Early Life Stress Patterning of the Gut-Brain Axis: An Intergenerational Approach

肠-脑轴的早期生命压力模式：代际方法

基本信息

批准号：
10227802
负责人：
Liisa Victoria Hantsoo
金额：
$ 8.51万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10227802
关键词：
Acetates Acids Address Adult Affect African American Age-Months Bacteria Blood specimen Brain Butyrates C-reactive protein Caproates Caucasians Child Abuse Childhood Chronic stress Complex Consumption Data Development Dietary intake Enterobacteriaceae Eubacterium Family Feces Fetal health Future Growth Health High Risk Woman Immune system Infant Inflammation Inflammatory Intake Interleukin-1 Interleukin-6 Intervention Intestines Laboratories Lead Life Link Low Birth Weight Infant Measures Mediating Mediator of activation protein Modeling Mothers Neuroimmune Neurosecretory Systems Nutrient Omega-3 Fatty Acids Outcome Pattern Pediatric Hospitals Peripheral Philadelphia Physiological Pilot Projects Population Pregnancy Pregnant Women Premature Birth Prevotella Production Propionates Psychiatric Diagnosis Publishing Recording of previous events Research Risk Rodent Model Role Sampling Serum Shapes Shotguns Stress TNF gene Third Pregnancy Trimester Vaginal delivery procedure Valerates Vertical Disease Transmission Volatile Fatty Acids Woman Work adverse childhood events bacterial community base beta diversity biological adaptation to stress cohort cytokine dietary early experience early life stress gut microbiome gut microbiota gut-brain axis high risk indexing infant outcome inflammatory disease of the intestine intergenerational lymphotoxin beta metabolome metabolomics metagenomic sequencing microbial community microbiome microbiome alteration mother nutrition neglect neurodevelopment novel offspring pre-clinical research pregnant programs stool sample stressor

项目摘要

PROJECT SUMMARY Adverse childhood experiences (ACEs), such as abuse or chronic stress, program a dysregulated neuroendocrine-neuroimmune axis that persists through adulthood and promotes elevated inflammation. A proinflammatory milieu during pregnancy may be particularly pernicious, with potential health effects on both mother and offspring. In African American (AA) women, childhood stress is associated with poor infant outcomes, independent of adulthood stress exposure. AA women have higher rates of ACE exposure and greater physiologic vulnerability to the inflammatory impact of stress than Caucasian women, and double the rate of preterm birth as Caucasians in the U.S., underlining the importance of studying stress and maternal- offspring health in this population. Data from our laboratory suggests that the gut microbiome may be a key link in the association between maternal ACE and elevated inflammation in pregnancy. While there are links between gut microbial composition and elevated proinflammatory cytokines, a gap in the research remains in establishing links from ACE to gut microbiome to inflammation, which our first aim addresses. Further, if ACE is associated with an altered gut microbiome during pregnancy, does this altered microbiome pass to the offspring during vaginal delivery? Our second aim addresses whether stress-induced alterations in the maternal gut microbiome are passed to the offspring, assessing offspring gut microbial community composition and metabolites (the metabolome). As the gut microbiome-metabolome shapes development of the offspring immune system and makes nutrients available for brain development, its function has important implications for offspring outcomes. Finally, our laboratory found that maternal dietary intake of omega-3 fatty acids may ameliorate the effects of ACE on inflammation during pregnancy. In women with a history of multiple ACEs (“high ACE”), those who consumed large amounts of omega-3 fatty acids had an inflammatory stress response similar to that of women with no ACE history, while high ACE women with low omega-3 consumption had elevated levels of proinflammatory cytokines. Our final aim assesses impact of maternal diet during pregnancy on the relationship between gut microbiome and inflammation, with implications for future intervention work in this high-risk pregnant AA population. To address these aims, we will study 200 mother-infant dyads from the existing Children’s Hospital of Philadelphia (CHOP) Infant Growth and Microbiome (IGRAM) cohort, with existing fecal and blood samples. We will measure gut microbial community composition at the sub/species level using leading-edge shotgun metagenomics sequencing, gut metabolites (short chain fatty acids; SCFAs) as an index of gut function, and serum proinflammatory cytokines in mothers and offspring. This would allow us to model the complex relationships among maternal ACEs, gut microbiome, and inflammation, and the relationship of these factors between mother and offspring.

项目摘要不良的童年经历（ACE），例如滥用或慢性压力，编程失调神经内分泌 - 神经免疫性轴持续到成年，并促进注射升高。一个怀孕期间的促炎环境可能特别有害，对这两者都有潜在的健康影响母亲和后代。在非裔美国人（AA）妇女中，童年的压力与婴儿贫穷有关结果，与成年应力暴露无关。 AA妇女的ACE暴露率较高，并且与白种妇女相比，对压力的炎症影响的生理脆弱性更大，两倍在美国作为高加索人的早产率，强调了研究压力和母体的重要性该人群的后代健康。我们实验室的数据表明，肠道微生物组可能是关键链接在怀孕期间的孕妇和感染升高之间的关联。虽然有链接在肠道微生物组成和促炎细胞因子之间，研究中的差距仍然存在建立从ACE到肠道微生物组到炎症的联系，我们的第一个目的解决了这一问题。此外，如果王牌与怀孕期间的肠道微生物组改变有关，这是否改变了微生物组阴道分娩期间的后代？我们的第二个目的解决了压力引起的改变母体肠道微生物组传递给后代，评估后代肠道微生物群落组成和代谢物（代谢组）。随着肠道微生物组 - 代谢组塑造后代的发展免疫系统并使营养可用于大脑发育，其功能对后代结果。最后，我们的实验室发现，omega-3脂肪酸的饮食摄入量可能改善ACE对怀孕期间炎症的影响。在有多个王牌史的女性中（“高王牌”），那些消耗大量omega-3脂肪酸的人具有炎症应激反应与没有ACE历史的女性类似，而欧米茄3消费率低的高ace女性促炎细胞因子水平升高。我们的最终目标评估在怀孕期间对饮食的影响关于肠道微生物组与注射之间的关系，对未来干预工作的影响这个高风险的怀孕AA人群。为了解决这些目标，我们将研究来自费城现有儿童医院（CHOP）婴儿成长和微生物组（IGRAM）同类现有的粪便和血液样本。我们将测量子/物种的肠道微生物群落组成使用前沿shot弹枪宏基因组学测序，肠道代谢物（短链脂肪酸； SCFA）的水平作为肠道功能的指数，以及母亲和后代的血清促炎细胞因子。这将使我们建模母体ac，肠道微生物组和注射之间的复杂关系，以及母亲和后代之间这些因素的关系。