The Gut Microbiome in Neurodegenerative Disease

神经退行性疾病中的肠道微生物组

• 批准号: 9129767
• 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 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9129767
• 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; 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; gut microbiome; innovation; longitudinal analysis; metabolic abnormality assessment; microbial; microbial community; microbiome; motor deficit; motor symptom; mouse model; mouse synuclein alpha; neurodegenerative phenotype; novel; overexpression; pars compacta; pre-clinical; prevent; prion-like; probiotic therapy; programs; relating to nervous system; symptom treatment; synuclein; theories; transcriptome; transcriptome sequencing; 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）：有益细菌永久定殖在许多身体部位，人们越来越认识到微生物组对人类健康的重要性。开创性研究表明，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，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，微生物组会影响焦虑、伤害感受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存在广泛的、目前尚未描述的联系。帕金森病 (PD) 是由神经退行性疾病引起的，会导致严重的运动缺陷，全世界有 300 万人患有这种疾病。大多数病例不是遗传性的；然而，环境风险因素的影响仍然很大程度上未知。基于胃肠道 (GI) 症状的常见发生以及支持神经退行性变可能始于肠道的假设的证据，检查帕金森病中微生物组与大脑的联系代表了一个令人兴奋的研究新领域。 PD 中的神经变性被认为是由朊病毒样蛋白 α-突触核蛋白 (alphaSyn) 的聚集和/或积累引起的。可以通过人 α-突触核蛋白 (Thy1-alphaSyn) 的过度表达在小鼠中模拟疾病症状。为了确定微生物组是否影响疾病，第一个目标是测试无菌（限菌）Thy1-alphaSyn 小鼠疾病的行为、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行性变和衰老。为了测试肠道细菌的变化是否与 PD 相关，我们将在第二个目标中使用宏基因组（鸟枪测序）和宏转录组 (RNAseq) 分析来分析 Thy1-alphaSyn 小鼠的微生物组。 Thy1-alphaSyn 和对照小鼠之间的差异可能揭示影响疾病的特定微生物和微生物途径。多巴胺信号传导对于帕金森病的运动症状很重要，多巴胺前体左旋多巴是一种主线疗法。最终目标将采用经过验证的微流体方法来筛选个体肠道微生物产生多巴胺的潜力，并将在临床前 PD 模型中测试新型益生菌治疗方法。该项目将首次研究肠道细菌的变化是否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观念上的变革性飞跃，即帕金森病可能源自肠道微生物，从而在神经退行性疾病的益生菌疗法方面取得明智的进展。

项目成果

A gut microbial factor modulates locomotor behaviour in Drosophila.

• DOI: 10.1038/s41586-018-0634-9
• 发表时间: 2018-11
• 期刊: Nature
• 影响因子: 64.8
• 作者: Schretter CE;Vielmetter J;Bartos I;Marka Z;Marka S;Argade S;Mazmanian SK
• 通讯作者: Mazmanian SK

Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease.

• DOI: 10.1016/j.cell.2016.11.018
• 发表时间: 2016-12-01
• 期刊: Cell
• 影响因子: 64.5
• 作者: Sampson TR;Debelius JW;Thron T;Janssen S;Shastri GG;Ilhan ZE;Challis C;Schretter CE;Rocha S;Gradinaru V;Chesselet MF;Keshavarzian A;Shannon KM;Krajmalnik-Brown R;Wittung-Stafshede P;Knight R;Mazmanian SK
• 通讯作者: Mazmanian SK