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

阿尔茨海默病中的微生物群-脑轴：MIND 饮食诱导的影响

• 批准号: 10092054
• 负责人: ROBIN M VOIGT-ZUWALA
• 金额: $ 62.83万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092054
• 关键词: Affect; Alzheimer' s Disease; Anti-Inflammatory Agents; Bacteria; Bacteroides; Bacteroidetes; Behavior; Brain; Butyrates; Cell physiology; Cells; Clinical Trials; Cognition; Cognitive; Communities; DASH diet; Dendritic Cells; Diet; Dietary Intervention; Disease; Disease Progression; Elderly; Enrollment; Evaluation; Family history of; Feces; Firmicutes; Functional disorder; Funding; Goals; Immune; Immune System Diseases; Immune system; Immunologic Markers; Impaired cognition; Incidence; Inflammation; Inflammatory; Intervention; Intestines; Life Style; Lipopolysaccharides; Metagenomics; Monitor; National Institute on Aging; Pathogenesis; Peripheral Blood Mononuclear Cell; Phase; Plasma; Population; Process; Production; Proteobacteria; Public Health; Quality of life; Randomized; Regulatory T-Lymphocyte; Research; Risk Factors; Serum; Structure; T-Lymphocyte; Testing; Therapeutic Intervention; Time; Volatile Fatty Acids; aged; cardiovascular health; cytokine; design; dysbiosis; epidemiology study; gut microbiota; immune function; immune system function; improved; intestinal barrier; metabolomics; microbiome; microbiota; microbiota metabolites; monocyte; phase III trial; pre-clinical; prevent; recruit; systemic inflammatory response; therapeutic target

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.

项目总结/摘要： 更清楚地了解阿尔茨海默病（AD）的发病机制，以及一般的认知能力下降， 为治疗干预提供机会，以减缓认知衰退的进展，并改善 老年人的生活质量。这项提案的长期目标，“微生物群-阿尔茨海默氏症的脑轴 疾病：MIND饮食诱导效应”是为了确定肠道概况（即，生态失调，屏障功能障碍）， 认知能力下降的关键调节因子我们的目标是确定一个异常或次优的肠道档案 促进或加剧认知能力下降，确定免疫机制，并找到治疗靶点， 可以减缓认知能力下降的进程我们的中心假设是，一个不利的肠道轮廓是 认知能力下降的危险因素为了验证我们的假设，我们将利用最近一项令人兴奋的III期试验， 由国家老龄化研究所资助，评估饮食干预减缓进展的能力， AD发病机制的研究（“MIND Diet Intervention to Prevent Alzheimer Disease，”AG 052583）。试验将招募 受试者年龄65-84岁，认知正常，但有AD家族史，并将他们随机分配到一个 饮食干预或常规饮食，以确定饮食对三年认知能力下降的影响。 这项研究的基本原理是肠道微生物群影响大脑功能和行为 这通过几种机制发生，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）、TH 1、TH 2、T调节细胞（T细胞））。许多生活方式 选择和疾病会影响肠道菌群，但没有比饮食更强大的了。饮食，如 地中海和饮食方法阻止高血压（DASH）改善心血管健康和延迟 认知能力下降，我们提出他们这样做是通过诱导更有利的肠道概况，包括：（1） 减少促炎细菌（例如，厚壁菌门/拟杆菌比率），（2）增加有益的SCFA- 产生细菌（例如，Blautia，Roseburia），（3）增加粪便和血清SCFA含量，（3）改善 肠屏障完整性（例如，降低的血清脂多糖），（4）改变的免疫系统（树突细胞， T细胞，单核细胞），和（5）减少全身炎症。我们将确定一个肠道的轮廓， 认知下降，确定延迟认知下降的饮食干预如何影响肠道 特征，确定从饮食干预中获益最多的肠道特征，并评估潜在的 包括细菌衍生代谢物和免疫系统的机制。 这项研究的成功完成，预计将确定肠道概况作为一个因素，有助于 并开始确定饮食干预可能延迟认知能力下降的机制 损伤这些研究将产生积极的影响，突出微生物大脑的重要性， 这对了解AD的发病机制和寻找潜在的治疗靶点具有重要价值。