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.

项目总结 不良童年经历(ACE)，如虐待或慢性压力，计划失调 神经内分泌-神经免疫轴，在成年期持续存在，并促进炎症升高。一个 孕期的促炎环境可能特别有害，对双方都有潜在的健康影响。 母亲和后代。在非裔美国人(AA)女性中，童年压力与贫穷的婴儿有关 结果，独立于成年期的压力暴露。AA女性有更高的ACE暴露和 比高加索女性更容易受到压力的炎症影响，并且是高加索女性的两倍 美国高加索人的早产率，强调了研究压力和母亲的重要性-- 在这个群体中的后代健康。我们实验室的数据表明，肠道微生物群可能是一个关键环节 孕妇血管紧张素转换酶与妊娠炎症升高之间的关系。虽然有链接 在肠道微生物组成和升高的促炎细胞因子之间，研究中的差距仍然存在 建立从ACE到肠道微生物组再到炎症的联系，这是我们的首要目标。此外，如果ACE 与怀孕期间肠道微生物群的改变有关，这种改变的微生物群是否会传递给 在阴道分娩过程中的后代？我们的第二个目标是解决应激诱导的 母体肠道微生物群传递给子代，评估子代肠道微生物群落组成 和代谢物(代谢体)。随着肠道微生物代谢组形成后代的发育 免疫系统，并为大脑发育提供营养物质，其功能对 后代的结果。最后，我们的实验室发现，母亲饮食中摄入omega-3脂肪酸可能会 血管紧张素转换酶对妊娠期炎症的影响有多个A级病史的女性 (“高ACE”)，那些大量摄入omega-3脂肪酸的人有炎症应激反应 与没有ACE病史的女性相似，而ACE水平高、omega-3摄入量低的女性有 促炎症细胞因子水平升高。我们的最终目标是评估孕期母亲饮食的影响 肠道微生物群与炎症的关系及其对未来干预工作的启示 这些高危的再生障碍性贫血孕妇。为了达到这些目标，我们将研究200个母婴双胞胎 现有的费城儿童医院(CHOP)婴儿生长和微生物群(IGAM)队列， 现有的粪便和血液样本。我们将测量亚种/物种的肠道微生物群落组成 水平使用领先的鸟枪式元基因组测序，肠道代谢物(短链脂肪酸；SCFAs) 作为肠道功能和母子血清促炎细胞因子的指标。这将使我们能够 建立母体ACEs、肠道微生物群、炎症和 这些因素对母子关系的影响。