Background and aims: Intestinal fibrosis is a major contributor to the high operation rate in Crohn's disease (CD) while current precise biomarker at the early stage of fibrosis as well as the effective treatment targeting fibroblasts is lacking. Fibroblast heterogeneity is central to the pathogenesis of intestinal fibrosis, but the underlying mechanism is unclear. Our group firstly identified Meflin (encoded by the ISLR gene) as a novel marker for mesenchymal stromal cells (MSCs) before, and we have characterized specific Meflin-positive fibroblasts in a single-cell atlas in CD patients. Therefore, the aim of our study was to explore the possibility and reveal the detailed mechanism that Meflin is a key biomarker and regulator in CD-associated fibrosis. Furthermore, we were focusing on Explore new methods which elevate Meflin expression levels and alleviate intestinal fibrosis in CD patients.
Methods and results: We found Meflin was highly expressed in the fibroblast of the non-stenosis lesion and downregulated in the stenosis region of CD patients. In dextran sulfate sodium (DSS)-induced intestinal fibrosis model, we found Meflin expression in fibroblasts were elevated in the early stage of fibrosis and downregulated in the late stage of fibrosis. Furthermore, Meflin deficiency led to more severe intestinal fibrosis in the DSS-induced chronic inflammation model indicated that Meflin-positive fibroblasts had anti-fibrotic properties to prevent intestinal fibrosis. We previously performed chemical library screen and identified a drug that induced Meflin expression in fibroblasts. Then we confirmed the drug we identified promoted Meflin expression in intestinal fibroblasts in vitro as well as in DSS-induced intestinal fibrosis model in vivo. Interestingly, we found that administration the special drug improved intestinal fibrosis in DSS-induced intestinal fibrosis model in vivo and reduced the secretion of pro-fibrotic mediators in human primary intestinal fibroblasts isolated from CD patients in vitro and ex vivo.
Conclusion: Our research identifies a novel biomarker for recognizing intestinal fibrosis at the early stage in CD patients which is lacking in clinic so far. Meanwhile, we reveal a new perspective for developing new drugs for countering intestinal fibrosis via modulating fibroblast heterogeneity. These findings provide new insights into the pathogenesis of CD and may guide the development of future therapeutics and our results uncover an underlying pathogenesis of intestinal fibrosis in CD patients which lays a solid foundation in supporting our new treatment target development.

Atsushi Enomoto

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