Israeli Scientists Discover Intestinal 'Memory' Mechanism Linked to Chronic Inflammatory Bowel Diseases
Researchers at the Weizmann Institute of Science have uncovered a mechanism in the intestinal extracellular matrix (ECM) that may contribute to the development of chronic inflammatory bowel diseases such as Crohn's disease and ulcerative colitis. Their study, published in the journal Immunity on Wednesday, shows that even after acute intestinal inflammation subsides, irreversible changes in the ECM persist, altering stem cell behavior and disrupting mucosal regeneration. This "negative memory" effect could perpetuate inflammation and lead to chronic disease.
The research team, led by Dr. Idan Adir under the guidance of Prof. Irit Sagi and Dr. Moshe Biton, used mouse models and lab-grown intestinal organoids to demonstrate that damage to the ECM during inflammation causes lasting structural changes. These changes include accumulation of collagen 18, which was previously identified as an early marker for inflammatory bowel disease. The altered ECM environment directs stem cells to differentiate into pro-inflammatory epithelial cells, which recruit immune cells and sustain inflammation.
Long-term follow-up of mice showed that the ECM remained disrupted for over a year after inflammation, with loss of normal tissue stiffness and architecture. When the gene encoding collagen 18 was deleted in mice, tissue regeneration improved and chronic inflammation was prevented. The researchers also analyzed human biopsy samples from ulcerative colitis patients, confirming similar ECM alterations and the presence of pathological epithelial cells marked by KRT7.
These findings suggest that the ECM acts as a "logistics center" storing and regulating signals that influence tissue renewal and inflammation. The team is now investigating whether ECM-related markers can predict disease severity, flare-ups, or response to biological therapies in patients. They are collaborating with Sheba Medical Center to track patients over time and explore treatments targeting collagen 18 accumulation to promote proper tissue healing and prevent chronic disease progression.
Prof. Sagi noted that this ECM "memory" phenomenon may extend beyond the gut, potentially impacting diagnosis and treatment of various diseases. The study highlights the need for therapies addressing the root causes of inflammation by targeting the ECM, stem cells, and immune system simultaneously, aiming to improve outcomes for patients who do not respond well to current immune-focused treatments.
