Understanding the Microbiome-gut-brain axisn Alzheimer disease and its Role in Cognitive Decline

摘要 “微生物-肠道-大脑轴”的概念起源于微生物组的行为研究， 重组小鼠，已经发展到目前的研究，支持微生物组可能是负责一些 最具破坏性的神经退行性疾病，包括阿尔茨海默病（AD）。最近的研究 研究了肠道微生物组之间的这种联系，并确定了肠道微生物丰度的显著变化， AD患者的某些分类群。因此，目前的一种理论认为，AD的发病机制是密切相关的失衡， 肠道微生物组，并可能起源于肠道。我们的团队最近发表了一项研究结果， 的养老院老年人表现出AD老年人的生态失调模式，其特点是 具有抗炎特性的细菌的流行，以及已知引起炎症的分类群的获得， 促炎状态在这项建议中，我们将：1）利用我们现有的养老院经验， 评估认知能力下降; 2）在当地老年中心的老年群体中推进我们的工作， 比较社区居住队列; 3）确定这些微生物群分类和基因功能 老年人; 4）利用粪便样本来确定微生物组如何诱导肠道炎症以及如何 这与观察到的全身性炎症相关;以及5）研究微生物组代谢产物 差异，并解释这些产品如何影响小胶质细胞的功能。我们假设有一个 AD老年人中特有的生态失调微生物组，无论生活环境如何， 炎症型生态失调与局部和全身炎症正相关， 认知能力下降我们进一步假设AD微生物组代谢物对小胶质细胞有负面影响， 功能具体而言，在目标1中，我们将评估来自不同组织的AD老年人微生物组的特征。 与无痴呆的老年人相比， 并将其与认知的变化联系起来。在目标2中，我们将确定微生物组生态失调的程度， AD老年人，将其与诱导（体内/体外）上皮功能障碍的水平相关联，然后回到老年人 炎症的细胞因子标志物和免疫衰老的T细胞群体标志物。最后，在目标3中， 进行代谢组学，以确定AD老年人和非痴呆老年人之间的代谢产物谱差异 并在我们的体内/体外试验中使用鉴定的代谢物来描述其对小胶质细胞功能的影响。这 这项工作迈出了关键的一步，通过展示AD如何与微生物群联系起来， 观察到的老年人微生物组生态失调可对肠上皮细胞稳态产生不利影响， 炎症、炎症引起的免疫衰老和最终的认知功能障碍。它还将 描述微生物代谢产物的差异以及这些代谢物如何影响小胶质细胞的功能。 了解这一关键的“微生物-肠道-大脑轴”如何影响AD的发展和进展， 新的治疗靶点，并使未来的试验旨在干预这些途径。

ABSTRACT The concept of the “microbiota-gut-brain axis”, which originated from behavioral studies in microbiome- reconstituted mice, has advanced to current research that supports the microbiome may be responsible for some of the most devastating neurodegenerative disorders, including Alzheimer's Disease (AD). Recent studies have interrogated this connection among the intestinal microbiome and identified significant changes in the abundance of certain taxa in AD patients. Thus, one current theory is that AD pathogenesis is closely related to the imbalance of the gut microbiome and may originate in the gut. Our group has recently published findings among a cohort of nursing home elders demonstrating a dysbiotic pattern in AD elders that is hallmarked by a reduction in the prevalence of bacteria with anti-inflammatory properties, as well as an acquisition of taxa that are known to cause pro-inflammatory states. In this proposal we will: 1) leverage our current nursing home experience to enroll elders assessing cognitive decline; 2) advance our work within the local Senior Centers' elder groups to enroll a comparative community-dwelling cohort; 3) determine both microbiota taxonomy and gene function among these elders; 4) utilize stool samples to determine how the microbiome can induced intestinal inflammation and how this correlates back to observed systemic inflammation; and 5) study the microbiome metabolic product differences and explain how these products can influence microglia functioning. We hypothesize that there is a characteristic dysbiotic microbiome among AD elders, regardless of living environment, and that the level of inflammation-type dysbiosis positively correlates with both local and systemic inflammation and eventually cognitive decline. We further hypothesize that the AD microbiome metabolites negatively impact microglial functioning. Specifically, in Aim 1 we will assess characteristics of the AD elder's microbiome from different environments in comparison to elders without dementia and longitudinally assess the microbiome composition and correlate it to changes in cognition. In Aim 2 we will determine the extent of microbiome dysbiosis among AD elders, correlate this with the level of induce (in vivo/vitro) epithelial dysfunction, and then back to elder cytokine markers of inflammation and T cell population markers of immunosenescence. Finally, in Aim 3 we will perform metabolomics to identify metabolite profile differences between AD elders and those without dementia and use the identified metabolites in our in vivo/vitro assays to describe its effects on microglial functioning. This work takes a critical step forward to bridge microbiome associations with AD to causality by showing how the AD elder's microbiome dysbiosis observed can adversely affect intestinal epithelial homeostasis leading to systemic inflammation, inflammation-causing immunosenescence, and ultimately cognitive dysfunction. It will also describe the microbial metabolic product differences and how these metabolites influence microglial functioning. Understanding how this crucial “microbiota-gut-brain axis” impacts AD development and progression will provide novel therapeutic targets and enable future trials aimed at intervening upon these pathways.