The Gut Microbiome in Neurodegenerative Disease

神经退行性疾病中的肠道微生物组

• 批准号: 8640692
• 负责人: Sarkis K Mazmanian
• 金额: $ 33.3万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8640692
• 关键词: Affect; Age-Years; Aging; Animal Model; Animals; Anxiety; Area; Bacteria; Behavior Disorders; Biological; Brain; Cognition Disorders; Corpus striatum structure; Data; Defect; Development; Disease; Disease Outcome; Disease Progression; Disease model; Dopamine; Elderly; Emotional disorder; Employee Strikes; Environmental Risk Factor; Etiology; Financial cost; Functional disorder; Funding Opportunities; Gastrointestinal tract structure; Gene Expression Profile; Genetic; Germ-Free; Gnotobiotic; Goals; Health; Human; Human Microbiome; Immune System Diseases; Immunity; Immunologics; Individual; Inflammatory Bowel Diseases; Inherited; Investigation; Laboratories; Learning; Link; Memory; Metabolic; Metabolic Diseases; Metabolism; Metagenomics; Microbe; Microfluidics; Modeling; Molecular; Monophenol Monooxygenase; Motor; Multiple Sclerosis; Mus; Myenteric Plexus; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neurologic; Neurotransmitters; Nociception; Obesity; Oral; Outcome; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Patients; Play; Population; Pre-Clinical Model; Probiotics; Production; Proteins; Reporting; Research; Risk Factors; Role; Seminal; Shotgun Sequencing; Signal Transduction; Site; Small Intestines; Substantia nigra structure; Symptoms; System; Testing; Therapeutic; Time; Transplantation; Tyrosine; Wild Type Mouse; age effect; alpha synuclein; base; behavior test; disability; dopaminergic neuron; effective therapy; frontier; gastrointestinal; gastrointestinal symptom; innovation; longitudinal analysis; metabolic abnormality assessment; microbial; microbial community; microbiome; motor deficit; mouse model; mouse synuclein alpha; neurodegenerative phenotype; novel; overexpression; pars compacta; pre-clinical; prevent; prion-like; programs; public health relevance; relating to nervous system; synuclein; synuclein, alpha (non A4 component of amyloid precursor) protein, human; theories; transmission process

DESCRIPTION (provided by applicant): Beneficial bacteria permanently colonize many body sites, with a growing appreciation for the importance of the microbiome to human health. Pioneering research has revealed that changes in gut bacteria impact metabolic and immunologic disorders such as obesity, inflammatory bowel disease (IBD) and multiple sclerosis (MS). Moreover, specific therapeutic bacterial molecules from the microbiome have been validated in experimental IBD and MS mouse models. Building on principles from the study of metabolism and immunity, reports have recently shown that the microbiome affects anxiety, nociception and aspects of brain development. These seminal studies may represent harbingers of extensive, currently undescribed, links between gut bacteria and the nervous system. Parkinson's disease (PD) results from neurodegeneration that leads to severe motor defects, with 3 million people worldwide suffering from this condition. Most cases are not hereditary; however, the contributions of environmental risk factors remain largely unknown. Based on the common occurrence of gastrointestinal (GI) symptoms and evidence supporting the hypothesis that neurodegeneration may initiate in the gut, examining a microbiome-brain connection in PD represents an exciting new frontier for research. Neurodegeneration in PD is believed to be caused by aggregation and/or accumulation of the prion-like protein, alpha-synuclein (alphaSyn). Disease symptoms can be modeled in mice by overexpression of human alpha-synuclein (Thy1-alphaSyn). To determine if the microbiome impacts disease, the first aim will test behavioral, cellular and functional features of disease in germ-free (gnotobiotic) Thy1-alphaSyn mice. Longitudinal analysis of disease progression will establish how gut bacteria contribute to neurodegeneration and aging. To test if changes in gut bacteria are relevant to PD, we will profile the microbiome of Thy1-alphaSyn mice using metagenomic (shotgun sequencing) and metatranscriptomic (RNAseq) analysis in the second aim. Differences between Thy1-alphaSyn and control mice may reveal specific microbes and microbial pathways that impact disease. Dopamine signaling is important for motor symptoms in PD, and the dopamine precursor L- DOPA is a mainline therapy. The final aim will employ a validated microfluidics approach to screen individual gut microbes for the potential to produce dopamine, and will test novel probiotic treatments in preclinical PD models. This project will investigate, for the first time, whether changes in gut bacteria affect the etiology of PD in mouse models. If successful, the key contribution of this project will be the transformative conceptual leap that PD may have a gut microbial origin, resulting in informed advances toward probiotic therapies for neurodegeneration.

描述(由申请人提供)：有益细菌永久定居在许多身体部位，越来越多的人意识到微生物群对人类健康的重要性。开创性的研究表明，肠道细菌的变化会影响代谢和免疫疾病，如肥胖、炎症性肠病(IBD)和多发性硬化症(MS)。此外，来自微生物组的特定治疗细菌分子已在实验性IBD和MS小鼠模型中得到验证。根据新陈代谢和免疫研究的原理，最近的报告表明，微生物群影响焦虑、伤害感和大脑发育的各个方面。这些开创性的研究可能预示着肠道细菌和神经系统之间广泛的、目前尚未描述的联系。帕金森氏症(PD)是由神经退行性变导致严重的运动缺陷引起的，全球有300万人患有这种疾病。大多数病例不是遗传性的；然而，环境风险因素的作用在很大程度上仍不清楚。基于常见的胃肠道(GI)症状和支持神经退行性变可能始于肠道的假设，研究帕金森病的微生物群与大脑的联系代表了一个令人兴奋的新研究前沿。帕金森病患者的神经退行性变被认为是由蛋白样蛋白α-突触核蛋白(AlphaSyn)的聚集和/或积聚引起的。疾病症状可以通过人类α-突触核蛋白(Thy1-alphaSyn)的过度表达在小鼠中模拟。为了确定微生物群是否会影响疾病，第一个目标是测试无菌(GnotoBiotic)Thy1-alphaSyn小鼠的疾病行为、细胞和功能特征。对疾病进展的纵向分析将确定肠道细菌如何导致神经退化和衰老。为了测试肠道细菌的变化是否与帕金森病有关，我们将使用元基因组(鸟枪测序)和元转录序列(RNAseq)分析Thy1-alphaSyn小鼠的微生物组。Thy1-AlphaSyn和对照组小鼠之间的差异可能揭示了影响疾病的特定微生物和微生物途径。多巴胺信号转导对帕金森病的运动症状很重要，而多巴胺前体L-多巴是一种主线治疗方法。最终目标将使用一种经过验证的微流体方法来筛选单个肠道微生物产生多巴胺的潜力，并将在临床前PD模型中测试新的益生菌治疗方法。该项目将首次调查肠道细菌的变化是否会影响小鼠模型中帕金森病的病因。如果成功，该项目的关键贡献将是变革性的概念飞跃，即帕金森病可能源于肠道微生物，从而在治疗神经退行性变的益生菌疗法方面取得知情进展。