Cadmium exposure persistently modulates the gut-liver axis in an Alzheimer’s disease mouse model

The human Apolipoprotein E4 (ApoE4) variant is the strongest known genetic risk factor for Alzheimer’s disease (AD).  Cadmium (Cd) has been shown to impair learning and memory at a greater extent in humanized ApoE4 knock-in (ApoE4-KI) mice as compared to the ApoE3 (common allele)-KI mice. In this study, we determined the extent that cadmium interacts with the ApoE4 gene variants to modify the gut-liver axis, which is important for xenobiotic biotransformation and nutrient homeostasis. Large intestinal content bacterial 16S rDNA sequencing, serum lipid metabolomics, and hepatic transcriptomics were analyzed in ApoE3- and ApoE4-KI mice orally exposed to vehicle, a low dose, or a high dose of Cd in drinking water.  Aligning with the previous report showing that the ApoE4-KI males are more susceptible to cadmium-induced memory deficit, ApoE4-KI males had the most prominent changes in gut microbiota, including an up-regulation of A. muciniciphila, which is a biomarker for AD in humans, as we...

人类载脂蛋白E4（Apolipoprotein E4，ApoE4）变体是已知的阿尔茨海默病（Alzheimer’s disease，AD）最强遗传风险因素。镉（Cadmium，Cd）已被证实，在人源化ApoE4基因敲入（ApoE4 knock-in，ApoE4-KI）小鼠中对学习与记忆的损害程度显著高于ApoE3（常见等位基因）-KI小鼠。本研究旨在阐明镉与ApoE4基因变体相互作用对肠-肝轴（gut-liver axis）的调控效应——肠-肝轴在异生物质生物转化及营养稳态中发挥关键作用。我们对经饮水口服给予溶媒、低剂量或高剂量镉的ApoE3-KI与ApoE4-KI小鼠，开展了大肠内容物细菌16S核糖体DNA测序（16S rDNA sequencing）、血清脂质代谢组学（serum lipid metabolomics）及肝脏转录组学（hepatic transcriptomics）分析。与此前关于ApoE4-KI雄性小鼠对镉诱导的记忆缺陷更易感的报道一致，ApoE4-KI雄性小鼠的肠道菌群发生了最显著的改变，包括黏蛋白阿克曼菌（Akkermansia muciniphila，A. muciniciphila）的上调——该菌是人AD的生物标志物，正如我们...