The Role of the Intestinal Microbiome in Anxiety and Depression

 描述（由申请人提供）：导致焦虑和抑郁的病理生理机制尚不清楚。这些疾病的发病率正在增加，给我们的卫生保健带来了沉重的负担。越来越多的数据表明，肠道微生物群会影响大脑的功能及其化学物质。可能涉及多种机制，包括细菌产生神经活性分子或激活免疫途径。我们将寻求研究的机制，肠道细菌导致焦虑和抑郁症的发展使用gnotobiotic小鼠模型。在R21阶段（目标1）中，我们将使用来自我们在麦克马斯特大学的临床生物库的样品，通过用来自广泛性焦虑症（GAD）和重度抑郁症（MDD）患者的粪便微生物群定殖无菌小鼠来开发焦虑和抑郁的无菌模型。我们将分别使用基于16 S DNA的Illumina测序和液相色谱-质谱（LC-MS）来表征小鼠行为、微生物群和代谢组学特征。由于压力已被证明在抑郁和焦虑中发挥作用，我们将对一组具有免疫激活迹象的gnotobiotic小鼠施加心理社会压力。我们假设细菌通过神经和免疫途径与大脑沟通，其中包括神经活性微量胺和炎症细胞因子，如IL-1。这些特定的通路将是我们在R33阶段研究的重点。使用Aim 1中确定的选定微生物群，我们将在其他无菌小鼠组中定殖，并详细研究其潜在机制。小鼠行为将与肠道、血清和脑神经递质以及细菌来源的神经活性和免疫调节代谢物相关。我们将通过免疫组化评估特定脑区的神经元激活。我们将使用药理学工具和转基因小鼠来研究微生物群-大脑通信的确切途径。利用我们的新方法，能够培养>92%的人类肠道细菌，我们将识别和分离与焦虑和/或抑郁样行为相关的细菌。为了确认因果关系，我们将用特定细菌或与焦虑和/或抑郁相关的细菌对其他无菌小鼠组进行单或多克隆，并评估小鼠受体行为和脑化学。

 DESCRIPTION (provided by applicant): The pathophysiological mechanisms leading to anxiety and depression are not understood. The prevalence of these disorders is increasing, imposing a significant burden on our health care. Accumulating data suggest that gut microbiota affects the function of the brain and its chemistry. It is likely that multiple mechanisms are involved, including bacterial production of neuroactive molecules or activation of immune pathways. We will seek to study the mechanisms, by which gut bacteria lead to development of anxiety and depression using gnotobiotic murine models. In the R21 phase (Aim 1) we will develop a gnotobiotic model of anxiety and depression by colonizing germ- free mice with stool microbiota from patients with Generalized Anxiety Disorder (GAD) and Major Depressive Disorder (MDD), using samples from our clinical bio bank at McMaster University. We will characterize mouse behavior, microbiota and metabolomic profiles using 16S DNA-based Illumina sequencing and liquid chromatography-mass spectrometry (LC-MS), respectively. As stress has been shown to play a role in depression and anxiety, we will apply a psychosocial stressor to a group of gnotobiotic mice with signs of immune activation. We hypothesize that bacteria communicate with the brain through both neural and immune pathways, which include neuroactive trace amines and inflammatory cytokines, such as IL-1. These specific pathways will be the focus of our research in the R33 phase. Using selected set of microbiota identified in Aim1, we will colonize additional groups of germ free mice and study in detail the underlying mechanisms. The mouse behavior will be correlated with gut, serum and brain neurotransmitters, as well as neuroactive and immunomodulatory metabolites of bacterial origin. We will assess neuronal activation in specific brain areas by immunohistochemistry. We will use pharmacological tools and genetically modified mice to study the exact pathways of microbiota-brain communications. Taking advantage of our novel approach, which enables to culture >92% of human gut bacteria, we will identify and isolate the bacteria associated with anxiety and/or depression-like behavior. To confirm the cause-effect relationship, we will mono or poly-colonize additional groups of germ-free mice with specific bacteria, or group of bacteria linked to anxiety and/or depression, and assess mouse recipient behavior and brain chemistry.