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

项目概要/摘要 超过5%的美国儿童和45%的美国青少年患有焦虑或抑郁症;这些比率 增长了十多年。焦虑和抑郁是高度共病的内在精神障碍， 通常在儿童时期开始，并与异常的下丘脑-垂体-肾上腺（HPA）轴有关 功能早期生活压力（ELS）增加了一生中对焦虑和抑郁的脆弱性。积累 有证据表明，ELS可能会导致肠道微生物群的长期变化，从而导致HPA异常 轴功能和行为，这可能在内化行为中发挥关键作用。有许多途径 其中微生物组组成可能影响行为和生理，其中之一是通过改变宿主 表观遗传学ELS减少了肠道微生物组中的叶酸产生菌株，叶酸是必需的成分 DNA甲基化。最近的工作突出了微生物组和宿主表观基因组之间的潜在相互作用， 微生物群参与调节宿主对环境信号如ELS的反应。尚不清楚 ELS是否影响人类早期发育中的肠道微生物组组成， 影响HPA活性和内化行为。我们假设早期的社会心理压力 影响HPA DNA甲基化和内化的肠道微生物组中的叶酸产生类型 行为阐明环境和肠道微生物组如何影响行为将为新的 制定有效的心理健康干预和治疗措施。该提案利用了现有的两个 队列：环境对儿童健康结果的影响（ECHO; K99阶段）和亚利桑那州双生子 项目（ATP; R 00阶段）。两个队列在研究期间都有广泛的纵向情感行为表型， 婴儿期、学步期和幼儿期。目标1将使用现有的ECHO纵向微生物组和ELS 元数据，以确定母亲抑郁症在幼儿期是否有助于叶酸产生的相对 丰饶。目的2将确定宿主DNA甲基化是否是肠道微生物群 成分影响内化行为。R 00目标将扩展我们的K99结果，并确定ELS是否 影响青春期的微生物组组成，并评估与内化相关的DNA甲基化 行为。使用双ACE模型，我们可以估计遗传和环境的影响， 微生物组、DNA甲基化和内化行为之间的关系。ACE模型结果将 精确定位环境的各个方面，不受基因影响的影响，这些影响是环境中的关键因素。 心理健康的机械途径。结果将为更广泛的科学研究提供有价值的信息。 社区通过发展了解早期环境对心理健康的影响。

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.