Wild Mouse Gut Microbiota Promotes Host Fitness and Improves Disease Resistance

Today we know that the phenotype of all mammals
from rodents to non-human primates to humans is driven by the metagenome. The metagenome itself is the combination of
the host genome and the microbial genome, also known as the microbiome. 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 regards to inflammatory immune stimuli such as infectious
pathogens but also toxins and mutagens frequently encountered in the natural world. In our study, we hypothesize that natural
microbiota shaped by evolution in a challenging environment, promote the fitness and survival
of their hosts upon whom they depend. These conditions dramatically changed when
wild mice, the source of all current laboratory mice, were removed from their natural habitat
and transferred into an ultra-clean laboratory environment. Importantly, wild mice were germ-free, rederived
to cleanse them from microbes and pathogens and recolonized in a restrictive laboratory
environment, leading to the loss of their natural microbiome and its positive impact
on health. Thus, we hypothesize that laboratory mice
lack physiologically important microbes present in natural microbiota and absent in laboratory
microbiota. Since the microbiome is an important part
of the phenotype defining mammalian meta-genome, laboratory mice can be regarded as a laboratory
meta organism with a specific physiology that only exists in the laboratory world and that
is very different from the natural meta-organism and its associated physiology, including responses
to infectious diseases. This might explain why laboratory mice, while
paramount for understanding basic biological phenomena, are limited in their predictive
utility for modeling complex diseases of humans and other free-living mammals. So, we decided to give laboratory mice back
what they have lost: a naturally co-evolved wild mouse gut microbiome. We identified a closely related wild living
kin to current laboratory mouse strains by looking at the genetics of wild mice trapped
in multiple locations across the globe. The natural gut microbiota of suitable donor
mice, were characterized and viably preserved for the subsequent transfer. As donors, we selected gut microbiota of wild
mice that tested negative for all currently known mouse pathogens. This approach allowed us to exclusively study
the effects of natural microbiota on host physiology, and not the effects driven by
infections. To achieve an efficient engraftment, pregnant
germ-free mice were reconstituted with natural gut microbiota of wild mice, leading to a
colonization of the mother, thereby allowing vertical microbiome transfer to newborn pups
and enabling microbiota mediated effects on the pups before and after birth. Thus, we have created a chimeric meta-organism
that combines the best features of both worlds, fitness promoting microbes of natural microbiota
and tractable genetics, an extremely important research tool of laboratory mice. These animals were subsequently used for breeding
and experiments. We hypothesize that natural microbiota promote
hosts fitness in regards to naturally occurring inflammatory stimuli like infectious diseases,
and toxins, and or mutagens. Indeed, when we challenged our chimeric mice
with an influenza dose lethal for almost all laboratory mice, they were protected and survived. This was associated with significantly reduced
inflammation in the lung. Likewise, when the mice were subjected to
a treatment that induces inflammation and mutagenesis in the colon, they had a much
lower tumor burden than standard laboratory mice. Thus, they were protected in two disease models
relevant to humans. We propose that creating animal models with
natural microbiota enables the discovery of protective mechanisms relevant in the natural
world and absent in current laboratory animals. Consequently, natural microbiota should increase
the predictive utility of laboratory mice for modeling complex diseases of free-living

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