GUT MICROBIOTA AND ANXIETY: A MECHANISTIC STUDY OF HUMAN INFANTS

肠道微生物群和焦虑：人类婴儿的机制研究

基本信息

批准号：
8880291
负责人：
Rebecca Knickmeyer
金额：
$ 25.37万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2016-08-03
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8880291
关键词：
1 year old Actinobacteria class Adult Affect Age Amygdaloid structure Animals Anxiety Bacteroidetes Behavior Birth Brain Cardiovascular system Clinic Code Complex Development Diffusion Magnetic Resonance Imaging Disease Early Intervention Ecosystem Exposure to Food Fostering Fright Functional Magnetic Resonance Imaging Goals Growth Health Hippocampus (Brain)Human Hydrocortisone Individual Infant Inflammatory Interferons Interleukin-6 Intervention Kynurenine Laboratories Lactobacillus Long-Term Effects Magnetic Resonance Imaging Measures Medial Mediating Mental Depression Mental Health Mental disorders Metabolic Pathway Mission Pathway interactions Pattern Phase Play Prefrontal Cortex Process Proteobacteria Public Health Recombinant DNA Research Resolution Rest Restriction fragment length polymorphism Risk Rodent Sampling Severities Signal Transduction Solid Stress Structure TNF gene Taxon Temperament Testing Therapeutic Translating Tryptophan Tryptophan Metabolism Pathway Vagina Weaning Work age related animal data anxiety-related behavior anxious behavior arm base behavior measurement cohort cytokine gut microbiota indexing infancy innovation microbial microbial colonization microbiome neural circuit neurodevelopment novel prevent pyrosequencing response

项目摘要

DESCRIPTION (provided by applicant): Studies in rodents show that the gut microbiome influences neurodevelopment and subsequent anxiety-related behaviors which are relevant to a wide range of psychiatric illnesses. However, there is a fundamental gap in translating animal data into the clinic: no study has directly tested whether differences in microbial colonization impact anxiety-related behavior in humans. Furthermore, the mechanisms and pathways by which microbiota alter brain development are poorly understood. Our long-term goal is to determine how colonization of the gut microbiome impacts human brain development and later risk for psychiatric illness. The objective of this application is to determine how microbial colonization impacts anxious behavior at 1 year of age and to identify signaling mechanisms and neural circuits mediating this relationship using high resolution magnetic resonance imaging (MRI), diffusion tensor imaging (DTI) and resting state fMRI (rfcMRI). The rationale for the proposed research is that modulation of the gut microbiota could normalize neurodevelopmental trajectories early in the disease process, ultimately preventing the onset of psychiatric illness o reducing its severity. We will achieve our objective through 5 specific aims. In the R21 phase we will: 1) Confirm that sufficient bacterial diversity is present in fecal samples at 2 weeks and 1 year of age to test relationships with anxious behavior, brain development, and hypothesized signaling mechanisms; and 2) Confirm that hypothesized signaling mechanisms can be successfully probed at 2 weeks and 1 year of age. In the R33 phase we will: 3) Determine how patterns of microbial colonization in infancy relate to anxious behavior at 1 year of age; 4) Identify neural circuits which mediate associations between gut microbiota and anxious behavior in human infants; and 5) Determine the signaling mechanisms by which microbiota affect neurodevelopment and anxious behavior in human infants. Our central hypothesis is that anxiety-related behaviors will differ between infants with different patterns of bacterial colonization and this relationship will be mediated by changes in the amygdala, hippocampus, and medial prefrontal cortex. We further hypothesize that microbiota will impact neurodevelopment by altering pro-inflammatory cytokines and cortisol reactivity, potentially through synergistic effects on the kynurenine arm of the tryptophan metabolic pathway. The application is innovative in that it will be the first study to test if and how microbial compositin relates to anxious behavior in a human cohort. The proposed research is significant in that it is an essential first-step in developing novel interventions to promote a healthy microbiome and reduce risk for psychiatric illness.

描述（由申请人提供）：对啮齿动物的研究表明，肠道微生物组影响神经发育和随后的焦虑相关行为，这些行为与多种精神疾病相关。然而，将动物数据转化为临床存在根本性的差距：没有研究直接测试微生物定植的差异是否会影响人类的焦虑相关行为。此外，人们对微生物群改变大脑发育的机制和途径知之甚少。我们的长期目标是确定肠道微生物组的定植如何影响人类大脑发育以及以后患精神疾病的风险。本应用的目的是确定微生物定植如何影响 1 岁时的焦虑行为，并使用高分辨率磁共振成像 (MRI)、扩散张量成像 (DTI) 和静息态功能磁共振成像 (fMRI) 来确定介导这种关系的信号机制和神经回路（rfcMRI）。这项研究的基本原理是，调节肠道微生物群可以在疾病过程的早期使神经发育轨迹正常化，最终预防精神疾病的发作或减轻其严重程度。我们将通过 5 个具体目标来实现我们的目标。在 R21 阶段，我们将： 1) 确认 2 周和 1 岁时粪便样本中存在足够的细菌多样性，以测试与焦虑行为、大脑发育和假设的信号机制的关系； 2) 确认可以在 2 周和 1 岁时成功探测假设的信号传导机制。在 R33 阶段，我们将： 3) 确定婴儿期微生物定植模式与 1 岁时的焦虑行为有何关系； 4）确定介导人类婴儿肠道微生物群与焦虑行为之间关联的神经回路； 5) 确定微生物群影响人类婴儿神经发育和焦虑行为的信号机制。我们的中心假设是，具有不同细菌定植模式的婴儿之间的焦虑相关行为会有所不同，并且这种关系将通过杏仁核、海马体和内侧前额叶皮层的变化来介导。我们进一步假设微生物群将通过改变促炎细胞因子和皮质醇反应性来影响神经发育，可能是通过对色氨酸代谢途径的犬尿氨酸臂的协同作用。该应用的创新之处在于，它将是第一项测试微生物复合素是否以及如何与人类群体的焦虑行为相关的研究。拟议的研究意义重大，因为它是开发新干预措施以促进健康微生物组和降低精神疾病风险的重要第一步。