Germ-free mice have been used widely during the last decade for studying the relevance and effect of resident bacteria on host physiology and pathology. Experimental data using animals with controlled gut colonization have identified three main primary functions of the gut microbiota: a) metabolic activities that result in salvage of energy and absorbable nutrients; b) protection of the host against invasion by foreign microbes; and c) trophic or structural effects on both intestinal epithelium and immune system.
A new study, led by Dr. Barbara Rehermann from the Immunology Section, Liver Diseases Brand, of the National Institutes of Health’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (Bethesda, USA), has found that laboratory mice that are transplanted with the gut microbiota of wild mice are less likely to die from a flu virus infection or develop colorectal cancer than laboratory mice with their own gut microbiota.
First of all, the researchers caught 800 wild house mice (Mus musculus domesticus) in the Washington D.C. metro area and compared their deoxyribonucleic acid (DNA) and gut microbiota with both a common strain of laboratory mouse, which was called C57BL/6 and was obtained from different sources.
In order to find an appropriate source for an external natural microbiome reference for standard laboratory mouse strains, the researchers selected wild type in 8 geographically distinct locations in Maryland and 21 wild mouse populations from Europe, Asia, and the Americas. Wild Mus musculus domesticus from Maryland were close relatives to standard laboratory mouse strains and the gut microbiomes between them differed significantly.
On the whole, there were 3 groups of mice: 1) Pregnant germ-free laboratory mice that were transplanted with the gut microbiota of healthy wild Maryland mice; 2) Pregnant germ-free laboratory mice that were transplanted with the gut microbiota of regular laboratory C57BL/6 mice; and 3) Laboratory mice that maintained their original gut microbiome.
In the fourth generation, the mice still carried either the wild gut microbiomes or the control laboratory microbiomes that had been transferred vertically from their mothers.
When researchers exposed offspring of the microbe-receiving laboratory mice to a high dose of influenza virus, about 92% of the laboratory mice with wild gut microbiomes survived, while only 17% of laboratory mice and mice in the control group survived.
Furthermore, when laboratory mice received the wild gut microbiota and were exposed to conditions that would normally cause colon cancer, they had fewer tumours and less severe cancer, whereas the other mice had a greater number of tumours and more severe disease. Reduced inflammation was the beneficial mechanism by which the wild gut microbiota led to less incidence of colon cancer.
Based on these results, the researchers suggest in the paper that by restoring the natural microbial identity of laboratory mice it might be possible to create laboratory mouse models that would be more predictive of disease in humans and other free-living mammals.
According to the authors: “The immunological benefits from the wild mice’s gut bacteria may, in part, explain a persistent problem in disease research as disease experiments in lab mice turn out very differently in humans or other animals”.
It is noteworthy to mention that a previous study also found that housing laboratory mice with mice from a pet store for 2 months resulted in a shift in baseline immune profile from that resembling a newborn baby to a profile closer toward that of an adult human (by increasing number and diversity of subsets of specialized T cells), increased immune response against Listeria monocytogenes, and altered T-cell differentiation in response to a de novo viral infection – leading together to lab mice with a stronger immune system.
In conclusion, environment has effects on the immune state and host response to infection and cancer, which suggests that restoring physiological microbial exposure in laboratory mice could help scientists discover protective mechanisms relevant to complex diseases in free-living organisms, including humans.
Although these results open a new approach for using wild mice as an appropriate model for human diseases, we still do not know whether genetic characterization of mice has been lost due to epigenetic changes induced by gut microbiota colonization and this could not make clear that wild mice are the best way for understanding human disease development.
Rosshart SP, Vassallo BG, Angeletti D, et al. Wild mouse gut microbiota promotes host fitness and improves disease resistance. Cell. 2017; doi: 10.1016/j.cell.2017.09.016.