National Institutes of Health scientists have developed a new mouse model that could help to improve the relevance of these invaluable laboratory test animals to human health and disease, and the development of human therapeutics. The new mice, which the researchers have called “wildlings”, have acquired the microbiomes of wild mice, but retain the genetics of laboratory mice so can easily be modified for research. In two preclinical studies investigating treatments for autoimmune and inflammatory diseases, and sepsis, the immune responses of wildling mice, but not those of regular laboratory mice, mirrored human immune responses. The researchers claim that using the wildlings instead of traditional laboratory mice in the preclinical studies could feasibly have stopped the scientists from moving on to carry out initial human trials that had potentially deadly results.

“We wanted to create a mouse model that better resembles a mouse you’d find in the wild,” said research lead Barbara Rehermann, MD, chief of the immunology section at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)’s Liver Diseases Branch. “Our rationale was that the immune responses and microbiota of wild mice and humans are likely shaped in a similar way—through contact with diverse microbes out in the real world.” The team reports on their development and analysis of the wildling mice in Science, in a paper titled, “Laboratory mice born to wild mice have natural microbiota and model human immune responses.”

Laboratory mice have been invaluable in the study of basic biological processes, but they don’t exactly mirror the biology of wild mice or humans. This is partly due to the difference in physiology and genetics between mice and humans, but also partly because conventional laboratory mice live in environments that are far removed from natural environmental conditions. “Mammals and their immune systems evolved to survive and thrive in a microbial world and behave differently in a sanitized environment,” the scientists pointed out. Wild and laboratory animals thus carry very different populations of microorganisms including bacteria, fungi, and viruses—collectively the microbiome. Even genetically identical lab mice kept in different laboratories will have different microbiota.

“Divergent microbiota contribute to variable and sometimes contradictory experimental results obtained from genetically identical animals …,” the team noted. “A further complication is that conventional laboratory microbiota lack resilience and change in composition upon even minor disturbances (e.g., transfer of mice to a different barrier within the same facility). Collectively this all means that conventional laboratory mice have limited translational research value “ … e.g., the transition from preclinical studies in mice to bedside practice in humans suffers a high failure rate ….”

To generate a mouse model that is more akin to wild mouse with respect to its microbial communities, including natural pathogens, but is easily engineered, the scientists transferred embryos from the common C57BL/6 strain of laboratory mouse into female wild mice (Mus musculus domesticus). The wild mice subsequently gave birth to a distinct colony of C57BL/6 mice, the wildlings.

Researchers harnessed natural microbiota and pathogens to address shortcomings of current mouse models. [Reprinted with permission from Rosshart et al., Science (2019)]

Tests showed that, as hoped, these wildling animals acquired the microbes and pathogens of the wild mice and carried communities of microorganisms that closely resembled those of the gut, skin, and vagina in wild mice. “A healthy microbiome is important not only for the immune system, but also for digestion, metabolism, even the brain,” said lead author Stephan Rosshart, PhD, who recently completed his fellowship in NIDDK and will open a new lab in Germany.

The researchers also demonstrated the stability and resilience of the wildlings’ microbiota across five generations, and in response to environmental changes. When given a seven-day course of antibiotics the regular lab animals’ gut microbiota were disturbed and did not recover after antibiotic withdrawal, whereas the wildlings’ microbiota fully recovered within 14 days of their last antibiotic treatment.

In another set of experiments, the mice were fed a high-fat diet (HFD) for 10 weeks. The dietary change was associated with alterations to the microbiota of both lab and wildling mice, but while lab animals’ microbiota changed significantly and continued to diverge from baseline weeks after the animals were put back on a normal chow diet, the wildlings’ microbiota changed more modestly in response to the HFD, and fully recovered when they were put back on their regular chow diet. “Natural bacterial gut microbiota are more resilient and better adapted to the mouse gut conventional laboratory microbiota,” the authors stated.

They then tested how well the wildlings could predict human immune responses to potential therapeutic strategies. To do this, the authors revisited two sets of preclinical studies in which drugs used to target immune responses in an inflammatory and autoimmune setting, and against sepsis, showed promising results in mice, but resulted in very different life-threatening responses when subsequently tested in humans. To see whether the wildling mice would have responded differently to the regular lab mice used in the original preclinical trials, the researchers treated both wildling and lab mice with the same drugs. The immune responses of the wildlings, but not the lab mice, recapitulated the human responses seen in the clinical trials, which could have informed the developers not to test their treatments in humans.

The image depicts the transfer of natural microbiota from the “Natural World” to the “Laboratory World.” [National Institutes of Health]

“Thus, wildlings better recapitulate human immune responses than conventional laboratory mice in selected preclinical models,” the authors stated. “In both preclinical studies, the wildling model but not the conventional laboratory mouse model phenocopied the response of humans and could have prevented two major failed clinical trials.”

The authors suggest that more widespread research use of wildling mice could improve the validity and reproducibility of biomedical studies. “The wildling model could help us better understand what causes diseases, and what can protect us from them, thus benefitting many areas of biomedical research,” Rosshart stated.

“Given the wide-ranging effects of the microbial genome on host physiology, natural microbiota may benefit different research fields (e.g., metabolism and neurodegenerative diseases) and may also be applicable to other animal models,” the researchers concluded. “Such models may enhance the validity and reproducibility of biomedical studies among research institutes, facilitate the discovery of disease mechanisms and treatments that cannot be studied in regular laboratory mice, and increase the translatability of immunological results from animal models to humans … We anticipate that the wildling model could be used more widely because immunotherapy, in particular with antibody-based drugs, is becoming an increasingly important strategy for the treatment of a wide range of diseases including transplant rejection, graft-versus-host diseases, cancer, infectious diseases, allergies, various autoimmune and inflammatory diseases, and even cardiovascular diseases,” the investigators concluded.

“We always strive for effective ways to shorten the gap between early lab findings and health advances in people, and the wildling model has the potential to do just that,” said NIDDK director Griffin P. Rodgers, MD. “By helping to predict immune responses of humans, the wildling model could lead to important discoveries to help treat and prevent disease, and ultimately, improve human health.”

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