Gegen Qinlian decoction (GQD) inhibits ulcerative colitis by modulating ferroptosis-dependent pathway in mice and organoids

Abstract

Background Gegen Qinlian decoction (GQD) is a classic prescription for treating ulcerative colitis (UC) in traditional Chinese medicine. However, the therapeutic mechanism has not been fully clarified. Purpose In the present study, we aimed to evaluate the role of ferroptosis-mediated IEC death in UC treated mice with GQD by using DSS-induced a colitis mouse model and RSL3-induced ferroptosis in intestinal organoids. Methods The effects of GQD on DSS-treated colitis were examined via daily body weight, DAI, colon length, HE staining, PAS staining, ZO-1 and Occludin immunohistochemical staining. Ferroptosis was determined by analysis of iron load, MDA, GSH, mitochondrial morphology, and expression of ferroptosis-associated proteins (GPX4, SLC7A11 and ACSL4). Results In vivo, GQD administration reduced body weight loss and DAI scores, increased colon length, and improved intestinal histological characteristics and epithelial barrier dysfunction. GQD administration obviously improved the levels of ferroptosis markers (iron load, MDA, GSH, and mitochondrial morphology) and the expression of ferroptosis-associated proteins (GPX4, SLC7A11 and ACSL4). Consistent with in vivo results, GQD administration partially reversed the levels of mtROS, Fe2+ and MDA in intestinal organoids induced by RSL3, and notably improved morphological destruction, histological damage and epithelial barrier dysfunction in organoids. Conclusions In this study, we demonstrated that ferroptosis was triggered in DSS-induced experimental colitis and that GQD adiministration could protect against colonic damage and intestinal epithelial barrier dysfunction by inhibiting ferroptosis.

Natural compounds target programmed cell death (PCD) signaling mechanism to treat ulcerative colitis: a review

“…Activating this signal can reverse it . In addition, increasing GPX4 activity can effectively improve colon histological damage and intestinal epithelial barrier dysfunction and reshape intestinal microecology (Wang et al, 2023). In addition, experiments using DSS-induced NCM460 cells revealed that activation of the Nrf2-GPX4 signaling pathway could effectively protect intestinal epithelial cells from Ferroptosis injury and alleviate UC (Dong et al, 2021).…”

Short Chain Fatty Acids: Essential Weapons of Traditional Medicine in Treating Inflammatory Bowel Disease

“…Of note, the role of GQD in inducing SCFAs was also observed in the treatment of type 2 diabetes, it could increase the abundance of probiotics and SCFA-producing bacteria such as Bifidobacteria [ 76 ]. Wang et al [ 77 ] found that GQD could suppress UC by modulating the ferroptosis pathway in mice. Under this circumstance, GQD-induced production of SCFAs in the intestine might play an important regulatory role in the suppression of UC-associated conditions.…”