Healthcare, UK (Commonwealth Union) – Researchers at the Francis Crick Institute, in collaboration with UCL and Imperial College London, have identified a new biological pathway that significantly contributes to inflammatory bowel disease (IBD) and related conditions, which can be targeted with the application of available drugs.
Researchers of the study pointed out that at present about 5% of the global population and one in ten people in the UK suffer from an autoimmune disease, including IBD, which encompasses Crohn’s disease and ulcerative colitis. The prevalence of these diseases is rising, with over half a million people in the UK living with IBD as of 2022, nearly double the estimation of 300,000 on a prior occasion.
The researchers pointed out that in spite the increasing prevalence, current treatments are not effective for all patients, and efforts to develop new drugs often fail due to an incomplete understanding of the causes of IBD.
In a study that appeared in Nature today, scientists at the Crick explored a ‘gene desert’—a non-coding region of DNA on prior occasions associated with IBD and several other autoimmune diseases.
They discovered that this gene desert contains an ‘enhancer,’ a DNA section functioning like a volume dial for nearby genes, capable of increasing the production of proteins. The team found that this specific enhancer was active only in macrophages, a type of immune cell crucial in IBD, and it boosted a gene called ETS2. Higher ETS2 levels were associated with an increased risk of the disease.
Using genetic editing, the scientists demonstrated that ETS2 is vital for nearly all inflammatory functions in macrophages, that consist of several that directly contribute to tissue damage in IBD. Remarkably, simply increasing ETS2 levels in resting macrophages transformed them into inflammatory cells that were similar to those from IBD patients.
The team also identified that many other genes previously associated to IBD are a component of the ETS2 pathway, further supporting its role as a major cause of IBD.
Since specific drugs targeting ETS2 are currently not available, the team searched for drugs that might indirectly bring down its activity. They found that MEK inhibitors, which are already prescribed for other non-inflammatory conditions, were forecasted to turn off the inflammatory effects of ETS2.
The researchers conducted a study to determine if MEK inhibitors could reduce inflammation in macrophages and gut samples from IBD patients. They found that these drugs were effective in both cases. Currently, they are collaborating with LifeArc to explore methods for delivering MEK inhibitors specifically to macrophages, as these inhibitors can cause side effects in other organs.
Blood samples from volunteer participants with and without IBD, provided by the NIHR BioResource, were utilized in this research., and the study involved collaboration with researchers across the UK and Europe. Interestingly, the disease variant in the ETS2 enhancer is quite common, with around 95 percent of IBD patients carrying one or two copies of it.
In the Ancient Genomics Laboratory at the Crick, Pontus Skoglund and Leo Speidel, together with James, conducted research on the origins of a specific genetic variant. Their findings revealed that this variant is remarkably ancient, with an estimated age of 500,000 to one million years, and was found in Neanderthals and other early human species as well. The high prevalence of this genetic variant is attributed to its role in activating ETS2, which appears to be crucial in the early stages of responding to bacterial infections. Prior to the discovery of antibiotics, this mechanism likely provided protection against infections, explaining why the risk variant is still widespread today and even more common in regions with high rates of infectious diseases.
James Lee, the head of the Genetic Mechanisms of Disease Laboratory at the Crick and a Gastroenterologist at the Royal Free Hospital and UCL, led the research. He indicated that IBD often affects young individuals, leading to debilitating symptoms that interfere with education, relationships, family life, and career. Improved treatments are in dire need.
“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.”
Christina Stankey, who is a PhD student at the Crick, and first author along with Christophe Bourges and Lea-Maxie Haag, added “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.”
