UK researchers have discovered a new biological pathway which drives inflammatory bowel disease (IBD) and could be targeted with existing drugs.

The work, carried out by researchers at the Francis Crick Institute, working with UCL and Imperial College London, uncovered a region of DNA which effectively dials up the activity of specific white blood cells, driving inflammation and increasing IBD risk.

What’s more, they find that a class of drugs already prescribed for other non-inflammatory conditions (called MEK inhibitors) can interrupt this pathway, reducing inflammation in immune cells and in gut samples from patients with IBD.

According to the researchers, while their work has shown this key inflammatory pathway can be targeted with drugs in the lab, the treatment has known side effects. They say the next step will be to show if the approach can be safe and effective in patients. Their findings are published this week in the journal Nature.

Christina Stankey, PhD student at the Crick and post-graduate researcher in Imperial’s Department of Immunology and Inflammation, said: “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.”

Inflammatory bowel disease

An estimated one in ten people in the UK, and 5% of people around the world, are currently affected by an autoimmune disease, such as IBD – the umbrella term for Crohn’s disease and ulcerative colitis. These diseases are also becoming more common, with over half a million people living with IBD in the UK as of 2022, nearly double the 300,000 previously estimated.

Despite increasing prevalence, current treatments do not work for every patient and attempts to develop new drugs often fail due to our incomplete understanding of what causes IBD.

In the latest study, the researchers looked at non-coding regions of DNA (or ‘dark DNA’) which don’t contain genes. In a region of DNA previously linked to IBD and other autoimmune diseases, they found a key ‘enhancer’ region was active – effectively dialling up the activity of nearby genes, and boosting the amount of protein they make.

The team discovered that this particular enhancer was only active in immune cells called macrophages, which are known to be important in IBD. In particular, it boosted the activity of a gene called ETS2, with higher ETS2 protein levels correlating with a higher risk of disease. 

Genetic analysis showed ETS2 was essential for almost all inflammatory functions in macrophages, and increasing the amount of ETS2 in resting macrophages turned them into inflammatory cells that closely resembled those from IBD patients. A number of other genes previously linked to IBD were also part of the ETS2 pathway, providing further evidence that it is a major cause of IBD.

Blocking the pathway

While specific drugs that block ETS2 don’t exist, the team investigated a class of drug called MEK inhibitors, which are already prescribed for other non-inflammatory conditions. They found that these drugs not only reduced inflammation in macrophages, but also in gut samples from patients with IBD.

However, MEK inhibitors can have side effects in other organs, so the researchers are now working with British life science medical research charity LifeArc to find ways to deliver MEK inhibitors directly to macrophages.

James Lee, Group Leader of the Genetic Mechanisms of Disease Laboratory at the Crick, and Consultant Gastroenterologist at the Royal Free Hospital and UCL, who led the research, said: “IBD usually develops in young people and can cause severe symptoms that disrupt education, relationships, family life and employment. Better treatments are urgently needed.

“Using genetics as a starting point, we’ve uncovered a pathway that appears to play a major role in IBD and other inflammatory diseases. 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.”

Real world impact

Volunteer participants from the NIHR BioResource, with and without IBD, provided blood samples that contributed to this research. The research was funded by Crohn’s and Colitis UK, the Wellcome Trust, MRC and Cancer Research UK, and the researchers worked with collaborators across the UK and Europe.

Ruth Wakeman, Director of Services, Advocacy and Evidence at Crohn's & Colitis UK said: “Every year, more than 25,000 people are told that they have Inflammatory Bowel Disease. 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.

"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.”

Lauren Golightly is 27 years old and was diagnosed with Crohn’s disease in 2018 after experiencing stomach cramps, irregular bowel habits, and bleeding.

She said: "Crohn’s has had a huge impact on my life. I’ve had a rocky road since diagnosis, with many hospital admissions, several different medications and even surgery to have a temporary stoma bag. One of the hardest things about having Inflammatory Bowel Disease (IBD) is the uncertainty around it.

"I still experience flare-ups and can still spend quite a bit of time in hospital. Learning about this research is so exciting and encouraging. I am hopeful this could potentially make a difference for myself and so many other hundreds of thousands of people living with IBD.”

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‘A disease-associated gene desert directs macrophage inflammation through ETS2’ by Stankey, CT., Bourges, C., Haag, LM. et al. is published in Nature. DOI: https://www.doi.org/10.1038/s41586-024-07501-1

This article is based on materials from the Francis Crick Institute.

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