Major cause of inflammatory bowel disease identified – and treated

For the first time, a major trigger for inflammatory bowel disease (IBD) and related conditions has been identified, and existing drugs can eliminate it, in what scientists call a 'massive step' in successful treatment of these debilitating chronic diseases.

Researchers from the Francis Crick Institute, in collaboration with University College London (UCL) and Imperial College London (ICL), have discovered a problematic gene enhancer that stimulates action along a specific biological pathway that causes IBD inflammation. Until now, our incomplete knowledge of the causes of IBD has made finding a “universal” medical intervention incredibly difficult.

This enhancer was discovered in an area of ​​DNA known as the “genetic desert” – where genetic material does not code for proteins – that has previously been linked to IBD and other autoimmune diseases. Although the enhancer, a section of DNA, does not code for proteins, it directly influences the protein production of neighboring genes.

What's more, they found that this enhancer was only active in immune cells called macrophages – a key immune cell in IBD – and that it enhanced the gene. ETS2. Upper ETS2 activity reflected a higher risk of inflammation.

“Using genetics as a starting point, we discovered a pathway that appears to play a major role in IBD and other inflammatory diseases,” said James Lee, group leader of the Genetic Mechanisms of Disease Laboratory at Crick. .

Zoom on ETS2, scientists found that it caused macrophage inflammation, particularly several immune responses that led to IBD-related tissue damage. The researchers were able to “arm” the dormant macrophages by calling ETS2which transformed them into inflammatory cells that mirrored those found in IBD patients.

In addition to the evidence, the team found that approximately 95% of people with IBD carry one or two copies of the ETS2 activator in their macrophage cells.

Why does this variant prevail and in so many people? The Crick team traced its origins and discovered that it first appeared between 500,000 and a million years ago and was found among Neanderthals. One hypothesis is that it once played a key role in stimulating an inflammatory response to bacterial infections, which would have helped fight these infections long before the advent of antibiotics.

The team also discovered that several genes already involved in intestinal inflammation were positioned along the ETS2 biological pathway, indicating that a root cause of these complex conditions had been discovered.

And there is already a drug that can treat it – in a way.

Although there are currently no specific drugs targeting ETS2 activity, the team found that indirect suppression was possible through the use of inhibitors of extracellular mitogen-activated signal-regulated kinases (MEKs) – which are commonly used in cancer treatment. MEK inhibitors reduced inflammation in macrophages and intestinal tissue of IBD patients.

“IBD and other autoimmune diseases are really complex, with multiple genetic and environmental risk factors, so finding one of the central pathways and showing how this can be deactivated with an existing drug is a big step forward “, said the first author. Christina Stankey, researcher at Crick.

However, MEK inhibitors can damage other organs, so researchers will need to find a way to directly target macrophages. This is what researchers are now focusing on.

“We have excitingly shown that this can be targeted therapeutically, and we are currently working on how to ensure this approach is safe and effective for treating patients in the future,” Lee said.

An estimated three million Americans suffer from IBD, which includes Crohn's disease and ulcerative colitis. Although various treatments and lifestyle choices can help people manage the disease, it cannot be cured, and “flares” that damage or inflame the intestines can be incredibly painful and debilitating.

“Crohn's disease and colitis are complex, lifelong illnesses for which there is no cure, but research like this helps us answer some of the big questions about their causes,” said Ruth Wakeman, Director of Services, Advocacy and Evidence at Crohn's & Colitis. Colitis UK. “The more we understand about inflammatory bowel disease, the more likely we will be able to help patients live well with these diseases. This research is a truly exciting step toward the possibility of a world free of inflammatory bowel disease. Crohn's and colitis one day.”

The research was published in the journal Nature.

Source: Francis Crick Institute