New approach to boost reliability of findings from animal experiments

Researchers transfer natural gut microbiome to laboratory mice, making them more robust against slight differences in the conditions in which they are held

Many findings in medical research come from experiments with mice. However, other working groups often fail to reproduce results gained in one particular laboratory. Researchers led by Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) in collaboration with the universities of Duisburg-Essen and Freiburg and the Helmholtz Centre Braunschweig have now presented one possible solution to this problem: they have transferred a largely natural gut microbiome from wild mice to laboratory mice. This is thought to be considerably more robust against small differences in conditions in which the animals are kept. The transplantation also led to the rodents’ immune defenses becoming more mature, thereby resembling the immune system of wild mice and adult humans. The results have been published in the journal Nature Communications.*

The first laboratory mice were bred approximately one hundred years ago. They descend from house mice. Over many generations, siblings were bred exclusively with each other. The result: the rodents’ genetic make-up is virtually identical. This means that in experiments, if differences are found between the test animals and the control group, they cannot be explained by differences in their genetic make-up. “In principle, this makes the animals the perfect subject for clarifying medical questions,” stresses principal investigator Prof. Dr. Stephan Rosshart, Professor of Microbiomics at FAU and head of the Department of Microbiomics Research at Universitätsklinikum Erlangen (UKER).

In order to avoid external influences from distorting the results of experiments like this, conventional laboratory mice are generally reared under predominantly sterile conditions. However, this procedure has two major disadvantages: First, rodents are unable to develop a mature immune system. Their immune cells behave differently from their relatives in the wild or in humans. That restricts the transferability of findings gained in experiments. For example, an active substance may prove to be extremely effective in laboratory mice, but fail completely in studies on humans.

Sensitive microbiome

The second disadvantage concerns the microbiome. This refers to the microorganisms that live on the mice’s skin, in their mouths or in their gastrointestinal tract. As the animals only come into contact with a very restricted range of bacteria, their microbiome differs significantly from that of their relatives living in the wild. It is also extremely sensitive: “Even small changes in the conditions in which the animals are kept can dramatically alter the make-up of the microorganisms,” says Rosshart.

Animals held in two different laboratories in the same city may have completely different microbiomes. The problem is that this can have a major influence on the results of experiments. Indeed, it may be one of the reasons for a phenomenon referred to in specialist jargon as “the “reproduction crisis”: it is often the case that results gained in one particular laboratory cannot be reproduced by other working groups.

Wild house mice as surrogates

In 2019, Rosshart, who was working at the time in the US, invented “wildlings” by using house mice as “surrogates” and implanting laboratory mouse enzymes into them. After their birth, the young animals had a microbiome resembling that of wild mice. Furthermore, the wildlings had an immune system comparable to the human immune system, increasing the relevance of the collected data for humans. In the current study, the team led by the researcher from Erlangen has now simplified and standardized the process to solve the problem posed by the reproduction crisis. “We isolated the microorganisms from the gastrointestinal tract of a wildling and transferred it via a tube to the stomach of a conventional laboratory mouse,” explains Rosshart.

Not only this mouse, but also the four mice kept in the same cage all developed a microbiome resembling that found in wild mice in just a few days. The researchers were able to show that it is extraordinarily stable. After all, the natural microbiome has evolved and optimized over time. The microorganisms found in wild mice are largely the same, even if you compare animals from the USA and Germany. It is therefore hoped that experiments using mice treated with the newly developed process should deliver reproducible results.

Transplanting the microbiome also caused the rodents’ immune system to mature. It then resembled the immune system of wild mice and adult humans. This may lead to experiments with these animals delivering more realistic results than those using mice reared in sterile conditions. “We can freeze the microbiome gained from wildlings and send it to interested laboratories across the globe,” explains Rosshart. “It is then very easy to transfer the bacteria on site to a large number of animals. We hope that this will establish a type of standard microbiome for laboratory mice, thereby improving the reproducibility and general validity of global biomedical research.”

*DOI: https://doi.org/10.1038/s41467-025-60554-2

Reference to the study from 2019: https://doi.org/10.1126/science.aaw4361

Further information:

Prof. Dr. Stephan P. Rosshart
Professorship for Microbiomics
Phone:+499131/85-45277
Stephan.Rosshart@uk-erlangen.de