The surprising impact of APOE alleles on gut microbiome: does altering the microbiome reduce AD risk?

APOE 等位基因对肠道微生物组的惊人影响：改变微生物组是否可以降低 AD 风险？

• 批准号: 9783096
• 负责人: Steven Estus
• 金额: $ 61.02万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9783096
• 关键词: APP-PS1; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid; Antibiotics; Bacteria; Behavior; Biological; Blood; Cerebrovascular Circulation; Cognition; Communities; Data; Diet; Disease; Disease Outbreaks; Elderly; Environment; Family; Genetic Diseases; Genotype; Gnotobiotic; Health; Human; Individual; Inflammation; Intestines; Lactobacillaceae; Link; Metabolism; Mus; Neurologic; Outcome; Pathology; Pathway interactions; Pattern; Peripheral; Phenotype; Plasma; Production; Reporting; Resistance; Single Nucleotide Polymorphism; Starch; TREM2 gene; Testing; Variant; Volatile Fatty Acids; amyloid pathology; base; cohort; gastrointestinal infection; genetic risk factor; gut microbiome; improved; indexing; inflammatory marker; meetings; microbiome; microbiome alteration; microbiota transplantation; mouse model; novel; operational taxonomic units; response; symposium; volunteer

This application focuses on the interface between Alzheimer's disease (AD) genetics, inflammation and the gut microbiome. APOE alleles are the most impactful AD genetic risk factor and modulate several pathways including inflammation. Microglial function itself is clearly linked to AD risk by TREM2 and CD33 single nucleotide polymorphisms (SNP)s. Hence, agents that modulate microglial function are excellent candidates to modulate AD risk. Recently, a gut microbiome metabolite, short chain fatty acids (SCFA)s, have emerged as promoting microglial function. The possibility that the microbiome may modulate AD is supported by findings that AD-related phenotypes are reduced in APP mice treated with antibiotics or maintained in a gnotobiotic environment. Here, we propose a novel link between AD genetics and the gut microbiome. This study resulted from a serendipitous meeting at an APOE conference with Richard Guerrant, who described his studies showing that gut health in humans and mice is associated with APOE genotype; when humans in a third world environment suffer from diarrheal outbreaks, APOE4 carriers have less severe disease and better outcomes, relative to APOE3 individuals. Similar findings were found in the widely used, APOE targeted replacement (TR) murine model wherein APOE4 was associated with an improved response to gastrointestinal infection and undernourishment, compared to APOE3. The possibility that APOE alters the gut microbiome is also supported by a report of microbiome variation between wild- type and APOE deficient mice. Considering these findings, we propose the global hypothesis that APOE alleles modulate the gut microbiome and that this contributes to APOE allelic effects on AD risk. As a corollary, we further hypothesize that changing the microbiome to that of APOE2 individuals will reduce AD risk. To evaluate this scientific premise, we submit the following Specific Aims: 1. Test the hypothesis that the gut microbiome is associated with APOE genotype in a murine model. Our preliminary results show a striking stepwise pattern in microbiome profiles from APOE2 to APOE3 to APOE4, with Ruminococcaceae highest in APOE2. 2. Test the hypothesis that the gut microbiome is associated with APOE genotype in humans. 3. Test the hypothesis that the gut microbiomes associated with APOE2 and APOE4 have opposing effects on AD-related phenotypes. If successful, we expect this interdisciplinary proposal to demonstrate (i) an APOE2-associated microbiome ameliorates AD-related phenotypes and (ii) dietary resistant starch mimics APOE2 effects on the microbiome, SCFA levels, microglial activation, amyloid burden and cognition in a murine model. Since resistant starch has been shown to increase Ruminococcaceae and SCFAs in humans, such results may be directly translatable to human trials.

该应用重点关注阿尔茨海默病 (AD) 遗传学、炎症和 肠道微生物组。 APOE 等位基因是最具影响力的 AD 遗传风险因素，可调节多种途径 包括炎症。小胶质细胞功能本身通过 TREM2 和 CD33 与 AD 风险明显相关 核苷酸多态性（SNP）。因此，调节小胶质细胞功能的药物是非常好的 调节 AD 风险的候选人。最近，肠道微生物组代谢物短链脂肪酸（SCFA）， 已出现促进小胶质细胞功能的现象。微生物组调节 AD 的可能性是 经抗生素治疗或治疗的 APP 小鼠中 AD 相关表型减少的研究结果支持了这一点 维持在限菌环境中。在这里，我们提出 AD 遗传学和肠道之间的新联系 微生物组。这项研究源于在 APOE 会议上与 Richard 的一次偶然会面 Guerrant 描述了他的研究表明人类和小鼠的肠道健康与 APOE 相关 基因型;当第三世界环境中的人类爆发腹泻时，APOE4 携带者 相对于 APOE3 个体，疾病不太严重，结果更好。类似的发现也被发现于 广泛使用的 APOE 靶向替代 (TR) 小鼠模型，其中 APOE4 与 与 APOE3 相比，改善了对胃肠道感染和营养不良的反应。可能性 APOE 改变肠道微生物组的观点也得到野生动物之间微生物组变异的报告的支持。 型和 APOE 缺陷小鼠。考虑到这些发现，我们提出了 APOE 的全局假设 等位基因调节肠道微生物组，这有助于 APOE 等位基因对 AD 风险的影响。作为 推论，我们进一步假设将微生物组改变为 APOE2 个体的微生物组将 降低 AD 风险。为了评估这一科学前提，我们提出以下具体目标： 1. 测试 假设肠道微生物组与小鼠模型中的 APOE 基因型相关。我们的 初步结果显示，从 APOE2 到 APOE3，再到微生物组谱，存在显着的逐步模式。 APOE4，其中瘤胃球菌科APOE2最高。 2. 检验肠道微生物组的假设 与人类的 APOE 基因型有关。 3. 检验肠道微生物组的假设 与 APOE2 和 APOE4 相关的基因对 AD 相关表型具有相反的作用。如果成功的话， 我们期望这一跨学科提案能够证明 (i) APOE2 相关微生物组可以改善 AD 相关表型和 (ii) 膳食抗性淀粉模拟 APOE2 对微生物组、SCFA 的影响 小鼠模型中的水平、小胶质细胞激活、淀粉样蛋白负荷和认知。由于抗性淀粉具有 已被证明可以增加人类的瘤胃球菌科和短链脂肪酸，这样的结果可以直接转化 到人体试验。