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

Background: 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: Histopathological score, biochemical parameters, molecular biology methods, and metabolomics of the results have been used for making an evaluation of therapeutic effect of STV-Na against IBD. Findings: Our data revealed that STV-Na could significantly alleviate colon inflammation in colitis. Specifically, STV-Na treatment improved body weight loss, shortened the involved colon length, decreased histology scores, and restored the hematological parameters of mice with colitis. Untargeted metabolomics analysis revealed that metabolic profiles were restored by STV-Na. Furthermore, STV-Na suppressed the number of macrophages and 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. Additionally, STV-Na restored intestinal barrier disruption 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. Interpretation: 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. Funding Statement: This work was supported through the National Science and Technology Major Projects of China (2019ZX09301120). Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: All experimental animal protocols were passed by the Institutional Animal Care and Use Committee of Sun Yat-sen University, Guangzhou, China (Ethical Approval No. IACUC 20140515171141).