Mechanisms Underlying Regulation of Susceptibility to CNS Autoimmunity by Commensal Lactobacillus Species

共生乳杆菌对中枢神经系统自身免疫易感性的调节机制

基本信息

批准号：
10516032
负责人：
Theresa Lynn Montgomery
金额：
$ 0.01万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2022-08-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10516032
关键词：
Adoptive Transfer Affect Alleles Animal Model Appointment Astrocytes Autoimmunity Axon Blood - brain barrier anatomy Blood Circulation Brain CD8-Positive T-Lymphocytes CNS autoimmune disease CNS autoimmunity Cells Central Nervous System Diseases Chronic Clinical Trials Communication Complex Core Facility Coupled Data Demyelinations Development Diet Disease Disease Resistance Disease susceptibility Distal Environment Environmental Risk Factor Etiology Exhibits Experimental Autoimmune Encephalomyelitis Flow Cytometry Future Genes Genetic Genomics Granulocyte-Macrophage Colony-Stimulating Factor Health Sciences Human Immune Immune system Immunology Incidence Indoles Inflammatory Intake Intervention Knowledge Lactobacillus Lactobacillus reuteri Lesion Mass Spectrum Analysis Medicine Mentors Mentorship Metabolic Microbiology Microglia Molecular Genetics Multiple Sclerosis Mus Myelin Neuraxis Neurodegenerative Disorders Neuroglia Neurologic Neurologic Dysfunctions Pathogenesis Pathology Peripheral Persons Phase Physiology Population Predisposition Production Regulation Resource Sharing Risk Risk Factors Role Science Severity of illness Shapes Site Smoking Stress Symptoms T cell response T-Lymphocyte Techniques Testing Therapeutic Training Tryptophan Tryptophan Metabolism Pathway Universities Vermont Vitamin D blood-brain barrier permeabilization college commensal microbes dietary disability educational atmosphere effector T cell genome sequencing gut bacteria gut microbiome gut microbiota immunoregulation in vitro Assay in vivo member metabolomics microbial microbiome microbiota microbiota transplantation microorganism mouse model multidisciplinary multiple sclerosis patient multiple sclerosis treatment neuroimmunology neuroinflammation neuropathology novel personalized medicine resident commensals response skills whole genome young adult

项目摘要

Project Summary: Multiple sclerosis (MS) is a chronic autoimmune central nervous system (CNS) disease and the leading cause of non-traumatic neurological disability in young adults. The cause of MS is complex and cannot be ascribed to any single gene with over 70% risk attributed to environmental factors. Recent studies identified an imbalance in the human gut microbiome within MS patients as one such environmental risk, including depletion of the Lactobacillus genus. Animal models support a causal role for the gut microbiome in MS, though the mechanism remains unclear. Utilizing a mouse model of MS, we have identified disease resistant and susceptible microbiomes, with stark differences in Lactobacillus species abundance and notable differences in their circulating metabolic by-products known to modulate the immune system. Further, we have identified a single commensal species, Lactobacillus reuteri (L. reuteri), which is sufficient to accentuate MS-like symptoms in the mouse with whole genome sequencing indicating the necessary enzymatic machinery to account for the observed differences in circulating metabolites. The focus of this proposal is to 1) determine the cellular mechanisms underlying the effects of L. reuteri on EAE including both impact on infiltrating peripheral immune cells and CNS resident glial cells and 2) determine the impact of L. reuteri-derived tryptophan metabolites on neuroinflammation. In direct support of the proposed studies, the training plan will develop the knowledge, expertise, scientific communication skills and technical abilities in 1) mouse models of multiple sclerosis focused on host interactions with the gut microbiome including directed microbiome manipulation, 2) immunology, with a focus on neuroimmunology, flow cytometry, and functional assays in vitro and in vivo, 3) microbiology, with a focus on commensal gut bacteria, their culture, isolation, genomic and metabolic characterization, and manipulation, 4) neuropathology, with a focus on techniques to investigate CNS pathology to characterize inflammatory demyelinating lesions in CNS autoimmune disease and blood brain barrier integrity analysis and 5) metabolomics with a focus on bacterial metabolites and their effects on host physiology. The training environment at the University of Vermont (UVM) is multidisciplinary with a collegial atmosphere that stresses active mentorship and as such is uniquely appropriate to support this proposal which bridges autoimmunity, CNS neuropathology and commensal microbiota. This is evidenced by co-mentors with appointments in the departments of Biomedical and Health Sciences (BHSC), Microbiology and Molecular Genetics (MMG), and Neurological Sciences which are connected to a hub of core facilities and the Larner College of Medicine offering ample opportunity to share resources and promote in-person communication.

项目摘要：多发性硬化症（MS）是一种慢性自身免疫性中枢神经系统（CNS）疾病，主要原因年轻人非创伤性神经残疾的疾病。 MS的原因很复杂，不能归因于任何归因于环境因素的风险超过70％的单一基因。最近的研究确定了失衡在MS患者中的人类肠道微生物组中，作为一种这种环境风险，包括耗尽乳杆菌属。动物模型支持MS中肠道微生物组的因果作用，尽管该机制仍然不清楚。利用MS的小鼠模型，我们已经确定了抗病性和易感性微生物组，乳酸杆菌的丰度有明显的差异，其显着差异已知可调节免疫系统的循环代谢副产品。此外，我们已经确定了一个共生物种，Reuteri乳酸菌（L. Reuteri），足以强调MS样症状带有整个基因组测序的鼠标，表明必要的酶促机器来解释观察到循环代谢产物的差异。该建议的重点是1）确定细胞 L. Reuteri对EAE影响的基础机制，包括对浸润外周免疫的影响细胞和中枢神经系统固定的神经胶质细胞和2）确定Reuteri衍生的色氨酸代谢产物对神经炎症。为了直接支持拟议的研究，培训计划将发展知识，专业知识，科学 1）多发性硬化症的鼠标模型的沟通技巧和技术能力，专注于宿主互动肠道微生物组（包括定向微生物组操纵），2）免疫学，重点神经免疫学，流式细胞术和体外和体内功能测定，3）微生物学，重点是共生肠道细菌，它们的培养，分离，基因组和代谢表征以及操纵，4）神经病理学，重点是研究CNS病理学以表征炎症的技术中枢神经系统自身免疫性疾病和血脑屏障完整性分析的脱髓鞘病变和5）代谢组学的重点是细菌代谢物及其对宿主生理的影响。佛蒙特大学（UVM）的培训环境是多学科的，有着大学氛围，压力积极的指导，因此是独特的，适合支持该提议的桥梁自身免疫性，CNS神经病理学和共生微生物群。该联合会与生物医学和健康科学系（BHSC），微生物学和分子的任命遗传学（MMG）和与核心设施和Larner相连的神经科学医学院提供了足够的机会共享资源并促进面对面的交流。