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

基本信息

批准号：
10247241
负责人：
Hariom Yadav
金额：
$ 60.42万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10247241
关键词：
AD transgenic mice APP-PS1 Address Adult Affect Alzheimer&apos s Disease Alzheimer&apos 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 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 microbiota microbiota profiles microbiota transplantation mild cognitive impairment mortality neuroinflammation normal aging outcome forecast personalized predictions prevent prognostic recruit responders and non-responders response translational study

项目摘要

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.

项目概要认知能力下降和阿尔茨海默氏病 (AD) 是全世界发病和死亡的主要原因，对受影响者、他们的照顾者和整个社会造成很大负担。仍然存在重要且这种疾病的诊断、预后和预防面临着巨大的挑战。轻度认知障碍（MCI）是这是早期 AD 的特征，针对 MCI 的干预措施可以预防 AD 的进展。目前，没有对于轻度认知障碍，有有效的治疗方法和高度可靠的基于共识的预后标准缺乏损伤（MCI）。此外，没有足够的证据支持使用药物用于预防/治疗 MCI/AD 的药物或膳食补充剂。然而，新兴研究表明肠道微生物群影响肠脑通讯和 AD 病理学。其他人和我们的初步数据表明与认知正常的患者相比，AD 和 MCI 患者的肠道存在受干扰且独特的微生物群（菌群失调）个人，表明肠道微生物群可能是 MCI/AD 新生物标志物的来源。饮食是单一的肠道微生物群最重要的调节剂。生酮饮食（KD）是大脑功能的强大调节剂并改善 AD 病理学，同时调节肠道微生物群。但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。我们的初步数据显示，在 MCI 参与者中，MMKD 改善了肠道微生物群特征和标记物脑脊液（CSF）中的AD。此外，肠道微生物群特征在个体之间存在显着差异有或没有 MCI，以及与 MCI 状态相关的某些细菌。总体而言，MMKD 有效改善了脑脊液和微生物群中的 AD 标记。然而，某些人（反应者）的反应比其他人（非反应者）更好。反应者）改善 AD 标记并改变独特的微生物群特征。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 反应，(b) MMKD 通过减少 AD 病理的微生物群。为了检验我们的假设，我们建议使用一组参与者尚未招募 MCI 参与维克森林阿尔茨海默病研究中心正在进行的研究（ADRC）由 Craft 博士领导。我们将研究我们新的基于微生物群的标记是否可以增强 MCI 预后并预测 MMKD 反应，并测试 MMKD 是否调节肠道微生物群，从而改善 AD 病理学。设计了三个具体目标：1）确定肠道微生物群特征是否可以预测人类 MCI，2) 确定肠道微生物群特征是否可以预测 MMKD 反应者和非 MMKD 反应者改善 AD 标志物的反应者，3) 评估肠道微生物群是否介导 MMKD 的有益作用改善 AD 病理。由高度跨学科的团队完成这些最先进的研究将建立基于肠道微生物群的标记物可以增强 MCI 预后的概念验证，并将开启探索使用 MMKD 作为改善 AD 的非药物方法的转化机会病理。