INTRODUCTIONEmerging evidence links changes in the gut microbiome to late‐onset Alzheimer's disease (LOAD), necessitating examination of AD mouse models with consideration of the microbiome.METHODSWe used shotgun metagenomics and untargeted metabolomics to study the human amyloid beta knock‐in (hAβ‐KI) murine model for LOAD compared to both wild‐type (WT) mice and a model for early‐onset AD (3xTg‐AD).RESULTSEighteen‐month female (but not male) hAβ‐KI microbiomes were distinct from WT microbiomes, with AD genotype accounting for 18% of the variance by permutational multivariate analysis of variance (PERMANOVA). Metabolomic diversity differences were observed in females, however no individual metabolites were differentially abundant. hAβ‐KI mice microbiomes were distinguishable from 3xTg‐AD animals (81% accuracy by random forest modeling), with separation primarily driven by Romboutsia ilealis and Turicibacter species. Microbiomes were highly cage specific, with cage assignment accounting for more than 40% of the PERMANOVA variance between the groups.DISCUSSIONThese findings highlight a sex‐dependent variation in the microbiomes of hAβ‐KI mice and underscore the importance of considering the microbiome when designing studies that use murine models for AD.Highlights Microbial diversity and the abundance of several species differed in human amyloid beta knock‐in (hAβ‐KI) females but not males. Correlations to Alzheimer's disease (AD) genotype were stronger for the microbiome than the metabolome. Microbiomes from hAβ‐KI mice were distinct from 3xTg‐AD mice. Cage effects accounted for most of the variance in the microbiome and metabolome.

中文翻译：

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AD 基因型与人淀粉样蛋白敲入 (hAβ-KI) 小鼠微生物组之间的性别特异性关联

简介新出现的证据将肠道微生物组的变化与迟发性阿尔茨海默病 (LOAD) 联系起来，因此需要在考虑微生物组的情况下检查 AD 小鼠模型。方法我们使用鸟枪法宏基因组学和非靶向代谢组学来研究人类淀粉样蛋白 β 敲入 (hAβ-KI) ）与野生型 (WT) 小鼠和早发 AD 模型 (3xTg-AD) 相比，LOAD 小鼠模型。结果 18 个月的雌性（而非雄性）hAβ-KI 微生物组与 WT 微生物组不同，AD 发生通过排列多元方差分析 (PERMANOVA)，基因型占方差的 18%。在女性中观察到代谢组多样性差异，但没有个体代谢物丰度存在差异。 hAβ-KI 小鼠微生物组与 3xTg-AD 动物有区别（随机森林模型的准确度为 81%），分离主要由回肠榄仁木和图里奇杆菌属物种。微生物组具有高度的笼特异性，笼分配占各组之间 PERMANOVA 方差的 40% 以上。讨论这些发现强调了 hAβ-KI 小鼠微生物组的性别依赖性变异，并强调了在设计研究时考虑微生物组的重要性使用小鼠模型进行 AD。亮点 人类淀粉样蛋白敲入 (hAβ-KI) 女性的微生物多样性和多个物种的丰度存在差异，而男性则没有差异。 微生物组与阿尔茨海默病（AD）基因型的相关性比代谢组的相关性更强。 hAβ-KI 小鼠的微生物组与 3xTg-AD 小鼠不同。 笼子效应是微生物组和代谢组差异的主要原因。