Researchers at the Francis Crick Institute, in collaboration with UCL and Imperial College London, have identified a new biological pathway that plays a key role in inflammatory bowel disease (IBD) and related conditions. This pathway can be targeted using drugs that are already available. About 5% of the world’s population, and one in ten people in the UK, are currently dealing with an autoimmune disease.such as IBD, which encompasses Crohn’s disease and ulcerative colitis. These diseases are on the rise, with over half a million people in the UK living with IBD in 2022, nearly double the previous estimate of 300,000. Current treatments do not work for every patient, and efforts to develop new drugs often fail due to our incomplete understanding of what causes IBD. In a study published in Nature, scientists at the Crick explored a ‘gene desert’ – an area of DNA that does not code for proteins – which has previously been associated with IBD and several other diseases.Autoimmune diseases have been linked to a specific gene desert that contains an “enhancer,” a section of DNA that can increase the production of nearby proteins. This enhancer was found to be active only in macrophages, a type of immune cell associated with inflammatory bowel disease (IBD). The enhancer boosted the activity of a gene called ETS2, and higher levels of this gene were found to be correlated with a higher risk of disease.
Through genetic editing, scientists demonstrated that ETS2 is essential for most inflammatory functions in macrophages, including those that directly contribute to tissue damage in IBD.The researchers were surprised to find that by simply increasing the amount of ETS2 in resting macrophages, they were able to transform them into inflammatory cells that closely resembled those found in IBD patients. Furthermore, the team discovered that many other genes associated with IBD are part of the ETS2 pathway, providing additional evidence of its significant role in causing IBD. As for treatment options, there are currently no specific drugs that block ETS2, however, the team has been searching for drugs that could indirectly reduce its activity. Their research led them to MEK inhibitors, which are already being prescribed for other conditions.The researchers found that MEK inhibitors, which are commonly used to treat cancer and other non-inflammatory conditions, were able to turn off the inflammatory effects of ETS2. They tested this discovery and found that the drugs not only reduced inflammation in macrophages, but also in gut samples from patients with IBD. Since MEK inhibitors can have side effects in other organs, the researchers are working with LifeArc to figure out ways to deliver the inhibitors directly to macrophages. James Lee, who led the research, explained that they are working on finding ways to specifically target macrophages with MEK inhibitors to treat IBD.Young people often develop IBD, which can have serious effects on their education, relationships, family life, and employment. It is crucial to find better treatments for this condition.
“Starting with genetics, we have identified a pathway that seems to play a significant role in IBD and other inflammatory diseases. Excitingly, we have demonstrated that this pathway can be targeted for treatment, and we are now working on ensuring that this approach is safe and effective for future use in patients,” stated Christina Stankey, a PhD student at the Crick and the first author of the study, along with Christophe Bourges and Lea-Maxie Haag. “IBD and other autoimmune conditions are a major focus of our research.”Inflammatory bowel diseases are extremely complex, with various genetic and environmental risk factors. Identifying a central pathway and demonstrating how it can be targeted with an existing medication represents a significant advancement.”
Volunteers from the NIHR BioResource, both with and without IBD, provided blood samples for this study. Funding for the research came from Crohn’s and Colitis UK, the Wellcome Trust, MRC, and Cancer Research UK. The researchers collaborated with partners in the UK and Europe.
Ruth Wakeman, Director of Services, Advocacy and Evidence at Crohn’s & Colitis UK, remarked: “This discovery is a major breakthrough in our understanding of IBD and offers hope for new treatment options in the future.”
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Every year, more than 25,000 people receive a diagnosis of Inflammatory Bowel Disease. Crohn’s and Colitis are complicated, lifelong conditions that currently have no cure. However, ongoing research is helping to shed light on some of the major questions regarding their causes. The more we learn about Inflammatory Bowel Disease, the better equipped we will be to assist patients in managing these conditions and maintaining a good quality of life. This research represents a significant step forward in the hope for a future without Crohn’s and Colitis.”
Lauren Golightly, 27, was diagnosed with Crohn’s Disease in 2018 after experiencing stomach cramps, blood.
During her struggles with Crohn’s disease, the individual has faced challenges such as stomach pain and irregular bowel habits. She expressed the impactful effect of the condition on her life, detailing hospital visits, various medications, and even surgery to address the issue. Living with Inflammatory Bowel Disease (IBD) has brought uncertainty, with ongoing flare-ups and time spent in hospitals. The individual finds hope and encouragement in potential research advancements, believing it could make a difference for herself and the countless others dealing with IBD.
