Isosteviol Sodium Exerts Anti-Colitic Effects on BALB/c Mice with Dextran Sodium Sulfate-Induced Colitis Through Metabolic Reprogramming and Immune Response Modulation

Abstract

Shanping Wang,1 Jiandong Huang,1 Fei Liu,1 Keai Sinn Tan,2,3 Liangjun Deng,1 Yue Lin,1 Wen Tan3,4 1Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, People’s Republic of China; 2College of Pharmacy, Jinan University, Guangzhou, People’s Republic of China; 3Post-Doctoral Innovation Site, Jinan University, Yuanzhi Health Technology Co, Ltd, Zhuhai, People’s Republic of China; 4Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, MalaysiaCorrespondence: Wen TanPost-Doctoral Innovation Site, Jinan University, Yuanzhi Health Technology Co, Ltd, Hengqin New District, Zhuhai, People’s Republic of ChinaTel/Fax [phone]Email [email protected]: Inflammatory bowel diseases (IBDs) are global health problems that are associated with immune regulation, but clinical IBDs treatment is currently inadequate. Effective preventive or therapeutic methods for immune disorders rely on controlling the function of immune cells. Isosteviol sodium (STV-Na) has antioxidant activity, but the therapeutic effect of STV-Na against IBD remain undocumented. Herein, we investigated the therapeutic effect of STV-Na in mice models with IBDs.Methods: Mice received 3.5% DSS for 7 days to establish IBD models. Intraperitoneal STV-Na was given 2 days before DSS and lasted for 9 days. Commercially available drugs used in treating IBDs (5-aminosalicylic acid, dexamethasone, and infliximab) were used as positive controls. Samples were collected 7 days after colitis induction. Histopathological score, biochemical parameters, molecular biology methods, and metabolomics were used for evaluating the therapeutic effect of STV-Na.Results: Our data revealed that STV-Na could significantly alleviate colon inflammation in mice with colitis. Specifically, STV-Na treatment improved body weight loss, increased colon length, decreased histology scores, and restored the hematological parameters of mice with colitis. The untargeted metabolomics analysis revealed that metabolic profiles were restored by STV-Na treatment. Furthermore, STV-Na therapy suppressed the number of CD68 macrophages and F4/80 cell infiltration. And STV-Na suppressed M1 and M2 macrophage numbers along with the mRNA expressions of proinflammatory cytokines. Moreover, STV-Na administration increased the number of regulatory T (Treg) cells while decreasing Th1/Th2/Th17 cell counts in the spleen. Additionally, STV-Na treatment restored intestinal barrier disruption in DSS-triggered colitis tissues by ameliorating the TJ proteins, increasing goblet cell proportions, and mucin protein production, and decreasing the permeability to FITC-dextran, which was accompanied by decreased plasma LPS and DAO contents.Conclusion: These results indicate that STV-Na can ameliorate colitis by modulating immune responses along with metabolic reprogramming, and could therefore be a promising therapeutic strategy for IBDs.Keywords: inflammatory bowel disease, isosteviol sodium, macrophage polarization, Th cells, barrier function, metabolomics

Keywords

• inflammatory bowel disease
• isosteviol sodium
• macrophage polarization
• th cells
• barrier function
• metabolomics