The Effect and Mechanism of Thalidomide in Ameliorating Crohn’s Disease-Related Intestinal Fibrosis

Objectives: A common side effect of inflammatory bowel disease (IBD) is intestinal fibrosis, which frequently leads to intestinal blockage and stricture formation. Although Thalidomide (THD) has shown anti-fibrotic benefits in hepatic and renal models, little is known about how it affects intestinal fibrosis and the underlying processes. The present research examines the molecular targets of THD and its potential as a treatment for intestinal fibrosis brought on by colitis. Methods: Clinical samples from Crohn’s disease (CD) patients with intestinal strictures treated with infliximab (IFX) and THD combined with IFX were collected. Dextran sulfate sodium (DSS) was used to develop a mouse model of intestinal fibrosis in C57BL/6 mice. Anti-tumor necrosis factor-alpha (Anti-TNFα), THD, or a combination of the two were administered to the mice. Body weight, colon length, histology, and disease activity index were used to evaluate the disease’s severity. In vitro, THD was tested on colonic fibroblast lines (CCD-18Co and MPF) to assess its effects on cell proliferation, motility, and transdifferentiation. To examine changes in gene expression and signaling pathway modifications, namely in the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway, RNA sequencing, qRT-PCR, and Western blotting were carried out. Results: In DSS-induced colitis, THD therapy lowered fibrosis, as seen by downregulated fibrotic markers (α-smooth muscle actin (α-SMA), collagen I, and collagen III) and decreased collagen deposition. Mechanistically, THD prevented fibroblasts from transdifferentiating and decreased their vitality. Furthermore, THD inhitited the PI3K/AKT/mTOR pathway in vivo and in vitro. Conclusion: THD inhibits the PI3K/AKT/mTOR signaling cascade and suppresses colonic fibroblast transdifferentiation, which protects against DSS-induced colitis-associated fibrosis, especially when combined with anti-TNFα therapy.