While trying to improve cancer immune therapy, researchers unexpectedly produced the most accurate mouse model to date of inflammatory bowel disease (IBD).
IBD is a group of conditions that afflict approximately 1.4
million Americans with abdominal pain, constipation and diarrhoea. The two most
common forms of IBD are Crohn's disease and ulcerative colitis (UC), which can
be fatal in extreme cases.
The mouse model, developed by Thaddeus S. Stappenbeck, M.D.,
Ph.D., assistant professor of pathology and immunology and of developmental
biology and his colleagues, closely resembles the most serious form of human UC
that is uniformly fatal.
However, the scientists were able to successfully treat the
mice with a pair of broad-spectrum antibiotics, easing gut inflammation and
"The antibiotics we gave the mice were used
individually in unsuccessful clinical trials as ulcerative colitis treatments,
but now we have colleagues who are thinking of giving combined therapy an
informal try. The antibiotics probably won't be a cure by themselves, but they
may provide us with a potent new approach to combine with other
therapies," said Stappenbeck.
With the help of these mice, the scientists can learn which
species of gut microorganisms are getting involved in battles with host immune
systems, initiating UC symptoms. This information could allow the development
of stronger and more specific treatments.
The mouse model was created by crossbreeding two mouse lines
developed for cancer immune therapy research. Each mouse line had one protein
knocked out that restrained immune T cells from shifting into attack mode.
"The idea was to see if we could create super killer T
cells we could use to attack tumors. But all the mice became sick early on,
started to lose weight and we soon realized that they all had serious
gastrointestinal issues," said one of the co-authors of the study.
"I've looked at quite a few proposed mouse models of
IBD, and I recognized right away that this had the potential to be outstanding.
The colons of the mice were incredible. They were filled with inflammatory T
cells. We found the mice almost exactly replicated the most acute types of
ulcerative colitis ," said Stappenbeck.
It was found that the mice constantly developed
gastrointestinal problems within a short time period and at a predictable point
in their lifespan, unlike prior models of IBD. After the mice were treated at
three weeks with the antibiotics ciprofloxacin and metronidazole, it was
discovered that colon inflammation was reduced and the mice were able to gain
weight and survive longer.
According to the scientists, IBD is caused when host immune
system damages the tissues of the gut while mistakenly attacking food and gut
microorganisms that aid food digestion. However, it is difficult to sort out
which species are being attacked by the immune system as there are an estimated
500 different species of microbes living in the gut.
The new model may considerably ease this difficulty. Even
though the dual antibiotics used to treat the mice are broad-spectrum, they
were unable to sterilize the guts of the mice, indicating that the treatment
happened to eliminate the microorganisms causing IBD.
"We'd like to treat the mice and then reintroduce
candidate microorganisms into their guts to see if this restarts the
inflammatory reaction," said Stappenbeck.
The results of this study were reported in Public
Library of Science-Medicine.