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

宿主 DNA 甲基化作为微生物组影响内化行为的机制

• 批准号: 10531997
• 负责人: Candace Renee Lewis
• 金额: $ 24.9万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-06 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10531997
• 关键词: 16S ribosomal RNA sequencing; Address; Adolescence; Adolescent; Adrenal Glands; Affective; Anti-Bacterial Agents; Anxiety; Arizona; Behavior; Behavioral; Bifidobacterium; Brain; Breast Feeding; Child; Child Health; Childhood; Clinical; Clinical Trials; Communities; DNA; DNA Methylation; Data; Data Analyses; Development; Diet; Economic Burden; Emotional; Environment; Epigenetic Process; Etiology; Folic Acid; Future; Generations; Genes; Genetic; Genetic Identity; Human; Hypothalamic structure; Immune response; Infection; Intervention Trial; Joints; Knowledge; Lactobacillus; Life; Maternal Age; Mediating; Mediation; Mental Depression; Mental Health; Mental disorders; Metadata; Methods; Methylation; Modeling; Outcome; Pathway interactions; Phase; Physiology; Pituitary Gland; Play; Population; Prevotella; Process; Psychosocial Stress; Research; Role; Sampling; Signal Transduction; Stress; Taxonomy; Testing; Therapeutic; Time; Twin Multiple Birth; Work; bead chip; behavior influence; behavioral phenotyping; cohort; comorbidity; early childhood; early life stress; effective intervention; effective therapy; epigenome; gut microbiome; gut microbiota; gut-brain axis; hypothalamic-pituitary-adrenal axis; infancy; insight; maternal depression; methylation pattern; microbiome; microbiome composition; microbiota; neurodevelopment; prospective; recruit; treatment trial

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.

项目摘要/摘要 美国5％以上的儿童和45％的美国青少年患有焦虑或抑郁。这些费率有 增加了十多年。焦虑和抑郁是高度合并的内在精神障碍 通常从童年开始，与异常下丘脑 - 垂体 - 肾上腺（HPA）轴有关 功能。早期的生活压力（EL）增加了一生中对焦虑和抑郁的脆弱性。累积 有证据表明，EL可能会在肠道菌群中产生持久的变化，导致异常HPA 轴功能和行为，可以在内部化行为中起关键作用。存在许多途径 微生物组组成可能会影响行为和生理学，其中之一是通过改变宿主 表观遗传学。 ELS减少肠道微生物组中的叶酸产生菌株，而叶酸是必要的组成部分 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， 随着微生物群的调节对宿主对环境信号（例如EL）的反应。这是未知的 ELS是在人类的早期发育中影响肠道微生物组的组成还是微生物组的方式 影响HPA活动和内在化行为。我们假设早期的社会心理压力减少 肠道微生物组中产生叶酸的类型，影响HPA DNA甲基化并内在化 行为。阐明环境和肠道微生物组如何影响行为，将为新的见解提供见解 生成有效的干预措施和精神健康治疗方法。该提议大写了两个现有的 队列：环境对儿童健康成果的影响（Echo; K99阶段）和亚利桑那双胞胎 项目（ATP; R00阶段）。这两个队列在期间都有广泛的纵向，情感行为表型 婴儿期，幼儿和幼儿。 AIM 1将使用现有的Echo纵向微生物组和ELS 元数据确定儿童早期孕产妇抑郁是否有助于产生叶酸的相对 丰富。 AIM 2将确定宿主DNA甲基化是否是肠道菌群的机制 组成会影响内在的行为。 R00目标将扩大我们的K99结果并确定是否ELS 影响青春期的微生物组组成并评估与内在化有关的DNA甲基化 行为。使用双ACE模型，我们可以估计 微生物组，DNA甲基化和内在行为之间的关系。 ACE模型结果将 查明环境的各个方面，不受遗传影响的不符，这些影响是至关重要的参与者 心理健康的机械途径。结果将为更广泛的科学提供宝贵的信息 社区了解早期环境通过发展对心理健康的影响。