Gut microbiota-based biomarkers of Alzheimer's disease and its modulation by a ketogenic diet

基于肠道微生物群的阿尔茨海默病生物标志物及其生酮饮食的调节

• 批准号: 10461652
• 负责人: Hariom Yadav
• 金额: $ 60.42万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10461652
• 关键词: AD transgenic mice; APP-PS1; Address; Adult; Affect; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; American; American Heart Association; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Amyloid deposition; Bacteria; Biological Assay; Biological Markers; Brain; Caregivers; Cerebrospinal Fluid; Characteristics; Clinical Research; Clinical Trials; Cognition; Cognitive; Consensus; Data; Dementia; Deposition; Diagnosis; Diet; Dietary Intervention; Disease; Disease Marker; Elderly; Family; Fatty acid glycerol esters; Feces; Goals; Health; Human; Impaired cognition; Individual; Intervention; Measures; Mediating; Morbidity - disease rate; Mus; Nerve Degeneration; Older Population; Participant; Pathology; Patients; Persons; Pharmacologic Substance; Pilot Projects; Play; Prevention; Prognosis; Research; Role; Senile Plaques; Societies; Source; Symptoms; Testing; Time; Validation; base; candidate marker; cohort; design; dietary supplements; disorder prevention; dysbiosis; early detection biomarkers; effective therapy; fecal transplantation; feeding; forest; gut bacteria; gut microbiota; gut-brain axis; improved; individual patient; ketogenic diet; microbial; microbial signature; microbiota; microbiota profiles; microbiota transplantation; mild cognitive impairment; mortality; neuroinflammation; normal aging; personalized predictions; prevent; prognostic; recruit; responders and non-responders; response; translational study

Project Summary Cognitive decline and Alzheimer's disease (AD) are major causes of morbidity and mortality worldwide and are substantially burdensome to those affected, their caregivers, and society in general. There remain important and formidable challenges in diagnosis, prognosis and prevention of this disease. Mild cognition impairment (MCI) is characteristic of early stage AD, and interventions targeting MCI can prevent progression of AD. Currently, no effective treatments are available and highly reliable consensus-based prognostic criteria for mild cognitive impairment (MCI) are lacking. Moreover, there is insufficient evidence to support the use of pharmaceutical agents or dietary supplements to prevent/treat MCI/AD. However, emerging research demonstrates that gut microbiota influences gut-brain communication and pathology of AD. Others and our preliminary data show that AD and MCI patient's gut harbors a perturbed and unique microbiota (dysbiosis) compared to cognitively normal individuals, suggesting that the gut microbiota could be a source of new biomarkers for MCI/AD. Diet is the single most significant modulator of the gut microbiota. A ketogenic diet (KD) is a powerful modulator of brain function and improves AD pathology, along with modulating the gut microbiota. However, currently it is unknown whether a modified Mediterranean KD (MMKD) primarily acts on the brain or the gut microbiota to ameliorate AD. Our preliminary data show that in participants with MCI, MMKD improved the gut microbiota signature and markers of AD in cerebrospinal fluid (CSF). In addition, gut microbiota signatures were significantly different in individuals with and without MCI, with certain bacteria associated with MCI status. Overall, MMKD was effective to improve AD markers in CSF and microbiota. However, certain people responded better (responders) than others (non- responders) in improving markers of AD and changing unique microbiota signature. We thus hypothesize that (a) gut microbiota-based biomarkers can predict MCI and MMKD response, and (b) MMKD acts through the microbiota to reduce AD pathology. To test our hypotheses, we propose to use a cohort of participants with and without MCI already being recruited for ongoing studies at Wake Forest Alzheimer's Disease Research Center (ADRC) led by Dr. Craft. We will examine whether our new microbiota-based markers could strengthen MCI prognosis and predict MMKD response, and test whether a MMKD modulates gut microbiota and thereby improves AD pathology. Three specific aims are designed to: 1) establish if the gut microbiota signature can predict MCI in humans, 2) determine whether gut microbiota signature can predict MMKD responders and non- responders to ameliorate AD markers, and 3) assess whether gut microbiota mediates MMKD's beneficial effects to ameliorate AD pathology. Completion of these state-of-the-art studies by a highly interdisciplinary team will establish proof-of-concept that gut microbiota-based markers can strengthen prognosis of MCI and will open translational opportunities to explore the use of MMKD as a non-pharmacological approach to ameliorate AD pathology.

项目摘要 认知能力下降和阿尔茨海默氏病（AD）是全球发病率和死亡率的主要原因，并且是 对于受影响的人，他们的照顾者和整个社会而言，这实质上负担重大。仍然很重要 诊断，预后和预防这种疾病的巨大挑战。轻度认知障碍（MCI）是 早期AD的特征和针对MCI的干预措施可以防止AD的发展。目前，没有 有效的治疗可用，并且基于高度共识的预后标准是轻度认知 缺乏损害（MCI）。而且，没有足够的证据支持药物的使用 预防/治疗MCI/AD的代理或饮食补充剂。但是，新兴研究表明肠道 微生物群会影响AD的肠道沟通和病理。其他人和我们的初步数据表明 与认知正常相比 个人，表明肠道菌群可能是MCI/AD的新生物标志物的来源。饮食是单一的 肠道菌群最重要的调节剂。生酮饮食（KD）是大脑功能的强大调节剂 并改善AD病理，并调节肠道菌群。但是，目前尚不清楚是否 改良的地中海KD（MMKD）主要作用于大脑或肠道微生物群以改善AD。我们的 初步数据表明，在MCI的参与者中，MMKD改善了肠道菌群签名和标记 脑脊液（CSF）中的AD。此外，个体的肠道微生物群特征显着差异 在有和没有MCI的情况下，与MCI状态相关的某些细菌。总体而言，MMKD有效改进 CSF和Microbiota中的AD标记。但是，某些人的反应比其他人更好（响应者）（非 - 响应者）改善AD标记并改变了独特的微生物签名。因此，我们假设 （a）基于肠道微生物群的生物标志物可以预测MCI和MMKD响应，并且（b）MMKD通过 微生物群以减少AD病理学。为了检验我们的假设，我们建议与 没有MCI在Wake Forest Alzheimer's Diseanty Research Center中招募MCI （ADRC）由Craft博士领导。我们将检查我们的新基于微生物群的标记是否可以增强MCI 预后和预测MMKD响应，并测试MMKD是否调节肠道微生物群 改善AD病理学。设计三个特定目标是：1）确定肠道菌群签名是否可以 预测人类的MCI，2）确定肠道菌群特征是否可以预测MMKD响应者和非响应者 缓解广告标记的响应者，3）评估肠道微生物群是否介导MMKD的有益效果 改善AD病理学。由高度跨学科的团队完成这些最先进的研究将 确定概念概念，即基于肠道菌群的标记可以增强MCI的预后，并将开放 转化机会探索使用MMKD作为改善广告的非药物方法 病理。