A new OMRF discovery could lead to new therapies for ulcerative colitis—a disease which has no cure.
For patients suffering from ulcerative colitis, days are marked by discomfort and pain. For others, the condition can be life-threatening. Ulcerative colitis and Crohn’s disease are chronic digestive disorders of the intestines collectively known as inflammatory bowel diseases, or IBD. About 1.4 million Americans suffer from IBD, with 30,000 new cases diagnosed each year.
In new research, Oklahoma Medical Research Foundation scientist Lijun Xia, M.D., Ph.D., an associate member of the Cardiovascular Biology Research Program, has made a discovery that may help explain why some people develop this debilitating gastrointestinal condition.
The large intestine is lined with a protective mucus layer made up of large sugar molecules called O-glycans. One role of the mucus is to separate bacteria and immune cells in the colon. In ulcerative colitis, the mucus layer is severely degraded, allowing the bacteria and immune cells to fight, causing inflammation.
Scientists have long wondered at the root cause of the disease, said Xia.
“For years, it’s been a ‘chicken-or-the-egg’ debate,” said Xia, who is also an adjunct associate professor in the Department of Biochemistry and Molecular Biology at the University of Oklahoma Health Sciences Center. “No one was sure if the reaction between the bacteria and the immune cells caused damage to the mucus layer or if damage to the mucus layer allowed the bacteria and immune cells to get at one another.”
Xia’s research found that O-glycans makes up 80 percent of the weight of the barrier. When there is a deficiency of the sugar, the barrier gives way to the bacteria and immune cells. Their fight causes inflammation in the colon, leading to colitis.
“We knew the mucus layer was damaged in ulcerative colitis—we just didn’t know whether the damaged mucus was a cause of the disease,” he said.
Xia’s lab developed genetically engineered mice lacking intestinal O-glycans. These mice develop spontaneous ulcerative colitis that closely resembles the human disease, implicating O-glycan depletion as a disease-causing factor.
After testing the disease in mice, Xia compared the results to samples from humans with colitis and found they had the defective sugar. “We cannot say this is the only way patients get colitis, but we know it may be one way the disease can start,” he said.
In addition to allowing scientists to understand the complex immune system response in the development of colitis, the O-glycan-lacking mice also allow researchers to immediately begin testing available agents for treatment or prevention of the disease. Xia’s research has found that in many cases, the disease begins when the mucus barrier in the colon separating bacteria from immune cells is breached.
Xia said the next step in the research is to expand the base of human colitis samples for more testing. “By better understanding how the disease begins, scientists can begin working on ways to prevent colitis from beginning,” he said.
The research was a collaborative effort, including Xia’s research team of Drs. Jianxin Fu, Tao Wen, Xiaowei Liu, Michael McDaniel, Xiaowei Liu, and Sam McGee, OMRF scientist Dr. Hong Chen, and scientists from the University of California at Los Angeles, the University of Gothenburg in Sweden, and the University of Oklahoma Health Sciences Center.
The research is published in the The Journal of Clinical Investigation. It was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Crohn’s and Colitis Foundation of America.
