If you follow research on IBD, sooner or later you see news about a ‘cure’ or ‘breakthrough’ treatment that gives you hope — then learn it was only tested in mice. For example: “This fish and chip STAPLE could CURE a painful bowel condition.” (hint: it’s vinegar.)
There are plenty of these stories: fecal transplants ‘cured’ colitis; a leukemia drug ‘reversed’ colitis symptoms; a ‘breakthrough’ gel binds to bowel ulcers. The one thing they all have in common: they were only tested in mice.
So you might wonder: why is STAPLE capitalized, too? But also, what doesn’t cure colitis in mice? And most importantly: is colitis in mice really all that similar to Crohn’s disease & ulcerative colitis?
The answer to the last question is… maybe. Researchers have several ways to give mice colitis, and some are more similar to human IBD than others. Mice have helped us learn a great deal about human IBD, but many therapies that showed promise in mice have been disappointing in humans.
Researchers give mice colitis in four basic ways: first, they give the mice chemicals that damage their intestines. This is the cheapest and easiest way. The most common chemical used is dextran sulfate sodium (DSS), which damages the gut lining, allowing leakage, and thus produces weight loss, bloody stools, and diarrhea.
Other chemicals used include trinitrobenzene sulfonic acid(TNBS), oxazolone, and acetic acid. While DSS produces UC-like symptoms, TNBS produces Crohn’s-like symptoms. Acetic acid, by the way, is the main ingredient in vinegar — but apparently it also cures colitis in DSS mice. (Yay… science!)
The second way researchers give mice colitis is the natural way: the mice just happen to have colitis. Mice are bred for science very carefully — like pedigreed dogs — to make sure they have the right traits for specific research. In some of these pedigrees, the mice develop colitis on their own. Those mice make handy research subjects, but often it’s easier just to give healthy mice DSS.
The third way is to take mice bred to be immunodeficient, and then inject them with immune cells. These mice are called SCID mice, and are born without functioning immune systems; when researchers inject them with CD4+CD25− T cells — a kind of white blood cell — the mice develop intestinal inflammation. If they give them CD4+CD25+ T cells, the mice get better.
The fourth way is by using ‘knock-out’ techniques to change the mouse’s immune system. In this technique, researchers have used genetic engineering to delete genes, which then leads to intestinal inflammation. The genes involved are usually for cytokines — chemicals that the immune system uses as signals to start or stop inflammation.
These last three types of mice — natural mutations, immunodeficient, and knock out — have helped scientists understand the role of the immune system, cytokines, and genetics in human forms of inflammatory bowel disease. All types of colitis mice have helped emphasize the importance of the microbiome: if the mice are raised in sterile conditions, they never develop inflammation. This is because bacteria and other microbes in the gut are necessary for colitis in mice.
Mice have also helped us better understand the role diet plays in gut inflammation. For example, DSS mice have helped scientists understand how high-fat diets make colitis worse. Researchers have also found that dietary iron — something many people with IBD are told to take as a supplement — can make colitis worse in mice treated with DSS. Of course, this research still needs to be tested in humans before we know for sure.
That said: for all the good these little critters do us, there are still limits to what a mouse can tell us about IBD in humans. For example, IL-10 therapy was very promising in mice — but showed little effect in humans. Stem cell transplantation was very effective in mice — but not in humans. Nicotine helps DSS mice — but the evidence in humans is mixed for UC, and zero for Crohn’s. Not everything that cures colitis in mice will help in humans. Many of the headlines that trumpet these ‘breakthroughs’ are only scientific clickbait, so don’t let your hopes get away from you.
So the next time you see a headline trumpeting a ‘cure’ for colitis, read it again and add “in mice” to the end. If it sounds disappointing, that’s because it probably is. Mice are good little helpers in the fight against IBD, but their help only goes so far.
The main papers used in this post include:
Boismenu, R.; & Y. Chen. “Insights from mouse models of colitis.” Journal of Leukocyte Biology 67 (March 2000), pp. 267 – 278. Found at Sci-Hub.
Low, D.; Nguyen, D.D.; & Mizoguchi, E. “Animal models of ulcerative colitis and their application in drug research.” Drug Design, Development, & Therapy 7 (Nov 2013), pp. 1341-1357. Available free on PubMed.
Wirtz, S; et al. “Chemically induced mouse models of intestinal inflammation.” Nature Protocols 2:3 (2007), pp. 541-546. Found on Sci-Hub, and definitely worth checking out for the mouse colonoscopy pictures. That’s someone’s job, right?
Photo “Lab Mouse” by Flickr user Global Panorama used by Creative Commons license.