Gene polymorphism alters integrity of epithelial barrier to cause IBD

A genetic variant in C1orf106 that confers risk for inflammatory bowel disease (IBD) has been found to alter the integrity of cellular junctions involved in the formation of human gut epithelium, resulting in an impaired intestinal barrier function, or “leaky gut,” researchers have found. They report their discovery in the February online issue of Science Magazine.

Leaky gut has been observed in patients with ulcerative colitis (UC) as well as in healthy family members of some UC patients, which suggested that a genetic component may underlie the phenomenon.

“Increasing the stability of C1orf106 may be a potential therapeutic strategy to increase the integrity of the epithelial barrier for the treatment of IBD,” potentially offering symptom relief and disease remission, according to Ramnik Xavier, MD, PhD, and colleagues at Massachusetts General Hospital, Harvard Medical School, and the Broad Institute, Boston, MA.

C1orf106 protein is highly expressed in the human intestine and intestinal epithelial cell lines. C1orf106 was previously identified as being an IBD susceptibility gene through genome-wide association studies. Follow-up exome sequencing revealed that a polymorphism, *333F, in C1orf106 increased risk of IBD.

The researchers elucidated the function of C1orf106 in a mouse model in which the C1orf106 gene was knocked out. They found that C1orf106 functions as a “molecular rheostat.” The protein produced by C1orf106 forms a complex with other proteins known as cytohesin-1 and ARF6, and this complex regulates the integrity of the junctions between epithelial cells that form the intestinal barrier. Epithelial junction integrity is important in intestinal homeostasis as well as tissue repair after damage, they explained.

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

In mice lacking the C1orf106 gene, the researchers found that solutes were able to cross the intestinal barrier more easily. These mice were also found to exhibit increased susceptibility to bacterial infections.  Increased susceptibility to microbial pathogens as well as dysbiosis is commonly associated with IBD, the authors noted.

The researchers concluded that the *333F polymorphism decreases C1orf106 protein stability, which increases susceptibility to IBD by compromising gut epithelial integrity through impaired turnover and degradation of cytohesin-1.

“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,”  added Caren Heller, MD, MBA, chief scientific officer, Crohn’s & Colitis Foundation, which helped fund the study. “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.”

This research was funded by the Crohn’s & Colitis Foundation, the Helmsley Charitable Trust, and the National Institutes of Health.