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Researchers have identified a new biochemical pathway, a major cause of inflammatory bowel disease (IBD) and related disorders, that could be treated with existing drugs.
Autoimmune diseases such as IBD, which includes Crohn’s disease and ulcerative colitis, currently affect around 5% of the world’s population and one in 10 people in the United Kingdom. These diseases are also spreading rapidly, with more than half a million people in the UK expected to suffer from IBD by 2022, almost double the previous estimate of 300,000.
Despite the increasing prevalence, current treatments do not work for every patient and attempts to develop new drugs often fail because our understanding of the causes of IBD is incomplete.
Also read: Consumption of broccoli sprouts prevents colitis in bowel disease: Study
According to research carried out by the Francis Crick Institute in collaboration with UCL and Imperial College London, and their findings published in Nature, Crick scientists travelled to a ‘gene desert’ – a region of DNA that does not code for proteins – that has previously been linked to IBD and a number of other autoimmune diseases.
They found that this gene desert contains an ‘enhancer’, a section of DNA that is like a volume dial for nearby genes, able to increase the amount of protein they make. The team found that this particular enhancer was active only in macrophages, a type of immune cell known to be important in IBD, and boosts a gene called ETS2, high levels of which are associated with a higher risk of the disease.
Using genetic editing, the scientists showed that ETS2 was essential for nearly all inflammation-related functions in macrophages, including many that directly contribute to tissue damage in IBD. Surprisingly, increasing the amount of ETS2 in resting macrophages turned them into inflammatory cells that closely resembled cells from IBD patients.
The team also discovered that several other genes previously associated with IBD are part of the ETS2 pathway, providing further evidence that it is a major cause of IBD.
Specific drugs that block ETS2 do not exist, so the team looked for drugs that could indirectly reduce its activity. They found that MEK inhibitors, drugs already prescribed for other non-inflammatory conditions, were predicted to shut down ETS2’s inflammatory effects.
The researchers then tested the drugs and found that these drugs not only reduced inflammation in macrophages, but also in gut samples from patients with IBD.
Since MEK inhibitors can also have side effects on other organs, the researchers are now working with LifeArk 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 which disrupt education, relationships, family life and employment. Better treatments are urgently needed.
“Using genetics as a starting point, we have discovered a pathway that plays a major role in IBD and other inflammatory diseases. Excitingly, we have shown that it can be targeted therapeutically, and we are now working on how to make this approach safe and effective for treating people in the future.”
Christina Stanci, a PhD student at the Crick and first author with Christophe Borges and Lea-Maxi Haag, said: “IBD and other autoimmune conditions are really complex, with multiple genetic and environmental risk factors, so finding one of the central pathways and showing how it can be switched off with an existing drug is a huge step forward.”
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, the MRC and Cancer Research UK, and the researchers worked with colleagues 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 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 big questions about what causes them. The more we 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 very exciting step towards the possibility of a world free from Crohn’s and colitis one day.”
Lauren Golightly is 27 and was diagnosed with Crohn’s disease in 2018 after experiencing abdominal cramps, blood in her stool and irregular bowel movements.
She said: “Crohn’s has had a huge impact on my life. I have had a very up and down life since my diagnosis, being hospitalised several times, taking a variety of medications and even having surgery to put in 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 I could still spend a lot of time in hospital. It is very exciting and encouraging to learn about this research. I hope it could potentially make a difference for me and the many millions of other people suffering from IBD.”
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