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

项目摘要 认知衰退和阿尔茨海默病（AD）是世界范围内发病率和死亡率的主要原因， 这对受影响者、其照顾者和整个社会都是沉重的负担。重要的是， 对该病的诊断、预后和预防提出了严峻的挑战。轻度认知障碍（MCI）是 MCI是早期AD的特征，靶向MCI的干预可以预防AD的进展。当前没有任何 有效的治疗方法是可行的，高度可靠的基于共识的轻度认知障碍的预后标准 （MCI）缺乏。此外，没有足够的证据支持使用药物 预防/治疗MCI/AD的药物或膳食补充剂。然而，新的研究表明， 微生物群影响AD的肠-脑通信和病理学。其他人和我们的初步数据显示， 与认知正常相比，AD和MCI患者的肠道具有受干扰的独特微生物群（生态失调） 这表明肠道微生物群可能是MCI/AD的新生物标志物的来源。饮食是唯一的 最重要的肠道微生物群调节剂。生酮饮食（KD）是大脑功能的强大调节剂 并改善AD病理学，沿着调节肠道微生物群。不过，目前尚不清楚， 改良的地中海KD（MMKD）主要作用于脑或肠道微生物群以改善AD。我们 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志物， 脑脊液（CSF）中的AD。此外，肠道微生物群特征在个体中显着不同， 有和没有MCI，与MCI状态相关的某些细菌。总体而言，MMKD可有效改善 CSF和微生物群中的AD标志物。而有些人，比其他人，更有实力。 应答者）在改善AD标志物和改变独特的微生物群特征方面的作用。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，并且（B）MMKD通过 微生物群来减少AD病理。为了验证我们的假设，我们建议使用一组参与者， 如果MCI还没有被维克森林阿尔茨海默病研究中心正在进行的研究招募， 由Craft博士领导的ADRC。我们将研究我们的新的基于微生物的标记物是否可以加强MCI 预后和预测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 预测人类的MCI，2）确定肠道微生物群特征是否可以预测MMKD应答者和非应答者。 缓解AD标志物的应答者，以及3）评估肠道微生物群是否介导MMKD的有益作用 来改善AD病理学。由高度跨学科的团队完成这些最先进的研究将 建立基于肠道微生物标记物概念验证可以加强MCI的预后， 探索使用MMKD作为改善AD的非药物方法的转化机会 病理

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.