The Gut Microbiome in Neurodegenerative Disease

描述（由申请人提供）：有益细菌永久地定殖在许多身体部位，越来越多的人认识到微生物组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性细菌分子已在实验性IBD和MS小鼠模型中得到验证。基于代谢和免疫研究的原理，最近的报告表明，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。帕金森病（PD）是由神经退行性疾病引起的，导致严重的运动缺陷，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，环境风险因素的贡献在很大程度上仍然未知。基于胃肠道（GI）症状的常见发生和支持神经变性可能在肠道中启动的假设的证据，检查PD中的微生物组-大脑连接代表了一个令人兴奋的新研究前沿。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。疾病症状可以通过人α-突触核蛋白（Thy 1-alphaSyn）的过表达在小鼠中建模。为了确定微生物组是否会影响疾病，第一个目标将在无菌（gnotobiotic）Thy 1-alphaSyn小鼠中测试疾病的行为，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促进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）和元转录组（RNAseq）分析来描述Thy 1-alphaSyn小鼠的微生物组。Thy 1-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。多巴胺信号对于PD的运动症状是重要的，并且多巴胺前体L-DOPA是主线治疗。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。该项目将首次研究肠道细菌的变化是否会影响小鼠模型中PD的病因。如果成功，该项目的关键贡献将是PD可能具有肠道微生物来源的变革性概念飞跃，从而导致益生菌疗法在神经变性方面取得了知情的进展。

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.