GPR15 Gene Mutations Associated with Severe Inflammatory Bowel Disease in Children

Illustration of a regulatory cell that helps protect the intestinal lining from chronic inflammation. Illustration created by AI.

JAKARTA - Researchers at the National Institutes of Health or NIH have discovered an important pathway that helps protect the gut from chronic inflammation. A rare and detrimental variant in the GPR15 gene is associated with severe inflammatory bowel disease that appears from an early age.

NIH quoted from its official website on Friday, July 17, saying the findings open up opportunities for more targeted diagnosis and therapy. The results of the study were published in the journal Nature.

Inflammatory bowel disease (IBD) includes ulcerative colitis and Crohn's disease. Both cause chronic inflammation of the digestive tract and in some cases can develop into colon cancer.

To understand the mechanism of the disease, researchers interviewed families who had children with severe IBD from an early age. Through genetic sequencing, the team found that patients had rare and harmful variants in the GPR15 gene.

The protein produced by the GPR15 gene functions like a guidepost that leads certain regulatory cells to the lining of the large intestine.

The cells are called GPR15-guided mucosal regulatory CD8+ T cells or CD8+ TIGR cells. These cells help control inflammation in the intestinal tissue.

In patients with the defective GPR15 variant, the guiding mechanism fails to work. As a result, CD8+ TIGR protective cells are not found in the intestinal lining.

Researchers found the absence of these cells was followed by a buildup of inflammatory macrophages in the gut. Macrophages normally help maintain tissue health. However, their buildup in these conditions promotes severe inflammation.

Michael Lenardo, Calico Life Sciences Chief Scientific Officer and former NIH researcher, said the findings open up opportunities for more targeted therapies for diseases that can be very debilitating for sufferers.

Current IBD treatments often rely on broad immune system suppression through corticosteroids, biologic drugs, or anti-TNF therapy.

Anti-TNF therapy works by inhibiting one of the proteins involved in the inflammatory process. However, some patients do not respond to the treatment or lose response after some time. The therapy can also cause side effects.

Researchers are looking at therapies that work by restoring GPR15 signaling or helping CD8+ TIGR cells move toward the intestinal tissue.

"Therapies designed to restore GPR15 signaling or increase the migration of CD8+ TIGR cells to the intestinal tissue may be a more targeted strategy to relieve inflammatory bowel disease while avoiding the adverse effects of many inappropriate inflammatory suppression therapies," said Chuan Wu, one of the senior authors of the National Cancer Institute NIH.

This study provides a basis for the development of future inflammatory bowel disease therapies, including approaches that restore GPR15 signaling or help the migration of CD8+ TIGR cells to the intestinal tissue.