The Gut Microbiome in Neurodegenerative Disease

描述（由申请人提供）：有益细菌永久定植在许多身体部位，人们越来越认识到微生物组对人体健康的重要性。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，来自微生物组的特异性治疗性细菌分子已在实验性IBD和MS小鼠模型中得到验证。根据代谢和免疫研究的原理，最近的报告显示，微生物组影响焦虑、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广泛的、目前尚未描述的联系。帕金森氏症（PD）由神经退行性变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在很大程度上仍然未知。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PD中微生物组-脑连接代表了一个令人兴奋的新研究前沿。PD的神经退行性变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。通过过度表达人α -突触核蛋白（Thy1-alphaSyn），可以在小鼠中模拟疾病症状。为了确定微生物组是否会影响疾病，第一个目标是在无菌（非生物）Thy1-alphaSyn小鼠中测试疾病的行为、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变性和衰老。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）和亚转录组（RNAseq）分析来分析Thy1-alphaSyn小鼠的微生物组。Thy1-alphaSyn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。多巴胺信号在帕金森病患者的运动症状中起重要作用，多巴胺前体L-多巴是主要的治疗方法。最终目标将采用一种经过验证的微流体方法来筛选个体肠道微生物，以寻找产生多巴胺的潜力，并将在临床前PD模型中测试新的益生菌治疗方法。本项目将首次在小鼠模型中研究肠道细菌的变化是否影响PD的病因学。如果成功，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，从而导致益生菌治疗神经变性的知情进展。

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.