Intestinal fibrosis is a serious complication often found in patients with Crohn's disease. In treating patients with Crohn’s disease, medication is typically used to suppress intestinal inflammation. However, often the disease still progresses into formation of connective and scar tissue, making the intestinal walls thicker and stiffer. This process is also known as intestinal fibrosis. The intestine become narrower, and the passage of stool can be severely obstructed.
Despite advancements in treating chronic inflammation, existing anti-inflammatory medications cannot prevent the development of intestinal fibrosis. In over 70% of patients, it remains necessary to resect a portion of the small intestine during the disease course, and approximately 30% of patients even require a second procedure. Researchers from UZ Leuven and KU Leuven now identified several mechanisms crucial for the development of intestinal fibrosis in a recent study. With this information, they hope to develop potential new treatments.
Detailed work
The researchers conducted a highly detailed examination of cells in the intestines of patients with Crohn's disease. Previous studies only used samples taken during an endoscopy, but these did not provide the full picture of what goes on in the deeper intestinal layers. Therefore, this time, samples encompassing the full thickness of the intestinal wall from patients with different stages of inflammation and narrowing were used. This allowed the researchers to thoroughly study both the immune cells and the structural cells of the intestine.
The analyses revealed that certain immune cells, inflammatory white blood cells like monocytes, play a key role. They activate a specific group of tissue cells, fibroblasts, which contribute to chronic inflammation and the formation of excess connective tissue. The study also indicated that a certain protein, TWIST1, could be an important target for new treatments. By 'blocking' the protein in experiments, the researchers observed less accumulation of connective tissue in experimental models.
We hope that the findings of this study will ultimately result in novel drugs, which could prevent or reduce intestinal fibrosis.
Prof. dr. Séverine Vermeire
Prof. Dr. Séverine Vermeire, gastroenterologist at UZ Leuven and (co-)lead researcher of the study: “We hope that the findings of this study will ultimately result in novel drugs, which could prevent or reduce intestinal fibrosis. Obviously, a drug development programme takes years, but always starts in the lab with identifying drivers of disease, like TWIST1 in the case of fibrotic Crohn’s disease. Within the framework of this FIBROTARGET project, we aim to further unravel the underlying biological mechanisms driving fibrosis, select a first potential anti-fibrotic drug and ultimately run a proof-of-concept trial for patients with stricturing Crohn’s disease in Belgium, Italy, Germany and Spain”.
Prof. Gianluca Matteoli (Principal investigator at TARGID, KU Leuven): "There is an urgent need for new treatment options to slow down or counteract intestinal fibrosis in patients with Crohn's disease. Our study highlights new mechanisms leading to intestinal fibrosis, which could help develop effective anti-fibrotic treatments for various organs in the future, including the liver, lungs, heart, kidneys, and skin."
Approximately 3 in 1,000 people suffer from Crohn's disease, a chronic condition characterised by inflammation of the intestines and abdominal pain. The inflammation most often occurs at the junction of the last segment of the small intestine and the beginning of the large intestine, but other parts of the gastrointestinal tract can also be affected.
You can find more information at www.ibd-leuven.com
The in-press preview was published in The Journal of Clinical Investigation, and is part of the FIBROTARGET research project funded by the European Union’s Horizon Europe Research & Innovation programme under grant agreement No 101080523.