Researchers from the Francis Crick Institute, University College London (UCL) and Imperial College London have identified a new major cause of inflammatory bowel disease (IBD).
Published in Nature, the biological pathway that drives the autoimmune disease and related conditions can be targeted using already existing drugs.
Affecting more than 500,000 people in the UK as of 2022, IBD is a term for two conditions, Crohn’s disease and ulcerative colitis, which are characterised by chronic inflammation of the gastrointestinal tract.
After investigating an area of DNA that does not code for proteins, known as a ‘gene desert’, which has previously been linked to IBD and several autoimmune diseases, researchers discovered a section of DNA known as an ‘enhancer’ that increases the number of proteins they make up.
Only active in macrophages, a form of immune cells found in IBD, the enhancer also boosted a gene known as ETS2 with higher levels that correlated with a higher risk of disease.
The team used genetic editing to show that ETS2 was essential for almost all inflammatory functions in macrophages, particularly those that directly contribute to tissue damage in IBD.
By increasing the amount of ETS2 in resting macrophages, researchers found that they turned into inflammatory cells that closely resembled those from IBD patients.
In addition, researchers revealed that many other genes previously associated with IBD are part of the ETS2 pathway, further highlighting that it is a major driver of IBD.
When searching for specific drugs that could indirectly reduce ETS2 activity, researchers found that MEK inhibitors, drugs prescribed for other non-inflammatory conditions, were predicted to switch off its inflammatory effects.
In gut samples from patients with IBD, the MEK inhibitors reduced inflammation as well as in macrophages.
Researchers are now working with LifeArc to discover ways to deliver MEK inhibitors directly to macrophages as a possible treatment for IBD.
James Lee, group leader, Genetic Mechanisms of Disease Laboratory, the Crick and consultant gastroenterologist, Royal Free Hospital and UCL, commented: “We’ve uncovered a pathway that appears to play a major role in IBD and other inflammatory diseases.”