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

Abstract

Purpose: 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.

Macrophage polarization in inflammatory bowel disease

“…Previous immunotherapeutic treatments for IBD have focused on reducing M1 macrophages and increasing M2 macrophages to reduce the damage caused by pro-inflammatory factors secreted by M1 macrophages in the intestine [113]. However, M2-related genes have a greater role than simply suppressing inflammation, and subsequent adverse manifestations, such as fibrosis and granulomas, suggest that simply switching between M1 and M2 phenotypes is not a beneficial therapeutic approach [22,71]. Instead, sustaining a well-balanced ratio of polarized phenotypes or finding a solution to increase the number of anti-inflammatory phenotypic macrophages while mitigating the side effects associated with conventional therapies should be the focus of future research.…”

“…To elucidate if metabolism determines the macrophage phenotypes or whether macrophage polarization phenotypes determine metabolic status, numerous efforts have been made to determine the causal relationship between the two by demonstrating that alterations in specific cellular metabolism affect the macrophage phenotype and modulate the cytokine secretion profile at the level of bone marrow-derived macrophages [70]. The metabolic properties of M1 and M2 macrophages differ, and aerobic glycolysis is involved in macrophage M1 polarization, oxidative phosphorylation is involved in macrophage M2 polarization, and changes in metabolism have different effects on diverse macrophage phenotypes, which are reflected by a strong effect on the phenotype of M1 macrophages [70][71][72]. In IBD, Lee et al [73] found that LMT503 was able to alleviate IBD by promoting macrophage reprogramming.…”

Pretreatment with IPA ameliorates colitis in mice: Colon transcriptome and fecal 16S amplicon profiling

“…To investigate the ameliorative effect of IPA on colitis inflammation in mice, we established a DSS- induced acute colitis murine model. Weight loss, shortened colonic length, and increased colonic weight are commonly used as indicators of the severity of IBD ( 36 ). IBDs are characterized by body weight loss, bloody feces, diarrhea, shortening of the colon length, and splenomegaly.…”

Neutrophil extracellular traps induce intrahepatic thrombotic tendency and liver damage in cholestatic liver disease

“…M1 macrophages highly express TNF-α, which is associated with inflammation. [37] An immunohistochemical analysis of liver tissue using F4/80 (a marker of macrophages including M0) and CD86 (a marker of M1 macrophages) [37] demonstrated that BDL significantly increased both M0 and M1 macrophages in the liver on cholestatic mice on POD-14 (Fig. 5E, F).…”