Host DNA methylation as a mechanism of microbiome influence on internalizing behavior

项目摘要/摘要 超过5%的美国儿童和45%的美国青少年有焦虑或抑郁；这些比率 十多年来一直在增长。焦虑和抑郁是高度并存的内在化精神障碍， 常始于儿童时期，与下丘脑-垂体-肾上腺(HPA)轴异常有关 功能。早期生活压力(ELS)增加了一生中焦虑和抑郁的易感性。积累 有证据表明ELS可能会导致肠道微生物区系的长期变化，从而导致HPA异常 轴的功能和行为，这可能在内化行为中发挥关键作用。有很多途径存在 因此，微生物群的组成可能会影响行为和生理，其中之一是通过改变宿主 表观遗传学。ELS减少肠道微生物群中产生叶酸的菌株，而叶酸是必需的成分 用于DNA甲基化。最近的工作强调了微生物组和宿主表观基因组之间的潜在相互作用， 微生物群参与调节寄主对环境信号的反应，如ELS。这是未知的 ELS是否影响人类早期发育中的肠道微生物群组成，或者微生物群如何 影响HPA活性和内化行为。我们假设早期的心理社会压力会减少 肠道微生物群中影响HPA DNA甲基化和内化的叶酸产生类型 行为。阐明环境和肠道微生物群如何影响行为将为新的 产生有效的心理健康干预和治疗方法。这项提议利用了两个现有的 队列：环境对儿童健康结果的影响(ECHO；K99阶段)和亚利桑那州双胞胎 项目(ATP；R00阶段)。这两个队列都有广泛的纵向、情感行为表型 婴儿期、蹒跚学步和儿童早期。目标1将使用现有的回声纵向微生物组和ELS 确定儿童早期母亲抑郁是否对叶酸产生亲属有贡献的元数据 富足。目标2将确定宿主DNA甲基化是否是肠道微生物区系 成分影响内化行为。R00 AIMS将扩展我们的K99结果，并确定ELS 影响青春期微生物群组成并评估DNA甲基化与内化的关系 行为。使用孪生ACE模型，我们可以估计遗传和环境影响 微生物组、DNA甲基化和内化行为之间的关系。王牌模型结果将 准确定位环境的各个方面，不受基因影响的困扰，这些影响是 心理健康的机械途径。研究结果将为更广泛的科学研究提供有价值的信息 社区了解早期环境通过发育对心理健康的影响。

PROJECT SUMMARY/ABSTRACT More than 5% of US children and 45% of US adolescents have anxiety or depression; these rates have increased for over a decade. Anxiety and depression are highly comorbid internalizing mental disorders that often start during childhood and are associated with abnormal hypothalamic-pituitary-adrenal (HPA) axis function. Early life stress (ELS) increases vulnerability to anxiety and depression throughout life. Accumulating evidence suggests that ELS may produce long-lasting changes in gut microbiota contributing to abnormal HPA axis function and behavior, which could play a pivotal role in internalizing behaviors. Many avenues exist whereby microbiome composition may influence behavior and physiology, one of which is through altering host epigenetics. ELS reduces folate-producing strains in the gut microbiome and folate is a necessary component for DNA methylation. Recent work highlights potential interactions between microbiome and host epigenome, with microbiota involved in regulating the host response to environment signals such as ELS. It is unknown whether ELS influences gut microbiome composition in early development in humans or how the microbiome influences HPA activity and internalizing behavior. We hypothesize that early psychosocial stress decreases folate-producing genre in the gut microbiome which influences HPA DNA methylation and internalizing behavior. Elucidating how environment and gut microbiome influences behavior will provide insights for a new generation of effective interventions and treatments for mental health. This proposal capitalizes on two existing cohorts: the Environmental influences on Child Health Outcomes (ECHO; K99 Phase) and the Arizona Twin Project (ATP; R00 Phase). Both cohorts have extensive longitudinal, affective behavioral phenotyping during infancy, toddlerhood, and early childhood. Aim 1 will use existing ECHO longitudinal microbiome and ELS metadata to determine if maternal depression during early childhood contributes to folate-producing relative abundance. Aim 2 will determine if host DNA methylation is a mechanism by which the gut microbiota composition influences internalizing behavior. The R00 Aims will extend our K99 results and determine if ELS influences microbiome composition in adolescence and assess DNA methylation in relation to internalizing behaviors. Using twin ACE models we can estimate the genetic and environmental influences of the relationships between microbiome, DNA methylation, and internalizing behaviors. ACE model results will pinpoint aspects of the environment, unconfounded by genetic influences that are crucial players in the mechanistic pathway for mental health. Results will provide valuable information for the wider scientific community in understanding early environmental influences on mental health through development.