Uncharacterized bacterial species in the mouse microbiome are quantified with a novel pipeline and shown to be the responsible for most diet induced perturbation

The adoption of mouse models to study the role of the microbiome for host health is invaluable, although shotgun metagenomic analysis can profile only a very limited fraction of the microbiome diversity in mice compared to that in humans. We evaluated the ability of a recent metagenomic profiling method called MetaPhlAn 4 which includes 22,718 MAGs from mouse in its reference database. We combined a newly sequenced cohort of 97 mouse microbiome samples with public mouse studies (N=622 samples) and tested the potential of MetaPhlAn 4 to improve the identification of diet-related changes in the host microbiome via a meta-analysis approach. We found multiple, strong, and reproducible diet-related microbial taxonomic biomarkers in the mouse microbiome, largely increasing those identifiable by other available methods (~2.5 times more species than MetaPhlAn 3). The strongest drivers of the diet-induced changes in the mouse microbiome were mostly uncharacterized taxa without isolate sequencing or taxonomic assignment, confirming that the newly profiled microbes may add substantial information to current metagenomic analyses.