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

• 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
• 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

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）：啮齿动物的研究表明，肠道微生物组会影响与多种精神病有关的神经发育和随后与焦虑有关的行为。但是，将动物数据转化为诊所存在一个基本差距：没有研究直接测试微生物定植的差异是否影响人类与焦虑相关的行为。此外，对微生物群改变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殖如何影响人脑发育，后来又有精神病的风险。该应用的目的是确定微生物定植如何在1岁时影响焦虑行为，并使用高分辨率磁共振成像（MRI），扩散量张量成像（DTI）和静止状态fMRI（RFCMRI）来识别介导这种关系的信号传导机制和神经回路。拟议的研究的理由是，肠道菌群的调节可以在疾病过程的早期使神经发育轨迹正常化，最终阻止了精神病的发作o降低了其严重程度。我们将通过5个特定目标来实现我们的目标。在R21阶段，我们将：1）确认在2周和1岁的粪便样品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传导机制的关系； 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的模式与1岁大的焦虑行为有关； 4）确定介导肠道微生物群和人类婴儿焦虑行为之间关联的神经回路； 5）确定微生物群会影响人类婴儿神经发育和焦虑行为的信号传导机制。我们的中心假设是，与细菌定植的不同模式的婴儿之间的焦虑相关行为将有所不同，这种关系将由杏仁核，海马和内侧前额叶皮层的变化介导。我们进一步假设，微生物群将通过改变促炎性细胞因子和皮质醇反应性来影响神经发育，这可能通过对色氨酸代谢途径的Kynurenine Arm的协同作用来影响神经发育。该应用具有创新性，因为它将是第一项测试微生物综合素与人类队列中焦虑行为的关系的研究。拟议的研究很重要，因为它是开发新的干预措施以促进健康微生物组并降低精神病风险的重要第一步。