancy and how to optimize fetal iron bioavailability in the context of inflammation. Understanding the complex relationship between nutrition, inflammation, and neurodevelopment is a major research gap. The predominant approach to understanding mechanisms of prenatal brain development is derived predominantly from animal and observational studies. Here, we present an unprecedented opportunity to leverage an ongoing, independently funded randomized controlled trial (RCT) to examine casual relationships and rigorously investigate biological pathways by which prenatal nutrition and inflammation influence human fetal brain development in an undernourished and high- risk population in rural Ethiopia. In the parent trial, women in early pregnancy are randomized to receive: 1) standard prenatal care, 2) a package of strengthened nutritional support (iron-folate, iodized salt, fortified balanced energy protein (BEP) supplement), 3) a package of infection management (deworming, treatment of urinary tract infections), or 4) both packages. The proposed project will support advanced, multi-modal, infant neurodevelopmental assessments (EEG/VEP, cranial ultrasound, neurologic exam, elicited imitation tasks) at 6 and 24 months of age, and analysis of maternal and newborn cord blood for inflammation biomarkers (C- reactive protein, alpha-1 acid glycoprotein, Interleukin (IL)-6), neurotropic factors (IL-6 soluble receptor), iron stores (serum ferritin, soluble transferrin receptor, total body iron), and hepcidin. Our specific aims are to: (1) determine the effects of interventions on offspring neurodevelopment, (2) investigate the effects of interventions on maternal-newborn iron and inflammation biomarkers, and (3) examine the role of maternal- newborn iron status and inflammation on child neurodevelopment. Leveraging an ongoing RCT in Ethiopia, we will determine the effects of iron, BEP, and inflammation on advanced measures of childhood neurobehavior and function and will deepen the understanding of biological pathways and intervention targets. We will elucidate the complex dynamics of iron and inflammation in pregnancy and their effects on neural networks, brain structure, and behavior in childhood. Our work will help optimize prenatal intervention strategies to improve early human brain development in high disease burden and vulnerable populations globally.