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

基本信息

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
项目类别：
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

项目摘要

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；这些费率有增长了十多年。焦虑和抑郁是高度共存的内化精神障碍，通常始于儿童时期，并与下丘脑-垂体-肾上腺 (HPA) 轴异常相关功能。早期生活压力（ELS）会增加一生中焦虑和抑郁的可能性。积累中有证据表明，ELS 可能会对肠道微生物群产生持久的变化，从而导致 HPA 异常轴功能和行为，在内化行为中发挥关键作用。存在许多途径微生物组的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产生叶酸的菌株，而叶酸是必要的成分用于 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，微生物群参与调节宿主对环境信号（如 ELS）的反应。未知 ELS 是否影响人类早期发育中的肠道微生物组组成，或者微生物组如何影响影响 HPA 活性和内化行为。我们假设早期社会心理压力会减轻肠道微生物组中产生叶酸的类型，影响 HPA DNA 甲基化和内化行为。阐明环境和肠道微生物组如何影响行为将为新的研究提供见解制定有效的心理健康干预措施和治疗方法。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）和亚利桑那双胞胎项目（ATP；R00 阶段）。两个队列都具有广泛的纵向情感行为表型婴儿期、幼儿期和幼儿期。目标 1 将使用现有的 ECHO 纵向微生物组和 ELS 元数据以确定幼儿期母亲抑郁是否会导致亲属产生叶酸丰富。目标 2 将确定宿主 DNA 甲基化是否是肠道微生物群的一种机制成分影响内化行为。 R00 目标将扩展我们的 K99 结果并确定 ELS 是否影响青春期微生物组组成并评估与内化相关的 DNA 甲基化行为。使用孪生 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，不受遗传影响的影响，而遗传影响是环境的关键因素心理健康的机制途径。结果将为更广泛的科学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。