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

肠道微生物群在生酮饮食改善阿尔茨海默病功效中的作用

• 批准号: 10196134
• 负责人: Hariom Yadav
• 金额: $ 42.94万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10196134
• 关键词: 3xTg-AD mouse; Address; Adherence; Adult; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; American; American Heart Association; Blood Circulation; Butyrates; Cerebrospinal Fluid; Clinical Research; Clinical Trials; Cognition; Consumption; Data; Dementia; Development; Diet; Dietary Intervention; Dietary Practices; Disease Marker; Elderly; Family; Fatty acid glycerol esters; Funding; Goals; Human; Individual; Intervention; Ketone Bodies; Knowledge; Lactobacillus; Link; Mus; Nutritional; Patients; Prevalence; Probiotics; Production; Public Health; Quality of life; Regimen; Research; Role; Safety; Sampling; Societies; Starch; Testing; Time; Transplant Recipients; Transplantation; Volatile Fatty Acids; Yogurt; base; cohort; effective therapy; experience; fecal transplantation; feeding; forest; good diet; gut microbiome; gut microbiota; high risk; human microbiota; improved; individual variation; innovation; insight; ketogenic diet; metabolomics; microbial; microbiota; mild cognitive impairment; mouse model; novel; novel therapeutics; patient subsets; prebiotics; responders and non-responders; response; sugar

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.

项目总结/摘要 阿尔茨海默病（AD）的患病率正在增加，并且迄今为止没有治疗方法。新出现的证据显示 健康饮食如生酮饮食（KD）可降低人类AD的风险。然而，只有一部分患者 经历KD的有益效果（应答者），而其他人没有（无应答者）。其基础 反应的巨大个体差异是未知的。这项研究将验证肠道微生物群 是KD无反应性的原因，独特的合生素治疗可以逆转它。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）肠道微生物群 在轻度认知障碍（MCI; AD的早期阶段）和AD患者中组成显著不同; (ii)改良的地中海式KD有益地调节肠道微生物群， 有益的微生物代谢产物，如丁酸盐;（iii）这些变化与AD标志物的减少有关 （iv）KD改善了MCI患者的肠道微生物群并减少了MCI患者的AD标志物; 应答者的CSF，但非应答者的CSF;和（v）新型合生素（即益生菌和益生元混合物） 结合了人类来源的益生菌（5种乳酸杆菌）和来自西米的新型益生元（棕榈淀粉）的酸奶， 有益地调节肠道微生物群并增加丁酸盐的产生。我们有趣又坚强 初步数据提出了一些重要的问题，例如：（a）肠道微生物群是否会导致KD对 改善AD？(b)无应答菌群在多大程度上影响微生物代谢产物的产生 和酮体吗以及（c）我们能否通过调节无反应菌群来逆转KD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翻译见解， 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肠道疾病中的因果作用。 KD对AD益处的反应性，使用携带AD（3xTg）小鼠的创新人源化微生物群 通过移植应答者和非应答者人类微生物群开发的模型。在目标2中，我们将确定 合生元酸奶疗法在挽救KD的无反应性方面的作用，通过喂养合生元酸奶- 补充KD的AD小鼠，其具有非应答者和应答者微生物群。我们预计将建立一个 使用人源化的微生物群携带物证明肠道微生物群导致KD的无反应性的概念 这些研究将解释KD的个体化效应，并为研究KD的治疗指明方向。 改善AD病理学的新疗法。如果我们独特的合生素疗法可以逆转KD的无反应性， 那么它可以作为KD的补充方案进行研究，这可能会提高长期依从性， 研究人员还发现，这一发现有助于提高KD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。