Inflammatory bowel diseases are disorders characterized by recurrent inflammation in the digestive tract. These diseases cause considerable discomfort and pain, and prolonged inflammation can escalate into extensive tissue damage. A recently published study proposes an new perspective: predicting the progression of inflammation by analyzing the properties of the extracellular matrix (ECM). This discovery could transform the way the disease is treated and improve patients’ lives.

Advertisement

Inflammatory bowel diseases (IBD), which include Crohn’s disease and ulcerative colitis, are characterized by chronic inflammation of the gastrointestinal tract or by cycles of inflammatory flare-ups and remission. Today, most patients are treated with a broad range of anti-inflammatory drugs, from corticosteroids to antibodies that modulate the immune system. Despite significant advances in therapy and patient monitoring, many still suffer considerably from the symptoms of the disease. Repeated hospitalizations, surgeries, and, in many cases, irreversible tissue damage are common. Possible complications include scarring of the intestinal tissue that narrows the gut (fibrostenosis) or the formation of abnormal passageways between the intestine and other organs (fistulas) [1]. Such profound structural changes involve simultaneous construction and degradation of the extracellular matrix—a network of proteins and sugars that forms a scaffold to which cells adhere in tissues. Through the matrix, cells connect and create a stable, functional tissue with its characteristic three-dimensional architecture. The matrix also serves as a barrier between different tissues and organs. One of the steps in fistula formation, for example, is damage to the matrix that breaks this physical barrier. In many cases, these complications cannot be prevented or treated pharmacologically, leaving surgery and other invasive procedures as the main options [2, 3]. Therefore, it is crucial to find ways to prevent damage to the tissue and the extracellular matrix in advance, rather than treating only the inflammation itself [4].

For years, the prevailing assumption was that chronic or recurrent inflammation gradually damages the matrix, making matrix injury a late side-effect of the disease. Over time, however, evidence accumulated that certain matrix-degrading enzymes (MMPs) play a role in disease development [5] and that inhibiting them may prevent inflammation [6]. Based on this evidence, my PhD advisor Prof. Irit Sagi (Weizmann Institute) and I asked two questions: At what stage of the disease do changes in the extracellular matrix begin? And do matrix-degrading enzymes significantly influence the matrix and future disease progression at these early stages?

In a study [7] recently published in Matrix Biology, we (together with our collaborators) show that, contrary to common belief, the extracellular matrix is not affected only when inflammation is already in full swing. Disease-related changes appear in the extracellular matrix while the disease is still pre-symptomatic—that is, before inflammatory symptoms emerge and before conventional diagnostics such as colonoscopy or biopsy can detect inflammation. We demonstrate that the pre-symptomatic matrix bears a unique “fingerprint” that distinguishes it from the matrix of a healthy gut: it is less rigid and differs in protein composition and spatial organization. Using two different mouse models of colitis, we show that the pre-symptomatic matrices in both models are highly similar, even though each model involves a distinct inflammatory pathway and different immune-cell populations. We therefore conclude that several forms of colitis share a common phenomenon: an extracellular matrix with a pre-symptomatic fingerprint that marks a “silent” state prepared to erupt into inflammation.

One striking feature of this pre-symptomatic fingerprint is damage to a specific part of the extracellular matrix called the basement membrane [8]. The basement membrane is a dense “fabric” on which the epithelial cells of the colon rest. It forms one of the gut’s defense layers, separating gut microbes from the inside on the body. Damage to the basement membrane can expose the immune system to the gut microbiota and trigger an inflammatory response. We found that a very small number of immune cells infiltrate the gut at the pre-symptomatic stage, and each disease model involves different cell types. Despite their low numbers, these pioneer immune cells bring with them an array of matrix-degrading enzymes, particularly ones capable of breaking down the basement membrane.

Thus, in contrast to the prevailing view that changes in the extracellular matrix are merely late by-products of inflammation, our study opens the door to a new understanding: matrix alterations occur in parallel with, and may even participate in, the development of inflammation. We propose that this interplay between matrix damage and pioneer immune cells breaches the barrier and paves the way for a larger influx of immune cells that culminates in full-blown inflammation.

These are pre-clinical findings, and much work remains before they can be used to improve patient monitoring or predict flare-ups. Nonetheless, we hope that follow-up studies will further unravel the extracellular matrix’s role in inflammation. This research direction could lead to advanced tools for early diagnosis, ultimately improving the quality of life of those living with IBD and guiding their treatment.

References:

1. Website of the Crohn’s and Colitis Foundation
2. An in-depth interview with Florian Rieder, one of the world’s leading experts on fibrostenosis
3. Review article on fistulas in Crohn’s disease
4. Review article on the extracellular matrix in IBD that calls for revisiting the prevailing paradigm
5. Review article on matrix-degrading enzymes in IBD
6. Article showing how targeted inhibition of gelatinases prevents colitis development in mice
7. The original article in Matrix Biology
8. Review article on the basement membrane