Researchers from the Francis Crick Institute, in collaboration with UCL and Imperial College London, have discovered a new biological pathway that is a major driver of inflammatory bowel disease (IBD) and related disorders and that can be targeted with existing drugs.
About 5% of the world’s population, and 1 in 10 More than five million people in the UK currently live with autoimmune diseases such as IBD, the collective name for Crohn’s disease and ulcerative colitis. These diseases are also becoming increasingly common. Over 500,000 people suffer from IBD As of 2022, the number in the UK will be almost double the previous estimate of 300,000.
Despite the increasing prevalence, current treatments do not work for all patients, and attempts to develop new drugs often fail due to a poor understanding of what causes IBD.
in The study was published in Nature magazine.In 2011, scientists at the Crick Institute explored “gene deserts,” regions of DNA that do not code for proteins, that have previously been linked to inflammatory bowel disease (IBD) and several other autoimmune disorders.
The team found that this gene desert contains “enhancers,” sections of DNA that act like a volume dial on nearby genes, increasing the amount of protein the genes make. The team found that this particular enhancer was active only in macrophages, a type of immune cell known to be important in inflammatory bowel disease, and boosted a gene called ETS2, the higher its levels are associated with a higher risk of the disease.
Using gene editing, the scientists showed that ETS2 is essential for nearly all inflammatory functions of macrophages, including several that directly contribute to tissue damage in IBD. Remarkably, simply increasing the amount of ETS2 in resting macrophages transformed them into inflammatory cells that closely resemble those in IBD patients.
The team also found that many other genes previously associated with IBD are part of the ETS2 pathway, providing further evidence that this is a major cause of IBD.
ETS2 as a therapeutic target
Because there are no specific drugs that block ETS2, the team looked for drugs that might indirectly suppress ETS2 activity, and found that MEK inhibitors, already prescribed for other non-inflammatory diseases, were predicted to halt the inflammatory effects of ETS2.
The researchers tested this and found that not only did these drugs reduce inflammation in macrophages, but they also reduced inflammation in intestinal samples from IBD patients.
Because MEK inhibitors can cause side effects in other organs, the researchers are currently working with LifeArc to explore ways to deliver MEK inhibitors directly to macrophages.
IBD patients and non-patient volunteers from NIHR BioResource provided blood samples for the study, which was funded by Crohn’s and Colitis UK, the Wellcome Trust, the MRC and Cancer Research UK, and the researchers worked with collaborators across the UK and Europe.
Why did we evolve to have genetic mutations associated with chronic inflammation?
What’s unusual about the ETS2 enhancer disease mutation is that it’s very common, with around 95% of IBD patients having one or two copies.
Pontus Skogland and Leo Spiedel, who work in the Crick Institute’s Ancient Genomics Lab, which studies ancient DNA, worked with James to determine when this genetic variant first appeared and showed that it is incredibly old – at least 500,000 to 1 million years ago – and that it was present in Neanderthals and other ancient humans.
The researchers conclude that this variant is so prevalent because activation of ETS2 appears to be an important part of the early response to bacterial infection. Before the advent of antibiotics, this may have had a protective effect during infection, which may explain why so many people still harbor this risk variant today, and why it is even more common in areas with a high incidence of infectious diseases.
What researchers say
James Lee, group leader in the Genetic Disease Mechanisms Laboratory at the Crick Institute and a gastroenterologist at the Royal Free Hospital and University of London, who led the study, said: “IBD typically affects young people and can cause severe symptoms that interfere with education, relationships, family life and employment. Better treatments are urgently needed.”
“Using genetics as a starting point, we discovered a pathway that appears to play an important role in IBD and other inflammatory diseases. Excitingly, we have demonstrated that this can be targeted therapeutically. We are now investigating how to ensure that this approach is safe and effective in treating people in the future.”
“IBD and other autoimmune diseases are incredibly complex, with many genetic and environmental risk factors, so finding one of the central pathways and showing how we can block this with existing drugs is a major step forward,” said Christina Stankey, a doctoral student in the Crick Institute and first author with Christophe Bourges and Lea Maxey-Haag.
Ruth Wakeman, director of services, support 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 illnesses and there is no cure, but research like this helps to answer some of the big questions about their causes. The more we understand about inflammatory bowel diseases, the better our chances of helping patients live well with these conditions. This research is a really exciting step towards the possibility of one day seeing a world free of Crohn’s and colitis.”
Lauren Golightly, 27, was diagnosed with Crohn’s disease in 2018 after experiencing stomach pains, blood in her stool and irregular bowel habits.
She said: “Crohn’s disease has had a huge impact on my life. Since being diagnosed it has been a difficult journey that has involved multiple hospital stays, several medications and even surgery to create a temporary stoma bag. One of the hardest things about living with Inflammatory Bowel Disease (IBD) is the uncertainty. I still experience exacerbations and spend a significant amount of time in hospital. It is so exciting and encouraging to find out about this research and I hope it can make a difference for me and hundreds of thousands of others living with IBD.”
Attached Video: https://www.youtube.com/watch?v=l0o-zXZ70BE&t=2s
