Unravelling the Matrix in Crohn’s Disease

Crohn’s disease is a chronic inflammatory condition affecting the gastrointestinal tract, with rising rates of incidence and prevalence worldwide.¹ The hallmarks of disease include mucosal ulceration, transmural inflammation, and structural damage to the extracellular matrix (ECM), which when sustained can lead to fistula formation. Such penetrating fistulating disease predisposes to sepsis, increased nutritional requirements, and the need for surgical resections.² Remodeling of the ECM is a defining feature of fistulating Crohn’s disease. However, current licensed therapies are not targeted to matrix pathology and therefore have limited efficacy in the treatment of fistulae. Hence the need to improve the fundamental understanding of the molecular mechanisms that drive fistula formation.

The ECM encompasses a complex structural network of proteins, glycoproteins, and glycosaminoglycans, and has important functions in tissue injury and repair throughout the human body.³ Increasing evidence points toward a central role of the ECM microenvironment in perpetuating the chronicity of intestinal inflammation in Crohn’s disease, through mechanotransduction and sequestering of cytokines, growth factors, and ligands that create distorted morphogen gradients within the matrix.^4,5 In fistula formation the most prominent hypothesis to date involves epithelial-to-mesenchymal transition, whereby intestinal epithelial cells exhibit a loss of polarity and cell-cell adhesions, while acquiring migratory properties thus transforming into mesenchymal-like cells. Important previous studies demonstrated the strong expression of tumor necrosis factor (TNF) and the SNAIL family of transcription factors (SNAIL1) in the transition cells of Crohn’s-associated perianal fistula tracts.⁶

In this issue of Cellular and Molecular Gastroenterology and Hepatology, Rizzo et al⁷ bring this evidence one step further as they present an important mechanistic insight into the regulation of epithelial-to-mesenchymal transition in perianal fistula tracts. They first identify the gene TNFAI6 (TNF alpha induced protein 6) to be significantly upregulated along the fistula tract. TNFAI6 encodes the secretory protein (TSG-6) that contains a hyaluronan-binding domain known to be involved in ECM stability, cell migration, and inflammation-associated serine protease inhibitory activity. The peri-fistula ECM was observed to have higher pathologic crosslinks between hyaluronan and heavy chain complexes. This process was found to be mediated by mechanosensitive proteins highlighting new potential therapeutic targets. Furthermore, overexpression of recombinant human TSG-6 in Caco-2 cells resulted higher expression of SNAIL1 and hyaluronan synthase. These data were further supported in vitro using healthy human induced pluripotent stem cell–derived intestinal organoids, where SNAIL1 expression was markedly reduced in the epithelia of the organoids. Finally, in primary Crohn’s fistula-derived fibroblasts, overexpression of TSG-6 was found to promote an activated myofibroblast-like phenotype. Overall, their data reveal TSG-6 as a mesenchymal gene important for the conversion of epithelial to mesenchymal cells, independent of tissue origin. Interestingly, increased serum levels of TSG-6 have been found to be a biomarker closely affiliated to disease activity in other autoimmune inflammatory conditions, such as rheumatoid arthritis.⁸ Investigations into whether TSG-6 similarly offers biomarker potential in Crohn’s-related fistulating disease could prove highly impactful clinically. Future studies advancing knowledge in the mechanisms of stromal cell-matrix interactions, and microbial antigens, in Crohn’s disease will be crucial in identifying ECM-based therapeutic strategies for Crohn’s-related fistulating disease.