Vanillic acid protects against ulcerative colitis by modulating oxidative stress, inflammatory response, macrophage...

Ulcerative colitis (UC), a chronic inflammatory bowel disease, significantly impairs patients' quality of life. Although conventional therapies remain widely utilized, their effectiveness is often constrained by undesirable side effects and frequent relapses. Therefore, new treatment strategies are urgently needed to minimize toxicity and enhance sustainability. In this study, we investigated the protective effects and underlying mechanisms of vanillic acid (VA) against UC using both cells and mouse models. In vitro experiments demonstrated that VA pretreatment effectively attenuated the lipopolysaccharide (LPS) induced accumulation of reactive oxygen species and superoxide anions in RAW 264.7 cells. Furthermore, VA decreased the expression of NFκB, IL-6, and IL-1β while increasing the expression of Claudin-1, Occluding, and ZO-1 in LPS stimulated NCM460 cells. In vivo, UC was induced by dextran sulfate sodium (DSS) and VA was administered orally. The results indicated that, treatment with VA could significantly alleviate weight loss, shorten colon length, decrease DAI score, and alleviate intestinal damage caused by DSS. Mechanistically, VA ameliorated UC by reducing oxidative stress, suppressing inflammation, regulating macrophage polarization, and enhancing intestinal barrier integrity. Moreover, transcriptome analysis combined with KEGG pathway enrichment revealed that VA modulated key pathways in colon tissue, including the AMPK signaling pathways, PPAR signaling pathways, neuroactive ligand-receptor interaction, and linoleic acid metabolism. The results indicate the therapeutic potential of VA in the treatment of UC, providing a new insight into its mechanisms of action and establishing a foundation for future clinical applications.