The role of gut microbiota in the efficacy of ketogenic diet to ameliorate Alzheimer's disease

项目摘要/摘要 阿尔茨海默病(AD)的患病率正在上升，到目前为止还没有治疗方法。新出现的证据表明 生酮饮食(KD)等健康饮食可降低人类患阿尔茨海默病的风险。然而，只有一部分患者 体验KD(应答者)的有益影响，而其他人则没有(非应答者)。这一点的基础 目前尚不清楚个体在反应上的巨大差异。这项研究将检验肠道微生物区系的假设 是KD无反应的原因，一种独特的合生疗法可以逆转它。我们的假设是 基于多条新出现的证据，包括我们的初步数据表明：(I)肠道微生物区系 轻度认知障碍(MCI；AD的早期阶段)和AD患者的成分有显著差异； (Ii)改良的地中海式KD有益地调节肠道微生物区系，并增加 有益的微生物代谢物，如丁酸；(Iii)这些变化与AD标志物的减少有关 在MCI患者的脑脊液中；(Iv)KD改善肠道微生物区系并降低AD标志物 应答者的脑脊液，但不对无应答者；和(V)一种新的合生菌(即益生菌和益生菌的混合物) 含有人类来源的益生菌(5个乳杆菌)和一种来自西米的新型益生菌(棕榈淀粉)的酸奶， 有益地调节肠道微生物区系，增加丁酸盐的产量。我们有趣而强大的 初步数据提出了一些重要问题，如：(A)肠道微生物区系是否导致KD对 改善AD？(B)无反应微生物区系在多大程度上影响微生物代谢物的产生 还有酮体呢？以及(C)我们能否通过调节无应答微生物群来逆转KD的无应答 使用一种独特的合生体疗法？为了解决知识中的这些重要差距并获得翻译洞察力， 我们将调查两个具体目标。在目标1中，我们将确定肠道微生物区系在非 利用携带AD(3xTg)小鼠的创新人源化微生物区系研究KD对AD的益处 通过移植应答者和非应答者人体微生物群开发的模型。在目标2中，我们将确定 联合酸奶疗法通过喂养联合生物酸奶拯救KD无反应的效果-- 将KD添加到AD小鼠体内，使其具有无应答和应答的微生物区系。我们预计将建立一个 使用人源化微生物群--肠道微生物群导致KD无反应的概念验证 这些研究将解释KD的个性化效应，并为 改善AD病理的新疗法。如果我们独特的合生体疗法可以逆转KD的无反应性， 然后可以研究它作为KD的补充方案，这可能会增强长期依从性和 KD的安全性，并为减轻AD的负担铺平了道路--AD是老年人的一个令人衰弱的公共卫生问题。

Project Summary/Abstract Alzheimer’s disease (AD) prevalence is increasing and no treatment exists to date. Emerging evidence show that healthy diets such as ketogenic diet (KD) lowers the risk of AD in humans. However, only a subset of patients experiences the beneficial effects of KD (responders), while others do not (non-responders). The basis for this tremendous individual variations in response is not known. This study will test the hypothesis that gut microbiota is causal for non-responsiveness of KD and that a unique synbiotic therapy can reverse it. Our hypothesis is based on multiple lines of emerging evidence, including our preliminary data indicating that: (i) gut microbiota composition is significantly different in mild-cognitive impairment (MCI; an early stage of AD) and AD patients; (ii) a modified Mediterranean-style KD beneficially modulates gut microbiota and increases production of beneficial microbial metabolites like butyrate; (iii) these changes were associated with reduction of AD markers in the cerebrospinal fluid (CSF) of MCI patients; (iv) KD improves gut microbiota and reduces AD markers in CSF of responders, but not on non-responders; and (v) a novel synbiotic (i.e. probiotics and prebiotics mix) yogurt that incorporates human-origin probiotics (5 lactobacilli) and a novel prebiotics from sago (palm starch), beneficially modulates gut microbiota and increases production of butyrate. Our interesting and strong preliminary data raise important questions such as: (a) Does gut microbiota cause non-responsiveness of KD to ameliorate AD? (b) To what extent does non-responder microbiota impact the production of microbial metabolites and ketone bodies? And (c) Can we reverse KD’s non-responsiveness by modulating non-responder microbiota using a unique synbiotic therapy? To address these important gaps in knowledge and gain translational insight, we will investigate two specific aims. In aim 1, we will determine the causal role of gut microbiota in non- responsiveness of KD’s benefits to AD, using an innovative humanized microbiota harboring AD (3xTg) mouse model developed by transplanting responder and non-responder human microbiota. In aim 2, we will determine the effect of a synbiotic yogurt therapy in rescuing KD’s non-responsiveness, by feeding synbiotic yogurt- supplemented KD to AD mice harboring non-responder and responder microbiota. We anticipate to establish a proof-of-concept that gut microbiota causes KD’s non-responsiveness using a humanized microbiota-harboring AD mice model, and that these studies will explain the personalized effects of KD and point the direction of a new therapy to improve AD pathology. If our unique synbiotic therapy could reverse KD’s non-responsiveness, then it could be studied as a complementary regimen with KD, which may enhance long-term adherence and safety of KD, and pave the way to reduce the burden of AD - a debilitating public health problem in older adults.