Advances in the Pathogenesis of Crohn’s Disease-Associated Fistulas

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More than half of the patients with Crohn’s disease (CD) will develop intestinal fistulas, a distressing complication affecting the quality of life of the patients. Nowadays there are no satisfying treatment options for perianal fistulas, the most common fistula type. Surgeries are difficult due to the high risk of fecal incontinence. Furthermore, half of the surgically removed fistulas reoccur. Our knowledge about the pathophysiology of fistulas clearly needs improvement in order to develop new and/or more efficient therapeutic strategies to alleviate the burden of fistulas in patients. In a first study, we showed that active MMP9 (Matrix Metalloproteinase-9) which cleaves extracellular matrix (ECM), is present in human intestinal fistulas associated to CD. We showed that total and active MMP9 proteins are expressed in perianal as well as in entero-enteric fistulas of patients with CD. MMP9 is also expressed in fistulas in patients with CD, who do not respond to anti-TNF treatment. Interestingly, we detected a clear co-staining of active MMP9 and CK8 in fistulas, particularly in cells lining the fistula tract, such as transitional cells and myofibroblast-like single cells. Further, we found that total and active MMP9 are expressed in the human gut xenograft mouse model for intestinal fistulas. In the fistulas from mice treated with Humira (anti-TNF treatment), the expression pattern of MMP9 is similar to the one found in untreated xenograft fistulas and in clinical samples. MMP9 is thus a possible target for treatment of CD associated fistulas, and the human gut xenograft mouse model is a suitable in vivo model. In a second project, biomaterial from patients with perianal fistulas, with or without CD, were compared to gain further insight into the pathogenesis of fistulas of both origins. Only slight transcriptomic differences were detected between CD associated fistulas and fistulas of idiopathic/cryptoglandular origin, but clear differences in the microbiome composition. Systemic differences were observed in serum cytokine levels while differences in serum metabolomes were less prominent. We propose a transcriptional panel that can distinguish between cryptoglandular and CD derived fistulas using a single rectal biopsy. This is clinically relevant for patients with fistulas as the first manifestation of undiagnosed CD: initiating immunomodulatory or anti-TNF therapies could potentially delay luminal inflammation. In conclusion, this work demonstrates that MMP9 is a potential treatment target and can be tested in vivo in the human gut xenograft mouse model. Multi-OMICS analysis and comparison of fistulas, either CD associated or of cryptoglandular origin, revealed that the fistula-specific dysbiotic microbiome composition in CD might significantly contribute to fistula development. The biomolecular mechanisms involved in fistula development and maintenance are similar in both disease origins. Nevertheless, the single event or exact first mechanism of fistula formation has yet to be discovered. $\textit{Full-text embargoed until: 2026-11-20}$

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