Sex‐specific associations between AD genotype and the microbiome of human amyloid beta knock‐in (hAβ‐KI) mice

INTRODUCTION Emerging 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. METHODS We 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). RESULTS Eighteen‐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. DISCUSSION These 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.