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

项目概要/摘要 阿尔茨海默病 (AD) 的患病率正在增加，但迄今为止尚无治疗方法。新出现的证据显示 生酮饮食 (KD) 等健康饮食可降低人类患 AD 的风险。然而，只有一小部分患者 体验到 KD 的有益效果（有反应者），而其他人（无反应者）却没有。这样做的基础 反应的巨大个体差异尚不清楚。这项研究将检验肠道微生物群的假设 是导致川崎病无反应的原因，而独特的合生素疗法可以逆转它。我们的假设是 基于多种新出现的证据，包括我们的初步数据表明：(i) 肠道微生物群 轻度认知障碍（MCI；AD 的早期阶段）和 AD 患者的成分存在显着差异； (ii) 改良的地中海式 KD 有益地调节肠道微生物群并增加 有益的微生物代谢物，如丁酸盐； (iii) 这些变化与 AD 标志物的减少有关 MCI 患者的脑脊液 (CSF) 中； (iv) KD 改善肠道微生物群并减少 AD 标记物 有反应者的脑脊液，但无反应者的脑脊液则不然； (v) 新型合生元（即益生菌和益生元混合物） 含有人类益生菌（5 种乳酸杆菌）和西米（棕榈淀粉）中的新型益生元的酸奶， 有益地调节肠道微生物群并增加丁酸盐的产生。我们的有趣且强大 初步数据提出了一些重要问题，例如：(a) 肠道微生物群是否会导致川崎病对 改善AD？ (b) 无反应者微生物群在多大程度上影响微生物代谢物的产生 和酮体？ (c) 我们能否通过调节无反应者微生物群来逆转川崎病的无反应性 使用独特的合生元疗法？为了解决这些重要的知识差距并获得转化洞察力， 我们将研究两个具体目标。在目标 1 中，我们将确定肠道微生物群在非 使用携带 AD (3xTg) 小鼠的创新人源化微生物群，了解 KD 对 AD 益处的反应 通过移植响应者和非响应者人类微生物群开发的模型。在目标 2 中，我们将确定 合生元酸奶疗法通过喂养合生元酸奶来挽救川崎病无反应的效果- 向含有无反应和反应微生物群的 AD 小鼠补充 KD。我们预计建立一个 使用人源化微生物群进行概念验证，证明肠道微生物群导致 KD 无反应 AD 小鼠模型，这些研究将解释 KD 的个性化效应，并为研究指明方向 改善 AD 病理学的新疗法。如果我们独特的合生元疗法能够逆转川崎病的无反应性， 然后可以将其作为 KD 的补充方案进行研究，这可能会增强长期依从性并 川崎病的安全性，并为减轻 AD 的负担铺平道路——AD 是老年人中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.