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）：有益的细菌永久性地定居许多身体部位，对微生物组对人类健康的重要性越来越多。开拓性研究表明，肠道细菌的变化会影响代谢和免疫疾病，例如肥胖，炎症性肠病（IBD）和多发性硬化症（MS）。此外，在实验IBD和MS小鼠模型中已验证了来自微生物组的特定治疗细菌分子。基于对代谢和免疫力研究的原则，报告最近表明，微生物组会影响脑发育的焦虑，伤害感受和方面。这些开创性的研究可能代表了肠道细菌与神经系统之间广泛（目前未描述的）的预兆。帕金森氏病（PD）是由神经变性导致严重运动缺陷的神经变性的结果，全世界有300万人患有这种疾病。大多数情况不是世袭的；但是，环境风险因素的贡献在很大程度上未知。基于胃肠道（GI）症状的常见发生和支持神经退行性可能在肠道中启动的假设的证据，研究PD中的微生物组 - 脑连接代表了一个令人兴奋的研究领域。 PD中的神经变性被认为是由prion样蛋白α-核蛋白（alphasyn）的聚集和/或积累引起的。疾病症状可以通过人α-突触核蛋白（Thy1-Alphasyn）过表达在小鼠中进行建模。为了确定微生物组是否影响疾病，第一个目标将测试无菌（Gnotobiotic）Thy1-Alphashyn小鼠的行为，细胞和功能特征。疾病进展的纵向分析将确定肠道细菌如何促进神经退行性和衰老。为了测试肠道细菌的变化是否与PD相关，我们将使用元基因组（shot弹枪测序）和metatranscriptomic（RNASEQ）分析来介绍THY1-α-α-α-α-α-α-α-α-α-α-α-α-α-α-α-α-α-α-α-α-α-α-α。 Thy1-α-α与对照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。多巴胺信号对于PD中的运动症状很重要，多巴胺前体L-多帕是一种主线治疗。最终目标将采用经过验证的微流体方法来筛选单个肠道微生物，以产生多巴胺，并将在临床前PD模型中测试新型益生菌治疗。该项目将首次研究肠道细菌的变化是否影响小鼠模型中PD的病因。如果成功的话，该项目的关键贡献将是PD可能具有肠道微生物起源的变革性概念飞跃，从而导致益生菌疗法的神经变性疗法有明智的进步。