Abstract
Ulcerative colitis (UC) is a chronic inflammatory disease that affects the colon, and its incidence is on the rise worldwide. Resveratrol (RSV), a polyphenolic compound, was recently indicated to exert anti-inflammatory effects on UC. Consequently, the current study was conducted to investigate the mechanism of RSV on alleviating UC in mice by mediating intestinal microflora homeostasis. First, potential targets that RSV may regulate UC were screened using the TCMSP database. Next, mice were treated differently, specifically subjected to sham-operation and dextran sulfate sodium (DSS) induction, and then treated or untreated with RSV. Disease Activity Index (DAI) and Hematoxylin-Eosin (HE) staining were employed to analyze the pathological changes of mice colon. In addition, the expression patterns of inflammatory factors in spleen tissues were detected using ELISA, while the protein expression patterns of phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), and vascular endothelial growth factor A (VEGFA) in colon tissues were determined by means of immunohistochemistry (IHC) and Western blot analysis. Moreover, changes in intestinal flora and metabolite diversity in UC were analyzed by metabonomics. It was found that RSV played inhibitory roles in the PI3K/Akt pathway in mice. Meanwhile, the administration of RSV induced downregulated the expressions of TNF-α, IFN-γ, IL-1β, IL-6, and IL-4. The six floras of Haemophilus and Veillonella were significantly enriched in UC, while Clostridium, Roseburia, Akkermansia, and Parabacteroides were found to be enriched in control samples. Lastly, it was noted that Akkermansia could regulate the intestinal flora structure of UC mice through triacylglycerol biosynthesis, glycerol phosphate shuttle, cardiolipin biosynthesis, and other metabolic pathways to improve UC in mice. Altogether, our findings indicate that RSV suppressed the activation of the PI3K/Akt pathway and reduced the VEGFA gene expression to alleviate UC in mice.
Highlights
Ulcerative colitis (UC) is one of the most common forms of inflammatory bowel disease, characterized by damage to colonic epithelial cells (Kuwada et al, 2021)
To further define the role of RSV in the phosphoinositide 3-kinase (PI3K)/Akt pathway by regulating vascular endothelial growth factor A (VEGFA) expression, we introduced a PI3K/Akt activator (740Y-P) in mice and adopted real-time quantitative polymerase chain reaction (RT-qPCR), Western blot analysis, and IHC, which revealed that the protein expression levels of VEGFA, PI3K p-Akt, and Akt were all significantly reduced in the colon tissues in the RG group while being increased in the colon tissues in the MG + PI3K/Akt activator group compared with the RG group (Figures 3D–F)
The current study was conducted to investigate the mechanism of RSV on alleviating UC in mice by mediating intestinal microflora homeostasis through the PI3K/Akt/VEGFA pathway, and the obtained findings revealed that RSV suppressed the activation of the PI3K/Akt pathway and reduced the VEGFA gene expression to alleviate UC in mice (Figure 6)
Summary
Ulcerative colitis (UC) is one of the most common forms of inflammatory bowel disease, characterized by damage to colonic epithelial cells (Kuwada et al, 2021). There are numerous drug treatment options available for UC, its nonresponsive behavior to systemic steroid therapy remains a huge challenge in the field of inflammatory bowel disease (Hoffmann et al, 2019). Vascular endothelial growth factor A (VEGFA) has previously been identified as a central target gene of RSV and has been known to exhibit better affinity with RSV (Wang W. et al, 2020). The current study aimed to verify how RSV regulates the PI3K/Akt/VEGFA pathway to relieve UC
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