We might have better lab mice if we paid more attention to their guts

Wild microbes are better than tame.

Two white laboratory mice inside the cage, very shallow focus

Before any medication, vaccine, or other drug therapy reaches human use, it goes through extensive testing in the lab—often in animals, and typically in mice. This step in the evaluation process is extremely important. The way a drug affects a cluster of cells in a Petri dish often has little to do with the way it will behave inside a living organism, where multiple organ systems are at play.

Mice, being mammals, have a physiology relatively similar to our own, so their reactions to drugs often are as well. But that’s not always the case.

In a study out today in the journal Cell, researchers say they’ve figured out one possible reason for this variation. Their microbiomes—the collection of bacteria in animal guts that scientists are currently obsessed with—vary wildly depending on whether they were raised in the lab or in the wild.

So their gut microbes are different, what’s the big deal? The microbes that live in our intestines aren’t just there because it’s cozy; they also do a lot for our health. They help digest the food we eat, of course, but they also influence how our immune systems react to various infectious bugs and pathogens, as well as other diseases like cancer. And recent research suggests that they might also play a role in even lesser understood conditions like Alzheimer’s and autism.

The researchers wanted to figure out just how big of a difference this change in microbiome could have. So they exposed two groups of mice—mice with typical lab microbiomes and lab mice with microbiomes resembling those seen in the wild—to a high dose of the influenza virus. Turns out, 92 percent of the lab mice with wild microbiomes survived the infection whereas only 17 percent of the lab mice with typical lab mice microbiomes did.

They also induced other diseases, including colorectal tumors. The lab mice with wild microbiomes had fewer and less severe tumors than those with the lab microbiomes.

“We hypothesized that this might explain why laboratory mice, while paramount for understanding basic biological phenomenon, are limited in their predictive utility for modeling complex diseases of humans and [other mammals],” says Stephan Rosshart, a fellow at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and an author of the study.

Rosshart and his colleagues also showed that they could isolate the microbiomes found in wild mice and introduce them into laboratory mice, meaning that they could, in theory, do future experiments on mice with these wild gut bacteria. However, Rosshart and Barbara Rehermann, lead author of the study and director of the immunology section at NIDDK, say that’s not the ultimate goal. Rather, they say, researchers should use the wild microbiome as an additional component to their research. By directly comparing the two groups to other disease processes, like the researchers did in this case, the results could help pinpoint more exactly what protective mechanisms the wild bacteria have.

They also think a better understanding of mice gut microbiomes could help researchers figure out why they are sometimes unable to reproduce certain experiments. For example, if two scientists from different institutions order the same genetically identical mice from the same place, those two animals should have the same response to a particular drug, but they often don’t.

That could be because the mice go through different environments en route to their new homes, which can alter the diversity of bacteria in their guts. This difference could alter the outcomes of the studies that the researchers do on them.

Rosshart says that wild or natural microbiomes are likely more resilient to small environmental changes like a temporary modification in housing. That’s because this collection of bacteria often have a higher diversity of microbe species. That makes it harder for one bacterial strain to take over and wreak havoc on the fragile ecological system.

Mouse studies are crucial to drug and vaccine development. Since they are the step directly before human testing, their effectiveness is even more critical. It is imperative that scientists come to understand why mouse models react the way they do.