The microbiota, a possible link between Th17 cells and depression

微生物群，Th17 细胞与抑郁症之间可能存在的联系

• 批准号: 9307310
• 负责人: Eleonore Beurel
• 金额: $ 30.12万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-15 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9307310
• 关键词: Affect; Antibiotics; Autoimmune Diseases; Automobile Driving; Bacteria; Behavior; Blood - brain barrier anatomy; Brain; Cells; Communication; Complex; Data; Demyelinations; Depressed mood; Development; Disease; Equilibrium; Feces; Immune; Immune response; Immune system; Individual; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-17; Interleukin-6; Intervention; Intestines; Invaded; Learned Helplessness; Link; Maintenance; Major Depressive Disorder; Mammals; Mature T-Lymphocyte; Measures; Mediating; Mediation; Memory; Mental Depression; Multiple Sclerosis; Mus; Neuraxis; Outcome; Pathogenicity; Pathologic; Permeability; Pharmaceutical Preparations; Predisposition; Production; Regulation; Resistance; Role; Scheme; Signal Transduction; Signaling Molecule; Stress; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Testing; Therapeutic Intervention; axon injury; behavior influence; cytokine; depressed patient; depressive behavior; depressive symptoms; gut microbiota; microbiota; mood regulation; quorum sensing; response; trafficking

Modified Project Summary/Abstract section Major depressive disorder is a prevalent disease that is debilitating, recurring, progressive, and often inadequately treated with available medications. A better understanding of mechanisms contributing to depression is critically needed to develop new interventions. In this project, we will investigate the influence of microbiota on depressive-like behaviors in mice. Recent evidence has shown that alterations of the gut microbiota influence responses to stress. Microbiota also influences immune responses, in particular certain bacteria regulate the production of T helper (Th) 17 cells. We recently showed that Th17 cells are required for the induction of depressive-like behaviors. Therefore, our overall hypotheses are that stress that induces depression-like behaviors in mice alters signals generated by certain residents of the microflora, that these signals promote the production of pathogenic Th17 cells, which in turn mediate the induction of depression-like behaviors after stress, and that establishment of depression augments changes in the microbiota that facilitates the continued susceptibility to depression, in part through up-regulated production of Th17 cells. In Specific Aim 1, we will test the hypothesis that the microbiota regulates stress-induced pathogenic Th17 cells that promote depressive-like behaviors in mice. We will expand our proof-of-concept data that modulation of the microbiota affects depressive-like behavior and influences Th17 cells in mouse brain during depressive-like states. We identified bacteria that are increased during depressive-like behavior and will confirm their role in controlling depressive-like behavior and Th17 cells production. In Specific Aim 2, we will test the hypothesis that in mice bacterial quorum-sensing molecules are signals that regulate the production of Th17 cells, which promote depression-like behaviors. We generated proof-of-concept data identifying the importance of the quorum sensing molecule AI-2 in predicting depressive-like behavior. We will expand these results by developing therapeutic intervention strategies to modulate bacterial microflora via AI-2 quorum sensing molecules to regulate Th17 cells and depressive-like behavior. Altogether this project will provide evidence that the microbiota regulates depressive-like behavior through the production of Th17 cells.

修改项目摘要/摘要部分 重性抑郁症是一种使人衰弱、反复发作、进行性的流行病，并且通常可用药物治疗不足。更好地了解导致抑郁症的机制对于开发新的干预措施至关重要。在这个项目中，我们将研究微生物群对小鼠抑郁样行为的影响。最近的证据表明，肠道微生物群的改变会影响对压力的反应。微生物群也影响免疫反应，特别是某些细菌调节T辅助细胞（Th）17细胞的产生。我们最近发现，Th 17细胞是诱导抑郁样行为所必需的。因此，我们的总体假设是，在小鼠中诱导抑郁样行为的压力改变了由微生物群的某些居民产生的信号，这些信号促进了致病性Th 17细胞的产生，而这些细胞又介导了压力后抑郁样行为的诱导，并且抑郁的建立增强了微生物群的变化，从而促进了对抑郁的持续易感性，部分通过上调Th 17细胞的产生。在具体目标1中，我们将测试以下假设：微生物群调节应激诱导的致病性Th 17细胞，这些细胞促进小鼠的抑郁样行为。我们将扩展我们的概念验证数据，即微生物群的调节会影响抑郁样行为，并在抑郁样状态下影响小鼠大脑中的Th 17细胞。我们鉴定了在抑郁样行为期间增加的细菌，并将确认它们在控制抑郁样行为和Th 17细胞产生中的作用。在具体目标2中，我们将检验以下假设：在小鼠中，细菌群体感应分子是调节Th 17细胞产生的信号，Th 17细胞促进抑郁样行为。我们生成了概念验证数据，确定了群体感应分子AI-2在预测抑郁样行为方面的重要性。我们将通过开发治疗干预策略来扩展这些结果，以通过AI-2群体感应分子调节细菌微生物群来调节Th 17细胞和抑郁样行为。总之，该项目将提供证据表明，微生物群通过产生Th 17细胞来调节抑郁样行为。