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

这个应用专注于阿尔茨海默病(AD)遗传学、炎症和 肠道微生物群。载脂蛋白E等位基因是影响阿尔茨海默病遗传风险最大的因素，并调节多种途径 包括炎症。小胶质细胞功能本身通过TREM2和CD33单一信号与AD风险明显相关 S。因此，调节小胶质细胞功能的药物是很好的 应试者调节AD风险。近日，肠道微生物组代谢物短链脂肪酸S， 都是作为促进小胶质细胞功能出现的。微生物群可能调制AD的可能性是 支持用抗生素或药物治疗的APP小鼠AD相关表型减少的研究结果 维持在灵知生物环境中。在这里，我们提出了AD遗传学和肠道之间的一种新的联系 微生物组。这项研究源于与理查德在APOE会议上的一次偶然相遇 Guerrant描述了他的研究表明，人类和小鼠的肠道健康与APOE有关 当第三世界环境中的人类遭受腹泻暴发时，APOE4携带者有 与APOE3患者相比，病情较轻，预后较好。类似的发现也在 广泛使用的APOE靶向替换(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。这种可能性 APOE改变肠道微生物群的说法也得到了一份关于野生和野生动物之间微生物群变异的报告的支持。 APOE缺陷型小鼠。考虑到这些发现，我们提出了APOE的全球假设 等位基因调节肠道微生物群，这有助于APOE等位基因对AD风险的影响。AS 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，我们提出了以下具体目标：1.测试 假设肠道微生物群与小鼠模型中的APOE基因有关。我们的 初步结果显示，从APOE2到APOE3，再到APOE3，微生物组图谱呈现出明显的阶梯式模式 ApoE4，反刍球菌科APOE2含量最高。2.检验肠道微生物群是 与人类的载脂蛋白E基因相关。3.检验肠道微生物群落的假设 APOE2和APOE4对AD相关表型有相反的影响。如果成功， 我们希望这项跨学科的提案能够证明：(I)APOE2相关的微生物组可以改善 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。因为抗性淀粉已经 已被证明可以增加人类中的反式反式球菌科和单链脂肪酸，这样的结果可能是直接可翻译的 去做人体试验。

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.