Inflammatory bowel disease can occur at any age and is more common among adults. However, about 25% of cases develop in individuals18 years or younger, and some of these cases are early-onset ulcerative colitis. Children who develop the disease are at an increased risk of developing colon cancer. In addition, they may suffer from liver damage because the inflammation caused by the disease results in a narrowing of the bile ducts that connect to the liver. A research team from the David Geffen School of Medicine at UCLA and Pusan National University in South Korea have identified genetic factors involved in pediatric ulcerative colitis; the findings may lead to new approaches for prevention and treatment. The study was published online on September 3 in the journal Gastroenterology.
The research team conducted a mouse study that identified possible new targets for prevention and treatment strategies for early-onset ulcerative colitis. They developed a rodent model that simulates the disease that can be used to help test new drugs that can be used for treatment. “We hope that identifying these key genetic factors and providing a unique research model will help lead to new approaches to treat early-onset ulcerative colitis, a devastating disease that currently has no cure,” explained senior author Dr. Sang Hoon Rhee, an associate adjunct professor of medicine in the Division of Digestive Diseases at the David Geffen School of Medicine at UCLA.
“We knew that interleukin 10 played a role,” explained first author Dr. Eunok Im, an assistant professor at Pusan National University’s School of Pharmacy. He added, “But recent clinical and experimental evidence indicated that in addition to this protein’s crippled action, there may be other genetic factors at work causing early onset of this disease.”
The investigators discovered that phosphatase and tensin homologue (PTEN), a protein that plays an important role in cell functions such as growth and communication, might also work in tandem with interleukin 10 in helping ulcerative colitis to develop. The team also found that, among mice that do not have interleukin 10, the additional loss of the PTEN gene in the intestine produced extensive inflammation, severe colitis, and colon cancer development at very early ages, as early as one month after birth. In addition, the mice developed symptoms and early-onset ulcerative colitis in a similar manner as humans. Thus, the researchers noted, the mice may be an important tool for testing possible new treatments for ulcerative colitis.
The researchers also discovered that the loss of PTEN in the intestine disrupted antibacterial activity and altered the types of bacteria present in the colon. They found a large increase in a specific group of bacteria called Bacteroides, which have the capability to generate massive inflammatory responses that cause various inflammatory diseases.
With the use of both genetic and drug interventions, the investigators inhibited the bacteria’s ability to trigger inflammatory responses; the result was a significant reduction in the occurrence of early-onset ulcerative colitis in the mice. The authors note that their findings could eventually point the way toward new approaches to treat or prevent ulcerative colitis in humans.
“Future study may help us better understand how this bacteria has the potential to elicit inflammation in the colon and explore the molecular mechanisms of how the bacteria impacts disease onset,” explained Dr. Charalabos Pothoulakis, another author of the study and a professor of medicine in the division of digestive diseases. Dr. Pothoulakis holds the Eli and Edythe L. Broad Chair in Inflammatory and Bowel Disease at UCLA and is the director of the UCLA Center for Inflammatory Bowel Diseases.