Gut microbes from wild mice help make lab mice healthier.

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How gut bacteria saved ‘dirty mice’ from death

Even if you’re a clean freak, it’s hard to escape a decade of discoveries that some of the microbes naturally residing in your body—your microbiome—help keep you healthy. Researchers aware of this reality have now shown that transplanting gut bacteria from wild mice into “clean” lab mice has made those rodents less likely to die from the flu or develop cancer. The findings could usher in lab mice equipped with different kinds of bacteria to reflect real-world conditions.

“We might be able to make a better set of laboratory mouse models … [that] would be more predictive of human disease,” says John Wherry, an immunologist at the Perelman School of Medicine at the University of Pennsylvania, who was not involved in the study.

Today’s lab mice are raised in sterile conditions, often free of any infections. This makes it easier to get reproducible results. “It’s unquestionable that major medical advances have been discovered in hyper-hygienic mice,” says David Masopust, an immunologist at the University of Minnesota in Minneapolis who, with fellow immunologist Stephen Jameson, recently began exploring the possible advantages of “dirty” lab mice. Concerned that the immune systems of clean mice might not be good proxies for the human immune system—no human is brought up in such clean conditions and fed such clean food—they housed lab mice with mice from a pet store. The lab mice that survived exposure to the bacteria and viruses of the pet store rodents had stronger immune systems, suggesting to Masopust and Jameson that such dirty mice might be better for testing the safety of vaccines and new drugs.

Now, immunologists at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, have contaminated lab mice in a different way: by giving them gut bacteria from wild mice. Barbara Rehermann and Stephan Rosshart first collected 800 wild house mice (Mus musculus domesticus) in the Washington, D.C., metro area, and compared their DNA and gut bacteria both with a lab mouse strain and with wild mice from all over the world.

The gut bacteria from the wild mice were fairly similar, but the microbiomes of the lab mice were significantly different, with fewer Bacteroidetes and Proteobacteria, for example. The researchers then transplanted the gut bacteria from healthy, wild Maryland mice (which were most similar genetically to the lab mice) into the lab mice. They used only wild mice donors that had not had any obvious infections, so the researchers could assess the impact of a natural microbiome as opposed to the impact of transferred rodent pathogens.

Rehermann and her colleagues then exposed offspring of the microbe-receiving lab mice to a flu virus and to conditions that would normally cause colon cancer. They repeated the experiment for three more generations of those mice, all of which retained a stable version of the same wild microbiome. Altogether, about 92% of the “dirtied” mice survived the flu, compared with just 17% of “clean” lab mice, the researchers report today in Cell. The “dirty” mice also had fewer tumors and less severe cancer. With this approach, “you combine the best features of both mice,” Rosshart says. “They have the genetics of lab mice, but they also have a microbiome from the outside world that promotes fitness.”

“The microbes have a significant effect on the immune system,” says Jameson, who was not involved with the new study. Because wild mice are constantly exposed to germs and other environmental insults, he adds, they carry microbiomes that have evolved to help their hosts cope with these problems, seemingly making the immune system less reactive to harmless microbes and other environmental insults, yet more reactive to other, potentially deadly ones. Human microbiomes and immune systems have similarly coevolved, the researchers note. With these dirty mice, then, it may be possible to study how the microbiome helps its host have a better immune system.

But Wherry cautions that the dirty mice may simply be better models for studying wild mice, not human disease. Masopust agrees, noting that the study never explored whether the dirty mice were better mimics of the human immune system. Still, he says, the findings should encourage scientists to be “thoughtful” about how they maintain their laboratory mice.