Today we know that the phenotype of all mammals - from rodents, to non-human primates to humans - is driven by the metagenome, the combination of the host genome and the microbial genome. In the natural world, the microbiomes of free-living mammalian organisms, including wild mice and humans, co-evolved with their respective hosts under evolutionary pressure in regard to inflammatory immune stimuli such as infectious pathogens, but also toxins and mutagens. Based on the hypothesis that natural microbiota shaped by evolution in a challenging environment promote the fitness and survival of their host, upon whom they depend, we propose that standard laboratory mice lack physiologically important microbes present in natural microbiota and absent in laboratory microbiota and that this may limit their ability to model complex diseases of humans and other free-living mammals.
The aim of this study was to identify a naturally evolved reference microbiome to better recapitulate physiological phenomena relevant in the natural world outside the laboratory. Among 21 distinct mouse populations worldwide we identified a closely related wild relative to standard laboratory mouse strains. Its bacterial gut microbiome differed significantly from its laboratory mouse counterpart but could be transferred to and maintained in laboratory mice over several generations. Thus, we have established a mouse model that combines the tractable genetics of regular laboratory mice with the gastrointestinal microbiota of wild mice. Laboratory mice reconstituted with natural microbiota exhibited reduced inflammation and increased survival following influenza virus infection, and improved resistance against mutagen/inflammation-induced colorectal tumorigenesis. By demonstrating the host fitness-promoting traits of natural microbiota, these findings should enable the discovery of protective mechanisms relevant in the natural world and improve the modeling of complex diseases of free-living mammals.
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