Correct mice

Make the lab mouse more wild

Maxim Rousseau, Polit.roo

Laboratory mice perform an important service: numerous medications and other treatments are tested on them, which are then intended for humans. However, it happens that a drug that has successfully passed preclinical trials (in mice), then cannot show the same results in clinical trials (in humans).

One possible explanation for this difference is that the effect of the drug is influenced by the microbiome – a collection of bacteria, fungi, protists and viruses that live on the body of an animal and a person and inside the body. In laboratory mice and humans, it can differ significantly. Differences in microbiota diversity, resistance and the presence of pathogenic microorganisms between laboratory animals can also lead to limited reproducibility of animal experiments when trying to repeat them in different laboratories. The use of new wild mice each time will not solve the problem, since many studies require specially bred mice with the necessary genetic properties, and the mice participating in the experiment must be genetically homogeneous (belong to the same lineage).

Now a large group of American scientists has published a paper in the journal Science (Rosshart et al., Laboratory mice born to wild mice have natural microbiota and model human immune responses), which proves that laboratory mice, carried out and born by surrogate parents caught in the wild, serve as a more reliable model in research in the field of immunology. The initiator of the new method was the immunologist Stephan Rosshart from the National Institute of Diabetes, Diseases of the Digestive System and Kidneys of the USA (now he works at the University of Freiburg).

Since mammals inherit the original composition of their microbiota from their mother, the scientist decided to plant embryos of laboratory mice to surrogate mothers caught in nature. Thus, according to his plan, the diversity of microbiota characteristic of wild mice will be combined with the genetic homogeneity of laboratory animals. To collect future surrogate mothers, he has been setting traps at several horse farms in Maryland since 2014. When the number of mice caught exceeded two hundred, the researcher began the first experiments.

He planted embryos of laboratory mice in wild females and found out whether the "microbial profile" of newborns would become closer to the natural one. Indeed, the species composition and the number of microorganisms in the intestines, on the skin and genitals of these mice correspond to those that mice have in nature.

To assess how well such mice will simulate human immune responses, scientists reproduced two studies on them that previously gave good results on laboratory mice, but then failed when tested on humans. In one of them, in 2006, antibodies that had an anti-inflammatory effect in the body of laboratory mice almost killed healthy human volunteers at the first stage of a clinical trial. When these antibodies were now injected into mice born to surrogate wild mothers, they died, while laboratory mice from the control group, as expected, survived.

Another drug, the study of which was reproduced by the authors of the work, was supposed to help with sepsis. In laboratory mice, it did increase survival, but when switching to human testing, it had the opposite effect. When it was given to mice with an approximate natural microbiota, everything happened again: these mice died more often than the control individuals. Both of these experiments prove that such mice can be a more accurate model of the human immune response in preclinical drug trials.

The authors of the work also decided to test whether their mice would be able to preserve their microbiota of wild mice while living in laboratory conditions. Scientists treated these mice with antibiotics and changed their diet. After that, it turned out that the number and proportions of bacteria both on the surface of the body and in the body changed less dramatically than in laboratory mice that were exposed to the same effect. And soon the bacterial population recovered. Mice born to wild mothers preserved their wild microbiomes for several generations and even transferred their microbes to mice that were grown in the laboratory (this happened due to the typical eating of each other's feces for mice).

Scientists are confident that the method they have developed for growing laboratory mice has great prospects for improving the quality of research. They explain that it is not necessary to catch wild mice in nature every time. It is enough to keep a "wild colony" in your laboratory and from time to time update the microbiota by adding mice from nature there.

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