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

项目摘要 认知功能减退和阿尔茨海默病(AD)是全世界发病率和死亡率的主要原因， 对受影响的人、他们的照顾者和整个社会来说都是巨大的负担。仍然很重要，而且 在该病的诊断、预后和预防方面面临巨大挑战。轻度认知障碍(MCI)是 早期AD的特点，针对MCI的干预可以预防AD的进展。目前，没有 对于轻度认知障碍，有效的治疗是可用的和高度可靠的基于共识的预后标准 缺乏损害(MCI)。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，直觉 微生物区系影响AD的肠脑沟通和病理。其他人和我们的初步数据显示， 与认知正常相比，AD和MCI患者的肠道中存在一种受干扰的独特微生物区系(生物失调 这表明肠道微生物区系可能是MCI/AD新生物标志物的来源。节食是唯一的 肠道微生物区系最重要的调节者。生酮饮食(KD)是大脑功能的强大调节剂 并改善AD的病理，同时调节肠道微生物区系。不过，目前尚不清楚， 改良的地中海KD(MMKD)主要作用于大脑或肠道微生物区系，以改善AD。我们的 初步数据显示，在患有MCI的参与者中，MMKD改善了肠道微生物区系特征和标志物 脑脊液(CSF)中的AD。此外，肠道微生物区系特征在个体之间也有显著差异。 有或没有MCI，某些细菌与MCI状态有关。总体而言，MMKD是有效的改善 脑脊液和微生物区系中的AD标志物。然而，某些人(应答者)比其他人(非应答者)反应更好 应答者)在改进AD的标志物和改变独特的微生物区系特征方面。因此，我们假设 (A)基于肠道微生物区系的生物标记物可以预测MCI和MMKD的反应，以及(B)MMKD通过 微生物区系可减少AD的病理。为了检验我们的假设，我们建议使用一组参与者，其中 没有MCI已经被招募到维克森林阿尔茨海默病研究中心进行研究 (ADRC)由克拉夫特博士领导。我们将研究我们的新的基于微生物区系的标记是否可以增强MCI 预测和预测MMKD反应，并测试MMKD是否调节肠道微生物区系，从而 改善AD病理。设计了三个具体的目标：1)确定肠道微生物区系签名是否可以 预测人类的MCI，2)确定肠道微生物区系特征是否可以预测MMKD应答者和非应答者 应答者改善AD标志物，以及3)评估肠道微生物区系是否介导MMKD的有益影响 改善AD病理。由一个高度跨学科的团队完成这些最先进的研究将 建立概念验证：基于肠道微生物区系的标志物可以加强MCI的预后，并将 探索将MMKD作为一种非药物方法用于改善AD的翻译机会 病理学。

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.