Novel Role of an Ulcerative Colitis Risk Gene in Intestinal Barrier Function: New Discoveries Could Lead to New Treatment Options

New York, New York, April 4, 2018 – A break-through discovery being reported in the February online issue of Science Magazine advances our understanding of the genetic causes of ulcerative colitis. The research, funded by the Crohn’s & Colitis Foundation (the Foundation), and conducted by investigators at Massachusetts General Hospital and the Broad Institute, reveals a genetic variant associated with ulcerative colitis (a form of Inflammatory bowel disease (IBD) that controls the intestinal barrier. The finding could lead to new therapeutics that would restore patients’ normal intestinal functioning to relieve symptoms and put their disease into remission. 

The new study, led by Ramnik Xavier, MD, PhD, Professor of Medicine at Harvard Medical School and Chief of Gastroenterology at Massachusetts General Hospital and Kara Lassen, Ph.D., Research Scientist at The Broad Institute, identifies the mechanism by which a genetic change to a single protein produced by the C1ORF106 gene (a largely uncharacterized gene known to contain genetic variants that confer risk for ulcerative colitis) can alter the junctions that connect cells to form the lining of the human gut, resulting in impaired intestinal barrier function, or “leaky gut.” The fact that this condition has been observed in patients with ulcerative colitis, as well as in healthy family members of some patients, suggests a genetic component might underlie the phenomenon. 

C1ORF106 is one of the genes identified as involved in IBD by earlier research sponsored by the Foundation’s Genetics Initiative. It is expressed in specialized cells, called epithelial cells, that create a physical barrier between microbes in the gut and the rest of the body. Researchers found that the protein produced by this gene forms a complex with other proteins known as cytohesin-1 and Arf6, and that this complex regulates the integrity of the junctions between epithelial cells that form the intestinal barrier. They also found that mice lacking the C10RF106 gene, exhibit increased susceptibility to bacterial infections, and solutes are able to cross the barrier more easily. 

“Maintaining precise control over these junctions is critical to intestinal function,” explains Dr. Xavier, lead author of the study. “Even small changes in the stability of these junctions alter how our bodies are exposed to environmental stressors and microbes in our intestines.” 

“Although many current therapies that treat ulcerative colitis focus on suppressing the immune system, it is clear that other cell types in the intestine participate in advancing the disease,” adds Caren Heller, MD, MBA, the Foundation’s chief scientific officer. “By fully understanding how these intestinal junctions are controlled, we can develop new therapeutics aimed at strengthening and restoring the intestinal barrier and combine them with immune targeted therapies for pathways to correct leaky guts.”

“The Foundation is committed to supporting every possible opportunity for identifying potential therapeutic targets that will lead to better treatment options for IBD patients,” stresses Michael Osso, president and chief executive officer of the Foundation. “We’re casting a broad net to support clinical and translational research that opens promising new avenues for diagnosis, therapy, and prevention of IBD – as soon as possible. The discoveries published by Dr. Xavier and his colleagues show that our strategy is paying off." 


Crohn's & Colitis Foundation

The Crohn's & Colitis Foundation is a non-profit, volunteer-fueled organization dedicated to finding the cures for Crohn's disease and ulcerative colitis, and to improving the quality of life of children and adults affected by these diseases. It was founded in 1967 by Irwin M. and Suzanne Rosenthal, William D. and Shelby Modell, and Henry D. Janowitz, M.D.