Meningeal immunity - a middleman between gut microbiome and the brain

脑膜免疫——肠道微生物组和大脑之间的中间人

• 批准号: 8975315
• 负责人: Alban P Gaultier
• 金额: $ 27.04万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8975315
• 关键词: Address; Affect; Animal Model; Attention; Bacteria; Blood; Brain; Cells; Cellular Immunity; Chronic stress; Communication; Communities; Complex; Data; Deep Cervical Lymph Node; Defect; Excision; Functional disorder; Future; Genome; Goals; Helminths; Hippocampus (Brain); Human body; Immune; Immune system; Immunity; Impaired cognition; Impairment; Inflammatory; Inflammatory disease of the intestine; Interleukin-4; Lead; Learning; Light; Link; Lymphocyte; Maintenance; Mediating; Mediator of activation protein; Meningeal; Meninges; Mental Depression; Mental disorders; Modeling; Molecular; Molecular Profiling; Mus; Natural Immunity; Neurologic; Organ; Pathology; Peripheral; Phase; Phased Innovation Awards; Phenotype; Physiology; Population; Predisposition; Production; Role; Route; Stress; System; T-Lymphocyte; Testing; Th2 Cells; Therapeutic Intervention; Time; Vagus nerve structure; Work; adaptive immunity; adult neurogenesis; base; cell type; dentate gyrus; depressive behavior; egg; gut microbiota; insight; microbial; microbiome; neurogenesis; public health relevance; reconstitution; response; trafficking; vagus nerve stimulation

 DESCRIPTION (provided by applicant): We have demonstrated that lack or dysfunction of peripheral T cells is associated with impaired learning and aberrant neurogenesis. Moreover, we have revealed that these deficits can be remedied by reconstitution of immune deficient recipients with T cells from wild type donors. We showed that the T cells that patrol the meninges of the brain are central players in neuroimmune interactions that benefit brain function. It has also been widely demonstrated that chronic stress is correlated with gut inflammation and with impairments in learning and neurogenesis. We have addressed, at least partially, what type of immune cells is mediating neuro-immune interactions (T cells), and where (meningeal spaces), although how the changes in peripheral immunity as a result of stress are impacting the brain has not been addressed. Here we aim to provide new insights into these complex interactions. Our overarching hypothesis is that changes in the gut microbiota as a result of stress facilitate changes in the meningeal immune system, which in turn impacts brain function, thus creating a tripartite loop - brain, immune and gut. During the exploratory R21 phase we plan to characterize the interactions between the gut microbiota and meningeal immune cells under chronic stress, by addressing: (1) the phenotype change of meningeal T cells as a result of microbiome alterations during chronic stress; (2) contributions of the immune system vs. vagus nerve to changes in meningeal T cell phenotype; and (3) the molecular signature of blood metabolites as a result of microbiota changes during chronic stress. Successful completion of this phase will determine the underlying mechanistic link between the gut microbiota and the brain via the immune system, vagus nerve stimulation, and/or microbial metabolites. In the second, hypothesis-driven phase, we will test if a defect in Th2 cells is associated with depression. To our knowledge, this is the first attempt to mechanistically link the gut microbiota to brain function by a defined mediating cell type. We expect the gut microbiota to mediate IL-4 production by meningeal T cells in support of brain function and neurogenesis (directly, or via additional cellular mediators).

 描述（由申请人提供）：我们已经证明外周T细胞的缺乏或功能障碍与学习受损和异常神经发生相关。此外，我们已经揭示，这些缺陷可以通过用来自野生型供体的T细胞重建免疫缺陷受体来弥补。我们发现，在脑膜上巡逻的T细胞是神经免疫相互作用的核心参与者，有利于大脑功能。它也已被广泛证明，慢性应激与肠道炎症和学习和神经发生的损害。我们已经解决了，至少部分地，什么类型的免疫细胞介导神经免疫相互作用（T细胞），以及在哪里（脑膜空间），尽管压力导致的外周免疫变化如何影响大脑尚未解决。在这里，我们的目标是为这些复杂的相互作用提供新的见解。我们的总体假设是，由于压力导致的肠道微生物群的变化促进了脑膜免疫系统的变化，这反过来又影响了大脑功能，从而形成了一个三重循环-大脑，免疫和肠道。在探索性R21阶段，我们计划通过解决以下问题来表征慢性应激下肠道微生物群和脑膜免疫细胞之间的相互作用：（1）慢性应激期间微生物群改变导致的脑膜T细胞的表型变化;（2）免疫系统相对于迷走神经对脑膜T细胞表型变化的贡献;（3）免疫系统相对于迷走神经对脑膜T细胞表型变化的贡献。以及（3）在慢性应激期间由于微生物群变化而导致的血液代谢物的分子特征。这一阶段的成功完成将确定肠道微生物群与大脑之间通过免疫系统、迷走神经刺激和/或微生物代谢物的潜在机制联系。在第二阶段，假设驱动阶段，我们将测试Th 2细胞的缺陷是否与抑郁症有关。据我们所知，这是第一次尝试将 肠道微生物群通过确定的介导细胞类型对大脑功能的影响。我们预计肠道微生物群介导脑膜T细胞产生IL-4，以支持脑功能和神经发生（直接或通过其他细胞介质）。