Replacing laboratory mice's gut microbiomes with the microbial communities of their wild counterparts alters the lab animals' immune systems and boosts their resistance to colorectal cancer development and influenza.

Despite the many therapies that owe their foundation to findings in mouse models, there's a growing appreciation among scientists that typical lab mice—and, more specifically, the effects of their sterile environs—do not always accurately reflect real-world diseases. Now, a recent study has found that simply replacing their gut microbiome with the microbes of wild mice alters the animals’ immune response, perhaps for the better (Cell 2017;171:1015–28).

The lab mice who received a microbial boost from their wild counterparts were more resistant to inflammation-driven diseases, the authors report, including colorectal cancer and flu.

“Our starting hypothesis was that in nature, the microbiome has co-evolved with its host for millions of years and probably has beneficial health effects that we do not see in laboratory mice,” says study author Barbara Rehermann, MD, of the National Institute of Diabetes and Digestive and Kidney Diseases.

To test that hypothesis, the authors trapped more than 800 wild mice in barns in eight different locations around Maryland and Washington, DC. They characterized the gut microbiota of 98 of these mice using ribosomal RNA profiling and found that the barn animals’ microbiomes, though similar to each other, were very different from those of the laboratory mouse strain C57BL/6. The lab animals’ microbiomes were less complex and were deficient in certain bacterial species present in the wild animals, chiefly Bacteroidetes and Proteobacteria.

The researchers isolated wild gut microbiomes and those from laboratory animals and transplanted them into separate groups of laboratory mouse pups reared without microbes. Using a chemical mutagen and a colitis-inducing compound to trigger colorectal cancer, the researchers found that mice with wild microbiomes developed fewer and smaller tumors than those with lab-derived microbiomes. The wild microbiomes also appeared to be protective against influenza—an intranasal injection of the virus killed 83% of the lab microbe–bearing animals, but only 8% of those with wild bacteria on board.

Although the study did not investigate the exact immunologic mechanism behind these differences, “that this extremely diverse microbiota had protective effects [against tumorigenesis] was actually extremely interesting and calls for further in-depth analysis,” says Mathias Heikenwälder, PhD, of the German Cancer Research Centre in Heidelberg, who was not involved in the study.

The findings do not imply that all researchers should add wild microbiomes to their mouse models, says Stephan Rosshart, MD, first author of the study. However, for translational research, he and Rehermann believe the “chimeric meta-organism” they've created not only maintains many of the benefits of the traditional laboratory mouse, but may be more reflective of humans, who also have complex and diverse microbiomes. So far, the transplanted microbiomes have proven to be stable in the lab animals for four generations, even under typical laboratory conditions.

“There is no equivalent in the human population” to lab-reared mice, says Rosshart. “We thought we could preserve everything that is great about the laboratory mouse and optimize it by giving one part back, which is a natural microbiome.” –Rachel Tompa

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