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

• 批准号: 10057964
• 负责人: Liisa Victoria Hantsoo
• 金额: $ 10.33万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 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/10057964
• 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; Diet; 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; 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

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 不良童年经历（ACE），如虐待或慢性压力，程序失调， 神经内分泌-神经免疫轴，持续通过成年期，并促进炎症升高。一 怀孕期间的促炎环境可能特别有害，对双方都有潜在的健康影响。 母亲和孩子在非洲裔美国人（AA）妇女中，童年压力与贫穷的婴儿有关 结果，独立于成年压力暴露。AA女性的ACE暴露率较高， 更大的生理脆弱性，炎症的影响，压力比白人妇女，和一倍， 美国白人的早产率，强调研究压力和母亲的重要性- 这一人群的健康状况。我们实验室的数据表明，肠道微生物组可能是一个关键环节， 母体ACE与妊娠期炎症升高之间的关系。虽然有链接 肠道微生物组成和促炎细胞因子升高之间的关系， 建立从ACE到肠道微生物组到炎症的联系，这是我们的第一个目标。如果ACE 与怀孕期间肠道微生物组的改变有关，这种改变的微生物组是否会传递给 在阴道分娩时产下的后代我们的第二个目标是解决是否压力引起的改变， 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 代谢物组（Metabolome）随着肠道微生物组-代谢组塑造后代的发育， 免疫系统，使营养物质可用于大脑发育，其功能有重要意义， 后代的结果。最后，我们的实验室发现，母亲膳食中摄入的omega-3脂肪酸可能 改善ACE对妊娠期炎症的影响。有多次ACE病史的女性 （“高ACE”），那些摄入大量omega-3脂肪酸的人会出现炎症应激反应 与无ACE病史的女性相似，而高ACE女性低omega-3摄入量 促炎细胞因子水平升高我们的最终目的是评估孕妇饮食在怀孕期间的影响 关于肠道微生物组与炎症之间的关系，以及对未来干预工作的影响， 这个高危怀孕的戒酒人群为了实现这些目标，我们将研究200个来自美国的母婴对。 费城儿童医院（CHOP）婴儿生长和微生物组（IGRAM）队列， 粪便和血液样本我们将测量亚/种属的肠道微生物群落组成 水平使用领先的鸟枪宏基因组测序，肠道代谢物（短链脂肪酸; SCFAs） 作为肠道功能的指标，以及母亲和后代的血清促炎细胞因子。这将使我们 模拟母体ACE、肠道微生物组和炎症之间的复杂关系， 这些因素之间的关系母亲和后代。