Gut “Memory” May Explain Why IBD Flares Return

Inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis, are characterized by recurring flare-ups that damage the intestinal mucosa and remain difficult to predict. Although acute intestinal injury often precedes these conditions, the mechanisms that transform temporary damage into chronic inflammation are not fully understood. Clinicians also lack reliable markers to determine whether apparently healed tissue remains at risk. New findings show that lasting changes in the gut’s extracellular matrix can encode an inflammatory “memory” that alters stem cell fate long after symptoms have subsided.

Researchers at the Weizmann Institute of Science investigated whether short-lived intestinal inflammation leaves lasting imprints in the extracellular matrix (ECM), the protein-sugar scaffold surrounding epithelial cells. In mouse models of acute colitis, they tracked tissue architecture and ECM properties for more than a year after clinical recovery. The team also used miniature three-dimensional intestinal organoids grown from stem cells, along with single-cell RNA sequencing (scRNA-seq) resources and seven biopsies from patients with ulcerative colitis, to probe how ECM alterations influence epithelial differentiation.

Image: The findings have potential implications for predicting flare-prone regions and identifying therapeutic targets for inflammatory bowel diseases. (Image Credit: iStock)

The study identified collagen 18 as a key mediator of this inflammatory imprint. According to the authors, collagen 18 can trap signaling molecules within the ECM, disrupting pathways that normally direct stem cells to rebuild healthy epithelium and instead biasing them toward pro-inflammatory epithelial states. Silencing collagen 18 expression in mice prevented the ECM from sustaining irreversible damage and halted progression to chronic disease, supporting a causal role for ECM remodeling in persistent inflammation.

Even after the animals appeared to recover, the ECM remained less stiff, more porous, and disorganized at 80 and 400 days, revealing a long-lasting “memory” within the tissue microenvironment. Organoids grown on the disrupted ECM formed malformed sheets rather than normal crypt–villus structures, while transcriptomic profiling showed that the cells matured into inflammation-promoting epithelial states that recruit immune cells.

Published August 26, 2026, in Immunity, the findings suggest that the ECM acts as a “logistics hub” that stores and regulates signaling cues, with potential implications for predicting flare-prone regions and identifying therapeutic targets such as collagen 18.

“Growing stem cells as organoids within a disrupted extracellular matrix was enough to change their fate. Using a single-cell RNA sequencing database and seven biopsies from patients with ulcerative colitis, we found that these same pro-inflammatory epithelial cells also characterize inflamed regions in patients. These findings make it clear that the extracellular matrix plays a critical role in chronic inflammation and could potentially make it possible to predict which regions will develop inflammation or experience a future flare-up. More broadly, the new study reveals just how central the ECM is in creating a microenvironment, or niche, that supports stem cell regeneration,” said Dr. Moshe Biton of the Weizmann Institute of Science.

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Weizmann Institute of Science