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

基本信息

批准号：
9337061
负责人：
Alban P Gaultier
金额：
$ 43.95万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-15 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9337061
关键词：
Address Affect Animal Model Attention Bacteria Blood Brain Cell physiology Cells Cellular Immunity Chronic Chronic stress Communication Communities Complex Data Deep Cervical Lymph Node Excision Future Genome Goals Helminths Hippocampus (Brain)Human body Immune Immune system Immunity Impaired cognition Impairment Inflammatory Inflammatory disease of the intestine Interleukin-4 Kynurenine Lead Learning Light Link Lymphatic vessel Lymphocyte Maintenance Mediating Meningeal Meninges Mental disorders Molecular Molecular Profiling Mus Natural Immunity Neuroimmune Neurologic Organ Pathology Pathway interactions Peripheral Phase Phased Innovation Awards Phenotype Physiology Population Predisposition Production Role Route Social Behavior Stress System T-Lymphocyte Testing Therapeutic Intervention Time Vagus nerve structure Work adaptive immunity adult neurogenesis base dentate gyrus depression model depressive behavior egg gut microbiome gut microbiota insight microbial neurogenesis novel public health relevance reconstitution response targeted treatment trafficking

项目摘要

Modified Project Summary/Abstract Section Malfunction of peripheral T cells is associated with impaired learning, changes in social behaviors and reduced neurogenesis. Reconstitution of immune deficient recipients with T cells from wild type donors restores these brain functions. T cells mediate their beneficial effects on the brain through meningeal spaces, which are closely associated with peripheral immunity through the meningeal lymphatic vessels. It has also been 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 are 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 yet been addressed. Based on our new data, we aim to provide novel insights into these complex interactions. Our overarching hypothesis is that changes in the gut microbiota as a result of stress facilitate changes in the immune composition of the deep cervical lymph nodes, which are reflected in meningeal immunity, which in turn impacts brain function, thus creating a tripartite loop: brain-immune-gut. In this proposal, we will address how metabolites of the kynurenine pathway, found to be dysregulated during chronic mild stress by the gut microbiome, affect T cell function in the meningeal spaces, and how these immune changes impact brain function. Our results suggest that gut microbiota could be targeted therapeutically to mitigate abnormal immune changes during chronic stress, which in turn would protect the brain.

修改后的项目摘要/摘要部分外周 T 细胞功能障碍与学习能力受损、社会行为改变和神经发生减少有关。用来自野生型供体的 T 细胞重建免疫缺陷受体可恢复这些脑功能，从而通过脑膜空间介导其对大脑的有益作用。通过脑膜淋巴管与外周免疫密切相关，也已证明慢性压力与肠道炎症以及学习和神经发生损伤有关。尽管压力导致的外周免疫变化如何影响大脑尚未得到解决，但根据我们的新数据，我们的目标是提供新的见解。我们的首要假设是，压力导致的肠道微生物群的变化促进了颈深淋巴结免疫组成的变化，这反映在脑膜免疫中，进而影响大脑功能，从而产生三方循环：脑-免疫-肠道。在本提案中，我们将讨论在肠道微生物群的慢性轻度应激期间失调的犬尿氨酸途径的代谢物如何影响脑膜空间中的 T 细胞功能，以及这些免疫变化如何影响大脑功能。可以针对微生物群进行治疗，以减轻慢性压力期间的异常免疫变化，从而保护大脑。