Extensive culturing and metagenomics enable functional and taxonomic comparison of mouse and human gut microbiotas

Abstract The gut microbiota has been identified as a leading cause of irreproducibility in mouse models, but current resources are insufficient to address this core challenge in immunology research. Furthermore, although mouse models are central tools for biomedical science, it is not known how the bacteria in the mouse gut – important determinants of immunological phenotypes – affect their ability to recapitulate human disease. To better characterise the mouse gut microbiota and facilitate its functional and taxonomic comparison to the human microbiota, we developed the Mouse Microbial Genome Collection (MMGC), the most comprehensive representation of the global laboratory mouse microbiome to date. The MMGC is a repository of 276 genomes from cultured isolates and 18,075 non-redundant, near-complete metagenome-assembled genomes (MAGs) reassembled from 1,960 mouse metagenomes. Using the MMGC, we define species-level signatures of inter-institutional variation in the mouse gut microbiota and provide a roadmap to achieve more relevant and reproducible mouse models. In addition, we confirm that while only 2.65% of bacterial species are common to human and mouse gut microbiotas, over 80% of annotatable functions are shared between hosts. The MMGC further enables the identification of functionally equivalent taxa in the mouse and human gut microbiotas, which we illustrate by comparing the pathways for butyrate synthesis and drug metabolism as proof-of-concept examples. In conclusion, the MMGC facilitates unprecedented insights into the mouse gut microbiota and enhances the use of mouse models in immunology research by providing access to the conservation status and taxonomic locations of microbial functions of interest.