Lab Mice Point to Diarrhea Cause

When a family of genetically modified mice started dying in a Harvard School of Public Health lab, researchers were puzzled.

“How come you have so many cages of these mice breeding but don’t seem to have enough mice to do experiments?” Laurie Glimcher, a professor of immunology at the School of Public Health, recalled asking.

It turned out they had all contracted a lethal, bloody form of diarrhea.

That macabre discovery pointed the scientists to a key cause of an intestinal disease called ulcerative colitis.

The disease, which afflicts half a million Americans, has symptoms ranging from cramps to rectal bleeding and even potentially lethal swelling of the colon.

The mice had been genetically altered to lack a protein called ‘T-bet,’ which the researchers now believe acts as a ‘peacekeeper,’ preventing harmful bacteria from breaching the single layer of cells which protects the rest of the body from the microbe-infested gut.

“You could already see by looking at the intestine under the microscope that bad things were happening by three, three-and-a-half weeks of age,” said Glimcher, who authored the study. “A hundred percent of the mice got the disease—a very aggressive disease. We pretty much had to euthanize the mice by the time they were 12 weeks of age.”

The study, published yesterday in the journal Cell, said the mouse model of the disease will be a fertile testing ground for new colitis treatments in humans.

While a variety of treatments, such as steroids and anti-inflammatory agents, currently exist, they generally target only symptoms, according to Wayne I. Lencer, the chief of gastroenterology at Children’s Hospital and an associate professor at Harvard Medical School.

The study found that the mutant mice could also transmit the disease to other mice through feces, suggesting the genetic defect encourages the growth of aggressively infectious bacteria.

Glimcher said her team had not identified the bacteria responsible but was pursuing that line of research.

She also noted the possibility of using the mutant mice to study colon cancer, which long-term colitis patients have a heightened risk of developing.

—Staff writer Clifford M. Marks can be reached at cmarks@fas.harvard.edu.