Scientists uncover key cause of inflammatory bowel disease

A recent study by researchers at the Francis Crick Institute, University College London (UCL), and Imperial College London has shed light on a significant new cause of inflammatory bowel disease (IBD). This autoimmune condition, affecting over 500,000 individuals in the UK as of 2022, includes Crohn’s disease and ulcerative colitis, both characterized by persistent inflammation of the gastrointestinal tract.

The groundbreaking research, published in *Nature*, identifies a biological pathway that drives IBD and related conditions, which can be targeted using existing medications. The investigators focused on a non-coding DNA region, known as a 'gene desert,' that has previously been linked to IBD and various other autoimmune diseases. In this region, they discovered a DNA segment called an 'enhancer,' which has the function of increasing protein production.

This enhancer is specifically active in macrophages—immune cells involved in IBD—and it also amplifies a gene known as ETS2. Elevated levels of ETS2 were found to correlate with a higher risk of developing the disease. Through genetic editing techniques, the researchers demonstrated that ETS2 is crucial for nearly all inflammatory functions in macrophages, particularly those that contribute directly to tissue damage in IBD.

Further experiments showed that increasing ETS2 levels in resting macrophages transformed them into inflammatory cells resembling those found in IBD patients. Additionally, the study highlighted that many other genes previously associated with IBD are part of the ETS2 pathway, reinforcing the idea that this pathway is a significant driver of the disease.

In their search for drugs that could indirectly reduce ETS2 activity, the team identified MEK inhibitors—medications typically prescribed for non-inflammatory conditions—as potential candidates. These inhibitors were shown to reduce inflammation in gut samples from IBD patients as well as in macrophages.

The research team is now collaborating with LifeArc to explore methods of delivering MEK inhibitors directly to macrophages, potentially offering a new treatment approach for IBD. James Lee, the group leader at the Genetic Mechanisms of Disease Laboratory at the Crick and a consultant gastroenterologist at Royal Free Hospital and UCL, stated: “We’ve uncovered a pathway that appears to play a major role in IBD and other inflammatory diseases.”

This discovery opens up new avenues for therapeutic intervention and provides hope for more effective treatments for individuals suffering from these chronic and debilitating conditions.