Becoming unglued: how a genetic variant may affect the gut barrier and contribute to inflammatory bowel disease
Researchers have found that a genetic variant may impart risk for inflammatory bowel disease (IBD) by disrupting the cellular “glue” that keeps the gut’s lining intact. People with IBD suffer from chronic inflammation in the gut, resulting in symptoms such as diarrhea, cramping, and weight loss. Scientists have been sorting through the complicated mix of factors that contribute to IBD, including numerous possible genetic components that are important for maintaining effective physical and immunological barriers to the multitude of bacteria that inhabit the gut. The International IBD Genetics Consortium, of which the NIDDK-supported IBD Genetics Consortium is a member, has identified over 200 regions of the human genome that are associated with IBD. Scientists are now combing through these regions to identify genes—and variants of those genes—that are involved in the disease.
One of the genetic variations that consortium scientists had identified as a risk factor for IBD was in a gene called C1orf106; however, until recently it wasn’t clear exactly how variants of this gene might lead to disease. Researchers attempting to uncover the function of “normal” C1orf106 found that laboratory-grown gut cells produced high amounts of the C1orf106-encoded protein when they were in close contact with each other. This suggested that C1orf106 may contribute to cellular junctions—the “glue” that cobbles gut cells together to create a continuous sheet-like barrier. Another hint was uncovered when the researchers found that the C1orf106 protein interacts with cytohesin-1, a protein that disrupts cellular junctions by activating a molecular switch called ARF6. Functional C1orf106 in cells caused degradation of cytohesin-1 and lower ARF6 activity, stabilizing cellular junctions. These signs pointed to a role for C1orf106 in maintaining the intestinal barrier by keeping cytohesin-1 levels in intestinal cells relatively low.
Likewise, male and female mice engineered to lack C1orf106 had higher levels of cytohesin-1 than mice whose genes were unaltered. These mice also showed greater intestinal damage after they were infected by a bacterial pathogen, supporting the idea that C1orf106 is important for maintaining a barricade against gut pathogens. However, some variants of the C1orf106 gene may not be as effective as others. In fact, when the scientists replaced C1orf106 in cells with the specific variant of the gene that is associated with human IBD, the cells were unable to make enough of the C1orf106 protein to form proper junctions. These studies strongly imply that defects in C1orf106 contribute to IBD by failing to maintain an adequate intestinal barrier. This information could help to guide the development of improved therapy for people with this genetic variant, although more work is needed to determine if the observations from the mouse model hold true in humans.