Aucubin Alleviates Ulcerative Colitis in Mice by Repairing the Intestinal Barrier and Modulating the Microbiota-Metabolism Axis

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with a complex pathogenesis, necessitating the development of safe and effective therapeutic interventions. This study aimed to investigate the protective effects and underlying mechanisms of Aucubin (Auc) against dextran sulfate sodium (DSS)-induced UC in mice. Using a DSS-induced colitis model, we systematically evaluated the multifaceted effects of Auc by assessing the Disease Activity Index (DAI), colon length, histopathological changes, immunohistochemical staining, ELISA results, proteomic profiles, 16S rRNA sequencing data, and untargeted metabolomic analyses. Compared with the DSS group, Aucubin high-dose (Auc-H, 100 mg/kg) treatment significantly attenuated DSS-induced body weight loss, DAI score elevation, and colon shortening (all p < 0.05). The therapeutic efficacy of Auc-H was comparable to that of the positive control drug 5-aminosalicylic acid (5-ASA). Mechanistically, Auc restored intestinal barrier integrity by stimulating mucin 2 (Muc2) secretion and upregulating the expression of zonula occludens-1 (ZO-1) and Occludin, which in turn significantly reduced serum lipopolysaccharide (LPS) concentrations (p < 0.001). Proteomic analysis identified 2180 DSS-induced differentially expressed proteins, of which 679 were significantly counter-regulated by Auc-H, mainly involving the complement and coagulation cascades and immune-inflammatory pathways. Furthermore, gut microbiota analysis showed that Auc promoted the growth of beneficial bacteria, improving microbial balance. Untargeted metabolomics further revealed that Auc-H significantly restored the levels of 120 DSS-induced differential metabolites, including 86 upregulated and 34 downregulated metabolites, among which were protective tryptophan-derived indole metabolites (p < 0.05). Consequently, Aucubin exhibits significant clinical potential in alleviating UC via a multifaceted mechanism. These effects include reduced inflammation, restored epithelial barrier integrity, and modulated microbial metabolism. These findings provide crucial experimental evidence supporting the potential application of Auc as a preventive therapy for UC.