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; 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（由适用提供）：我们已经证明，周围T细胞的缺乏或功能障碍与学习受损和异常神经发生有关。此外，我们已经透露，可以通过与野生型供体的T细胞重建免疫缺陷的受体来补救这些缺陷。我们表明，巡逻大脑脑膜的T细胞是受益于大脑功能的神经免疫相互作用的核心参与者。还广泛证明，慢性应激与肠道注射以及学习和神经发生的损害相关。我们至少部分地解决了哪种类型的免疫电池正在介导神经免疫相互作用（T细胞）以及（脑膜空间）的地方，尽管由于压力会影响大脑的外周外观免疫细胞的变化如何尚未解决。在这里，我们旨在为这些复杂的互动提供新的见解。我们的总体假设是，由于脑膜免疫系统的压力紧急变化而导致肠道菌群的变化，这又影响了脑功能，从而产生了三方环 - 脑，免疫和肠道。在探索性R21期间，我们计划通过解决慢性压力下的肠道微生物群和脑膜免疫细胞之间的相互作用来表征：（1）由于慢性应激过程中微生物组改变而导致脑膜T细胞的表型变化； （2）免疫系统与迷走神经对脑膜T细胞表型的变化的贡献； （3）由于慢性应激期间菌群变化而导致血液代谢产物的分子特征。该阶段的成功完成将通过免疫系统，迷走神经刺激和/或微生物代谢产物来确定肠道微生物群和大脑之间的潜在机械联系。在第二个假设驱动的阶段中，我们将测试Th2细胞中的缺陷是否与抑郁症有关。据我们所知，这是机械链接的第一次尝试 肠道菌群通过定义的介导细胞类型到脑功能。我们期望肠道菌群通过脑膜T细胞介导IL-4的产生，以支持脑功能和神经发生（直接或通过其他细胞介质）。