Charité researchers find new approach to inflammatory bowel disease
Berlin, 30 May 2025
Chronic inflammatory bowel diseases are difficult to treat and harbour risks of complications, including the development of bowel cancer. Young people are particularly affected: If predisposition and certain factors come together, diseases such as ulcerative colitis or Crohn’s disease usually become apparent between the ages of 15 and 29 – a time when education and starting a career take centre stage. Prompt diagnosis and treatment are crucial. Researchers at Charité – Universitätsmedizin Berlin have now discovered a therapeutic target that makes a significant contribution to stopping the ongoing inflammatory processes. They describe it in the current issue of the journal Nature Immunology*.
Sometimes gradual, sometimes in episodes – associated with severe abdominal cramps and diarrhoea, accompanied by weight loss, fatigue and a high level of suffering – this is how the two most common chronic inflammatory bowel diseases Crohn’s disease and ulcerative colitis manifest themselves. While ulcerative colitis only affects the mucous membrane of the large intestine, Crohn’s disease affects the entire intestinal wall, especially in the small intestine, but sometimes also the stomach and oesophagus. The persistent inflammation permanently damages the tissue and increases the risk of cancer. Conventional treatment strategies usually suppress the immune system. Newer therapies, on the other hand, specifically intervene in the inflammatory reaction and block certain endogenous, inflammation-promoting messenger substances.
The triggers of severe systemic diseases are still not fully understood. In addition to genetic components, it is highly likely that environmental influences also contribute to their development. Prof. Ahmed Hegazy has been researching the inflammatory mechanisms and immune defence of the intestine at Charité’s Department of Gastroenterology, Infectiology and Rheumatology for several years. Together with his team, he has now been able to identify the interaction between two messenger substances of the immune system as the driving force behind chronic intestinal inflammation: Interleukin-22, a protein that supports cells in the innermost layer of the intestinal wall, the epithelium, and maintains the barrier function, and oncostatin M, a signalling molecule that is significantly involved in tissue regeneration and cell differentiation.
Uncontrolled chain reaction
‘At the clinic, we mainly see young patients who are at the beginning of their professional careers. So far, we have only been able to slow down the progression of the disease and alleviate symptoms. Not all patients respond equally to the available treatments. New therapeutic approaches are therefore urgently needed,’ says Ahmed Hegazy. In previous work, the research team has already intensively investigated the inflammation-promoting messenger substance oncostatin M. Produced by certain immune cells, this protein activates other inflammatory factors – a chain reaction is set in motion that leads to an uninhibited immune response. ‘What was particularly interesting for us was the observation that patients with high oncostatin M production do not respond to some of the known therapies,’ explains Ahmed Hegazy. ‘Oncostatin M expression can therefore indicate possible treatment failure and serve as a biomarker for severe disease progression. This is exactly where we started: We wanted to understand the underlying signalling chain even better – and interrupt it in a targeted therapeutic manner.’
The research team spent a whole five years investigating the mechanisms behind the inflammatory reactions triggered by oncostatin M. Initially using specific animal models and later on tissue samples from patients, they investigated the various stages of chronic diseases. State-of-the-art single-cell sequencing showed that – compared to healthy tissue – significantly more unexpected cell types in the inflamed intestine have binding sites for oncostatin M and additional immune cells produce the inflammatory protein. Interestingly, the originally tissue-protecting interleukin-22 also makes the intestinal epithelial cells more sensitive to oncostatin M by promoting the formation of additional docking sites. ‘The two immune messengers work together and further fuel the inflammation, attracting even more immune cells into the intestine – a fire that receives more and more nourishment and spreads,’ describes Ahmed Hegazy. ‘In our models, we specifically blocked the binding sites for the inflammatory messenger oncostatin M and were able to observe that this significantly reduced chronic intestinal inflammation and the associated cancer development.’
Targeted therapy for high-risk patients in sight
The researchers found a particularly high number of binding sites for the messenger substance oncostatin M around the tumours in tissue samples from patients with colorectal cancer caused by chronic intestinal inflammation – but not in the adjacent healthy tissue. This observation suggests that the discovered signalling pathway promotes cancer development. However, chronic inflammation does not directly lead to bowel cancer in all those affected. ‘Chronic inflammatory bowel diseases are very complex and vary from person to person. This is precisely what makes their treatment and prognosis so difficult,’ says Prof Britta Siegmund, Director of the Clinic for Gastroenterology, Infectiology and Rheumatology. ‘Based on the role of oncostatin M and its amplifying interaction with interleukin-22 that we have now uncovered, we have a better understanding of the mechanisms that drive chronic inflammation in certain patients. This opens up the possibility of testing and further developing a new therapeutic approach.’
The research team’s experimental successes should lead to a concrete treatment option: by specifically inhibiting the connection between the messenger substances interleukin-22 and oncostatin M. ‘Our results provide a reliable basis for therapeutically addressing this inflammation-promoting mechanism in chronic inflammatory bowel diseases – especially in patients with severe disease progression,’ says Ahmed Hegazy. A clinical trial with an antibody that specifically blocks docking sites for oncostatin M is already underway.
*Cineus R, et.al. The interleukin 22-oncostatin M axis promotes intestinal inflammation and tumourigenesis. Nature Immunology. 2025 May 29. doi: 10.1038/s41590-025-02149-z
About the study
The work was made possible by funding from the European Commission (ERC), the German Research Foundation (DFG) and the Volkswagen Foundation. In addition to scientists from Charité, researchers from the German Rheumatism Research Centre Berlin (DRFZ), a Leibniz Institute, and the antibody development company Genentech played a key role in the study.
Image: Drivers of cancer development: the inflammatory messenger oncostatin M is increasingly observed in the vicinity of tumours (red), less so in healthy intestinal tissue with a normal cell structure (right). Charité | Ahmed Hegazy