For the first time, a major trigger in inflammatory bowel disease (IBD) and related conditions has been identified, and existing drugs can stamp it out, in what scientists call a "massive step" in successfully treating these debilitating chronic conditions.
Researchers at the Francis Crick Institute, in collaboration with University College London (UCL) and Imperial College London (ICL), have uncovered a problem gene enhancer that stimulates action along a specific biological pathway that causes IBD inflammation. Until now, our incomplete knowledge of what drives IBD has made it incredibly hard to find a 'one-size-fits-all' medical intervention.
This enhancer was found in an area of DNA known as a 'gene desert' – where genetic material doesn't code for proteins – which has already been linked to IBD and other autoimmune conditions. While the enhancer, a section of DNA, doesn't code for proteins, it directly influences the protein production of nearby genes.
What's more, they found that this enhancer was only active in immune cells known as macrophages – a key immune cell in IBD – and it boosted the gene ETS2. Higher ETS2 activity reflected higher risk of inflammation.
"Using genetics as a starting point, we've uncovered 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 the Crick.
Zooming in on ETS2, the scientists discovered that it was driving inflammation from macrophages, in particular several immune responses that led to IBD tissue damage. The researchers were able to 'arm' dormant macrophages by dialing up ETS2, which turned them into inflammatory cells that mirrored those found in IBD patients.
Adding to the evidence, the team found that around 95% of IBD sufferers carry one or two copies of the ETS2 enhancer in their macrophage cells.
Why does this variant prevail and in so many people? The Crick team traced its origins, and found that it first appeared between 500,000 years and one million years ago, and it has been found in Neanderthals. One hypothesis is that it once served a key function in stimulating an inflammatory response to bacterial infections, which would have helped fight such infections long before the advent of antibiotics.
The team also found that several genes already implicated in bowel inflammation were positioned along the ETS2 biological pathway, indicating that a root cause of these complex conditions had been uncovered.
And, there's already a drug that can treat it – in a way.
While there are currently no specific medications that target ETS2 activity, the team found that indirect suppression was possible through the use of existing mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors – which are commonly used in cancer treatment. MEK inhibitors reduced inflammation in both macrophages and in the gut tissue of IBD patients.
"IBD and other autoimmune conditions are really complex, with multiple genetic and environmental risk factors, so to find one of the central pathways, and show how this can be switched off with an existing drug, is a massive step forwards," said first author Christina Stankey, a researcher at the Crick.
However, MEK inhibitors can cause damage to other organs, so researchers will need to find a way to directly target macrophages. Which is what researchers are now focused on.
"Excitingly, we've shown that this can be targeted therapeutically, and we're now working on how to ensure this approach is safe and effective for treating people in the future," said Lee.
It's estimated that three million Americans suffer from IBD, which includes Crohn’s disease and ulcerative colitis. While various treatments and lifestyle choices can help people manage the condition, it can't be cured, and 'flare ups' that damage or inflame the intestines can be incredibly painful and debilitating.
"Crohn's and Colitis are complex, lifelong conditions for which there is no cure, but research like this is helping us to answer some of the big questions about what causes them," said Ruth Wakeman, Director of Services, Advocacy and Evidence at Crohn's & Colitis UK. "The more we can understand about inflammatory bowel disease, the more likely we are to be able to help patients live well with these conditions. This research is a really exciting step towards the possibility of a world free from Crohn's and Colitis one day."
The research was published in the journal Nature.
Source: The Francis Crick Institute
