The Role of the Intestinal Microbiome in Anxiety and Depression

 描述(申请人提供)：导致焦虑和抑郁的病理生理机制尚不清楚。这些疾病的患病率正在增加，给我们的医疗保健带来了巨大的负担。越来越多的数据表明，肠道微生物区系会影响大脑的功能及其化学成分。这可能涉及多种机制，包括细菌产生神经活性分子或激活免疫途径。我们将利用灵知生菌小鼠模型来研究肠道细菌导致焦虑和抑郁发展的机制。在R21阶段(目标1)，我们将利用麦克马斯特大学临床生物库的样本，用广泛性焦虑障碍(GAD)和严重抑郁障碍(MDD)患者的粪便微生物群来定植无菌小鼠，从而建立焦虑和抑郁的诺生菌模型。我们将分别使用基于16S DNA的Illumina测序和LC-MS来表征小鼠的行为、微生物区系和代谢组谱。由于压力已被证明在抑郁和焦虑中起作用，我们将对一组有免疫激活迹象的灵知生菌小鼠应用心理社会应激源。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性细胞因子，如IL-1。这些特定的通路将是我们在R33阶段研究的重点。利用Aim1中确定的一组选定的微生物区系，我们将在更多的无菌小鼠群体中定居，并详细研究其潜在机制。小鼠的行为将与肠道、血清和大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。我们将通过免疫组织化学方法评估特定脑区的神经元激活情况。我们将使用药理学工具和转基因小鼠来研究微生物区系与大脑交流的确切途径。利用我们的新方法，可以培养92%的人类肠道细菌，我们将识别和分离与焦虑和/或抑郁行为相关的细菌。为了确认因果关系，我们将用特定的细菌或与焦虑和/或抑郁有关的细菌组来单一或多克隆额外的无菌小鼠组，并评估小鼠的接受行为和大脑化学。

 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.