GUT MICROBIOTA AND ANXIETY: A MECHANISTIC STUDY OF HUMAN INFANTS

描述（由申请人提供）：啮齿动物研究表明，肠道微生物组影响神经发育和随后的焦虑相关行为，这些行为与广泛的精神疾病有关。然而，在将动物数据转化为临床方面存在根本性的差距：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，微生物群改变大脑发育的机制和途径还知之甚少。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和以后患精神疾病的风险。本申请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）和静息状态功能磁共振成像（rfcMRI）来识别介导这种关系的信号传导机制和神经回路。拟议研究的基本原理是，肠道微生物群的调节可以使疾病过程早期的神经发育轨迹正常化，最终预防精神疾病的发作或降低其严重程度。我们将通过五个具体目标来实现我们的目标。在R21阶段，我们将：1）确认2周龄和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、大脑发育和假设信号机制的关系; 2）确认假设信号机制可以在2周龄和1岁时成功探测。在R33阶段，我们将：3）确定婴儿期微生物定植模式如何与1岁时的焦虑行为相关; 4）确定介导人类婴儿肠道微生物群和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传导机制。我们的中心假设是，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，这种关系将通过杏仁核、海马体和内侧前额叶皮质的变化来介导。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，这可能是通过对色氨酸代谢途径的犬尿氨酸臂的协同作用。该应用是创新的，因为它将是第一项测试微生物组成是否以及如何与人类队列中的焦虑行为相关的研究。这项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。

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.