Abstract
Inflammatory bowel diseases (IBDs) constitute a group of chronic intestinal conditions prominently featuring deranged metabolism. Effective pharmacological treatments for IBDs are lacking. Isosteviol sodium (STV-Na) exhibits anti-inflammatory activity and may offer therapeutic benefits in chronic colitis. However, the associated mechanism remains unclear. This study is aimed at exploring the therapeutic effects of STV-Na against chronic colitis in terms of metabolic reprogramming and macrophage polarization. Results show that STV-Na attenuated weight loss and colonic pathological damage and restored the hematological and biochemical parameters in chronic colitis mice models. STV-Na also restored intestinal permeability by increasing the goblet cell numbers, which was accompanied by lowered plasma lipopolysaccharide and diamine oxidase levels. Metabolomic analysis highlighted 102 candidate biomarkers and 5 vital pathways that may be crucial in the potential pharmacological mechanism of STV-Na in regulating intestinal inflammation and oxidative stress. These pathways were glycerophospholipid metabolism, phenylalanine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, the pentose phosphate pathway, and phosphonate and phosphinate metabolism. Furthermore, STV-Na significantly decreased M1 macrophage polarization in the spleen and colon. The mRNA and protein levels of IL-1β, TNF-α, and NF-κB/p65 in colonic tissue from the colitis mice were decreased after the STV-Na treatment. Overall, STV-Na could alleviate chronic colitis by suppressing oxidative stress and inflammation levels, reprogramming the metabolic profile, inhibiting macrophage polarization, and suppressing the NF-κB/p65 signaling pathway. STV-Na remains a promising candidate drug for treating IBDs.
Highlights
Both Crohn’s disease (CD) and ulcerative colitis (UC) are prototypical inflammatory bowel diseases (IBDs)
We subsequently investigated whether STV-Na inhibits nuclear factor-κB (NF-κB)/p65 protein nuclear translocation We found that Dextran sodium sulfate (DSS) increased the mRNA and protein expression of NF-κB/p65 pathway components in contrast to the control groups, while the STV-Na, 5-ASA, or IFX treatments reduced the expression of these pathway components (Figures 8(c)–8(e))
This study provides novel insight into the role and mechanism of action of STV-Na in treating chronic colitis by altering plasma metabolic profiles and regulating macrophage polarization
Summary
Both Crohn’s disease (CD) and ulcerative colitis (UC) are prototypical inflammatory bowel diseases (IBDs). These conditions manifest as waxing and waning gastrointestinal tract inflammation, and both harbor complex pathogeneses [1]. Patients with IBDs usually present with severe abdominal pain, diarrhea, anemia, and bloody stool symptoms, along with other markers of inflammation. Current evidence indicates that chronic intestinal inflammation significantly increases the risk of colorectal cancer [2]. IBDs are thought to arise from a combination of genetic factors, Oxidative Medicine and Cellular Longevity intestinal immune system dysfunction, metabolic disorders, and colonic barrier function disruption [3]. Considering the mucosal immune dysfunction and metabolic disorders involved in chronic colitis, more in-depth studies investigating the roles of the immune system and metabolite balances are critical for understanding the therapeutic effects and mechanisms
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