Berberine Improved the Therapeutic Efficacy of UC-MSCs for DSS-Induced Colitis via Aerobic Glycolysis.

Abstract

The global prevalence of inflammatory bowel disease (IBD) continues increasing, but effective targeted treatments remain elusive. Recently, mesenchymal stem cells (MSCs) have emerged as a promising candidate for IBD treatment, with energy metabolism playing a critical role. Berberine (BBR), a natural extract from Berberidaceae plants, has been shown to modulate various cell functions by reprogramming metabolism in immune-related diseases. This study aims to investigate the influence of BBR on the therapeutic effectiveness of MSCs in colitis. Using the colitis mice model, we compared the therapeutic effects of BBR treated MSCs (MSC_BBR) and untreated MSCs by evaluating colon length, Disease Activity Index, and histopathological change. Various methods were employed to detect the differences of MSC_BBR and MSCs, including seahorse analysis for energy metabolism, RNA-seq and qPCR for gene transcription, western blotting for protein expression, flow cytometry for phenotypic analysis, and cytokine production. Our results revealed that BBR treatment activated the AMPK signaling pathway, upregulated the expression of glucose transporter 1 (GLUT1), and promoted aerobic glycolysis in MSCs. Comparing to MSCs, MSC_BBR exhibited the increased expression of tumor necrosis factor-stimulated gene-6 (TSG-6), enhanced immunomodulatory function and superior therapeutic efficacy. Inhibition of either glycolysis or TSG-6 expression impaired the therapeutic effect of MSC_BBR, while overexpression of GLUT1 or TSG-6 obviously improved the therapeutic efficacy of MSCs. BBR treatment improved the therapeutic effect of MSCs in colitis by promoting aerobic glycolysis, providing a safe new approach for optimizing MSCs-based therapy in IBD through reprogramming energy metabolism.