Microbiota-Brain Axis in Alzheimer's Disease: MIND Diet-Induced Effects

项目摘要/摘要： 更清楚地了解阿尔茨海默病(AD)的发病机制，以及总体上的认知能力下降，可能会 为治疗干预提供机会，以减缓认知衰退的进展并改善 老年人口的生活质量。这项提案的长期目标是“阿尔茨海默氏症的微生物区系-脑轴” 疾病：精神饮食诱导的影响“是将肠道特征(即，生物失调、屏障功能障碍)确定为 认知衰退的关键调节器。我们的目标是找出不正常或不太理想的肠道特征 促进或加剧认知能力下降，确定免疫机制，并找到治疗靶点 可以减缓认知功能衰退的进程。我们的中心假设是，不利的肠道状况 认知能力下降的风险因素。为了验证我们的假设，我们将利用最近一个激动人心的第三阶段试验。 由国家老龄研究所资助，评估饮食干预延缓进展的能力 阿尔茨海默病发病机制的研究(“精神饮食干预预防阿尔茨海默病”，AG052583)。审判将招募 65-84岁认知正常但有阿尔茨海默病家族史的受试者，随机将他们分配到 饮食干预或常规饮食，以确定饮食对认知能力下降的影响超过三年。 提出这项研究的理由是肠道微生物区系影响大脑功能和行为。 这是通过几种机制发生的，包括微生物衍生的代谢物(短链脂肪酸 (SCFA)和免疫系统(树突状细胞(DC)、TH1、TH2、T调节细胞(Tregs))。许多生活方式 选择和疾病会影响肠道微生物区系，但最大的影响莫过于饮食。饮食，如 地中海和饮食方法控制高血压(DASH)改善心血管健康和延迟 认知能力下降，我们建议他们通过诱导更有利的肠道特征来做到这一点，包括：(1) 减少促炎细菌(例如，菲米特/类杆菌比率)，(2)增加有益的SCFA- 产生细菌(如布鲁氏菌、玫瑰花)，(3)粪便和血清SCFA含量增加，(3)改善 肠道屏障完整性(例如，血清脂多糖降低)，(4)免疫系统改变(树突状细胞， T细胞、单核细胞)，以及(5)减轻全身炎症。我们会找出一种肠道特征来预测 认知功能减退，决定延缓认知功能减退的饮食干预如何影响肠道 简介，确定从饮食干预中受益最大的肠道简介，并评估潜力 机制包括细菌衍生的代谢物和免疫系统。 这项研究的成功完成有望将肠道特征确定为一个因素 认知能力下降，并开始确定饮食干预可能延缓认知能力的机制 减损。这些研究将通过强调微生物区系-大脑的重要性而产生积极的影响 Axis，对于了解AD的发病机制和确定潜在的治疗靶点具有一定的价值。

PROJECT SUMMARY / ABSTRACT: A clearer understanding of Alzheimer's disease (AD) pathogenesis, and cognitive decline in general, may provide opportunities for therapeutic interventions to slow the progression of cognitive decline and improve the quality of life in elderly populations. The long-term goal of this proposal, “Microbiota-Brain Axis in Alzheimer's Disease: MIND Diet-Induced Effects” is to identify the intestinal profile (i.e., dysbiosis, barrier dysfunction) as a critical regulator of cognitive decline. Our objective is to identify an abnormal or sub-optimal intestinal profile that promotes or exacerbates cognitive decline, identify immune mechanisms, and find therapeutic targets that can slow the progression of cognitive decline. Our central hypothesis is that an unfavorable intestinal profile is a risk factor for cognitive decline. To test our hypothesis we will leverage an exciting phase III trial recently funded by the National Institute on Aging evaluating the ability of a dietary intervention to slow the progression of AD pathogenesis (“MIND Diet Intervention to Prevent Alzheimer Disease,” AG052583). The trial will recruit subjects aged 65-84 who are cognitively normal but with a family history of AD and randomly assign them to a dietary intervention or the usual diet to determine the impact of a diet on cognitive decline over three years. The rationale for the proposed research is that the intestinal microbiota affects brain function and behavior and this occurs via several mechanisms including microbiota-derived metabolites (short chain fatty acids (SCFA)) and the immune system (dendritic cells (DC), TH1, TH2, T regulatory cells (Tregs)). Many lifestyle choices and diseases influence the intestinal microbiota, but none more robustly than diet. Diets such as the Mediterranean and Dietary Approaches to Stop Hypertension (DASH) improve cardiovascular health and delay cognitive decline and we propose that they do so by inducing a more favorable intestinal profile including: (1) decreased pro-inflammatory bacteria (e.g., Firmicutes/Bacteroides ratio), (2) increased beneficial SCFA- producing bacteria (e.g., Blautia, Roseburia), (3) increased stool and serum SCFA content, (3) improved intestinal barrier integrity (e.g., reduced serum lipopolysaccharide), (4) altered immune system (dendritic cells, T cells, monocytes), and (5) reduced systemic inflammation. We will identify an intestinal profile that predicts cognitive decline, determine how a dietary intervention that delays cognitive decline impacts the intestinal profile, identify an intestinal profile that most benefits from the dietary intervention, and evaluate potential mechanisms including bacterial-derived metabolites and the immune system. Successful completion of this study is expected to identify the intestinal profile as a factor that contributes to cognitive decline and begin to identify mechanisms by which a dietary intervention may delay cognitive impairment. These studies will have a positive impact by highlighting the importance of the microbiota-brain axis, and should be of value for understanding AD pathogenesis and identifying potential therapeutic targets.