Chronic inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis, present significant treatment challenges and elevate the risk of bowel cancer. These conditions often strike young adults during pivotal years of education and career progress,typically between ages 15 and 29. Early diagnosis and intervention are therefore critical. Now, scientists at charité — universitätsmedizin berlin have identified a therapeutic target that actively impedes ongoing inflammatory processes, with their discoveries featured in Nature Immunology.

Crohn’s disease and ulcerative colitis, the two moast prevalent forms of IBD, can manifest gradually or in sudden flare-ups, marked by severe abdominal pain, diarrhea, weight loss, fatigue, and considerable emotional distress. Ulcerative colitis exclusively affects the inner lining of the colon, while Crohn’s disease can permeate the entire intestinal wall, commonly impacting the small intestine but occasionally extending to the stomach and esophagus. Persistent inflammation can inflict lasting tissue damage and heighten cancer susceptibility. While conventional treatments generally suppress the entire immune system, newer, more targeted therapies aim to disrupt the inflammatory cascade by selectively blocking specific messenger substances that fuel inflammation.

The precise origins of these systemic diseases remain elusive. Besides genetic predispositions, environmental factors are believed to contribute significantly. Prof. Ahmed Hegazy and his team at Charité’s Department of Gastroenterology, infectiology and Rheumatology have been investigating gut inflammation and immune defense mechanisms for several years. Their work has now revealed that the interplay between two immune system messengers is a driving force behind chronic intestinal inflammation: Interleukin-22, a protein that fortifies the cells lining the gut and maintains it’s protective barrier, and oncostatin M, a signaling molecule crucial for tissue repair and cell differentiation.

Oncostatin M: An Uncontrolled Inflammatory Driver

According to Ahmed Hegazy, “At the clinic, we mainly see young patients who just beginning their professional lives. So far, we have only been able to slow down the progression of the disease and alleviate symptoms. But not all patients respond well to existing treatments, so new therapeutic approaches are urgently needed.” the research team’s prior investigations into oncostatin M, an inflammation-promoting messenger molecule, revealed that this protein, produced by specific immune cells, activates other inflammatory factors, initiating a chain reaction that provokes an excessive immune response.

“this means that Oncostatin M levels could help predict treatment failure and may serve as a biomarker for more severe disease.”
Ahmed Hegazy

Ahmed Hegazy further explains, “it was especially interesting for us to see that patients with high levels of oncostatin M do not respond to several common therapies. This means that Oncostatin M levels could help predict treatment failure and may serve as a biomarker for more severe disease. That’s exactly where we focused our efforts: we wanted to understand this signaling pathway better and find ways to block it with targeted treatments.”

Over five years, the researchers meticulously investigated how oncostatin M triggers inflammatory responses. They employed animal models and patient tissue samples to analyze various stages of chronic intestinal diseases. Advanced single-cell sequencing demonstrated that, in contrast to healthy tissue, a considerably greater number of unexpected cell types in the inflamed gut possess binding sites (receptors) for oncostatin M. Together, additional immune cells begin producing the inflammatory protein. Intriguingly, interleukin-22, typically a tissue-protecting agent, paradoxically enhances the gut lining’s sensitivity to oncostatin M by increasing the number of its receptors.

ahmed Hegazy describes this process: “These two immune messengers work together and amplify the inflammation, drawing more immune cells into the intestine, like a fire that keeps getting more fuel and spreads.In our models, we specifically blocked the binding sites for oncostatin M and saw a clear reduction in both chronic inflammation and the associated of cancer.”

toward Targeted Therapies for High-Risk IBD Patients

the research team observed a notably high concentration of oncostatin M receptors surrounding tumors in tissue samples from patients with colorectal cancer linked to chronic intestinal inflammation, but not in adjacent healthy tissue.This suggests that this signaling pathway might facilitate cancer development. Though, chronic inflammation does not invariably lead to bowel cancer, and individual patient experiences vary significantly.

Prof. Britta Siegmund, Director of the Clinic for gastroenterology, Infectiology and Rheumatology, notes, “Chronic inflammatory bowel diseases are highly complex and differ from person to person. That’s exactly what makes them so tough to treat and predict treatment.Thanks to the role of oncostatin M and its amplifying interaction with interleukin-22, which we have now identified, we have a clearer understanding of what drives chronic inflammation in some patients. This opens up the door to developing and testing a new therapeutic approach.”

The team’s findings may soon lead to practical therapies by selectively disrupting the detrimental interaction between interleukin-22 and oncostatin M. Ahmed Hegazy concludes, “Our results provide a strong scientific basis for developing targeted treatments against this inflammation-promoting mechanism in chronic inflammatory bowel disease — particularly in patients with more severe forms of the illness.” A clinical trial is currently underway to evaluate an antibody that blocks the receptors for oncostatin M.