Scientists have uncovered the mechanism of intestinal "memory" after inflammation
Even after the intestinal inflammation subsides and the person feels healthy, the tissues may not fully return to their previous state. Scientists from the Weizmann Institute of Technology have discovered that the extracellular matrix — a kind of "skeleton" of tissue — is able to preserve a kind of "inflammatory memory" for more than a year. According to researchers, it is she who can interfere with the normal recovery of the intestine and contribute to the development of chronic inflammatory diseases. About what inflammatory memory is, why it's not just about immune cells, and how a new discovery can change the approach to treating Crohn's disease and ulcerative colitis.
Not only the immune system: where the intestine stores memories of the disease
Inflammation is the body's natural defense response to infection or tissue damage. Usually, after eliminating the cause, the inflammatory process gradually subsides, and the tissues are restored. That is why for a long time it was believed that after recovery, the intestines almost completely return to their original state. However, a new study published in the journal Immunity shows that this does not always happen.
The extracellular matrix, a network of proteins and other molecules that surrounds cells, has become the focus of scientists' attention. Previously, it was considered mainly as a mechanical support for fabrics. Today it is becoming clear that the matrix is actively involved in the transmission of signals between cells, influences their behavior and helps regulate the recovery processes.
The researchers suggested that it is this structure that is able to preserve the effects of inflammation. To test the hypothesis, they induced short-term intestinal inflammation in mice, and then monitored the condition of the tissues for more than a year after recovery. Despite the disappearance of the symptoms of the disease, the extracellular matrix continued to be altered.
Irit Sagi, Professor
A month after the start of the experiment, all the mice recovered, but their extracellular matrix refused to "forget" the damage. The tissue failed to regenerate properly, and the shape of the intestine remained distorted even after 80 days. In fact, the extracellular matrix lost its characteristic rigidity; it became porous, and its structure remained disrupted even after 400 days.
How "memory" changes the work of stem cells
The intestine is considered one of the fastest-renewing body tissues. Its inner shell is completely renewed approximately every three to five days, and intestinal stem cells are responsible for this process. They are the ones who constantly form new epithelial cells, replacing old and damaged ones.
To understand whether the altered matrix affects these cells, the scientists used intestinal organoids, miniature three—dimensional models of the intestine grown in the laboratory. Healthy stem cells were placed in an extracellular matrix modified after inflammation. The result was unexpected: instead of forming normal tissue, the cells began to turn into epithelial cells that support inflammation.
Moshe Biton, the Doctor
Using a database of single cell RNA sequencing and seven biopsies from patients with ulcerative colitis, we found that these same pro-inflammatory epithelial cells are also characteristic of inflamed areas in patients. These results clearly show that the extracellular matrix plays a critical role in chronic inflammation and could potentially allow us to predict in which areas inflammation will develop or a future exacerbation will occur.
Interestingly, similar changes have previously been found in the intestinal stem cells of patients with inflammatory bowel diseases. A study published in the journal Cellular and Molecular Gastroenterology and Hepatology concluded that they are able to preserve epigenetic memory of inflammation even outside the body, which also indicates a long-term change in their properties.
Why it's important for Crohn's disease and ulcerative colitis
Chronic inflammatory bowel diseases include primarily Crohn's disease and ulcerative colitis. They are characterized by alternating periods of remission and exacerbations, but until now, scientists have not been able to fully explain why, after temporary damage, tissues in some people recover, while in others the disease becomes chronic.
The authors of the study believe that one of the missing elements may be the state of the extracellular matrix. If it retains the effects of previous inflammation, the tissue is predisposed to repeated episodes of the disease. It is especially important that the researchers found the most pronounced changes in those areas of the intestine where people most often develop ulcerative colitis.
Scientists associate the key role with the protein collagen XVIII. Previously, it was considered only as an early marker of inflammatory bowel diseases, but now it has been found that this protein is able to retain signaling molecules and alter the development of stem cells. When the researchers suppressed the formation of collagen XVIII in mice, irreversible changes in the matrix did not occur, and the development of chronic inflammation was prevented.
This means that collagen XVIII has the potential to become a new therapeutic target. Instead of dealing only with the inflammation that has already arisen, doctors in the future will be able to influence the processes that trigger the chronic disease much earlier.
What does this change for medicine?
Today, most modern medications for Crohn's disease and ulcerative colitis primarily affect the immune system, reducing inflammation and helping to achieve remission. However, even the most effective medications do not always prevent new flare-ups. According to the authors of the study, one of the reasons may be that the treatment eliminates the effects of inflammation, but does not change the environment in which the tissues are restored.
If further studies confirm the results, the extracellular matrix may become not only a new target for therapy, but also an early diagnostic tool. During its restructuring, numerous protein fragments are formed, some of which enter the bloodstream. Scientists are currently working on technologies that will make it possible to use such changes as biomarkers of various diseases.
Moshe Biton
Now that we understand that changes in the extracellular matrix determine the fate of stem cells and that these processes underlie the inflammatory response, it becomes clear that existing treatments are aimed at the end result, not the root of the problem. We hope that our discoveries will eventually lead to a therapeutic approach that will cover the entire chain of tissue regeneration, from the extracellular matrix, through stem cells, to the immune response.
So far, the work has been done on animal models, so it's too early to talk about the imminent appearance of new treatment methods. Nevertheless, the study changes the very idea of tissue repair: it turns out that even after the symptoms disappear, the body can continue to store a kind of "biological memory" of the disease.
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