Ursolic Acid Alleviates DSS-Induced Colitis and Associated Liver Damage by Restoring Treg/Th17 Balance and Modulating Gut Microbiota and Its Histidine Metabolism

Ursolic acid (UA), a natural compound abundant in fruits and vegetables, exhibits established anti-inflammatory and hepatoprotective properties. This study investigated the therapeutic potential of UA as a dietary supplement for DSS-induced colitis and secondary liver injury using both an <i>in vivo</i> DSS-induced colitis mouse model and an <i>in vitro</i> intestinal epithelial cell model. Colitis model mice were administered UA at doses of 5, 25, 100, and 250 mg/kg. Through comprehensive analyses, including enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), immunofluorescence (IF), Western blot, 16S rRNA sequencing, untargeted metabolomics, and transcriptomics, we demonstrated that 25 mg/kg UA optimally alleviated colitis symptoms. The mechanism involves restoring the balance between T regulatory cells (Treg) and T helper 17 cells (Th17) to reduce inflammation, potentially mediated by increased production of propionate from short-chain fatty acid (SCFA)-producing bacteria. Additionally, UA inhibits <i>Escherichia coli</i> (<i>E. coli</i>) growth through the action of the microbial metabolite l-histidine, thereby enhancing intestinal barrier integrity and inhibiting pyroptosis. Moreover, 25 mg/kg of UA exerts protective effects against liver injury by suppressing inflammation-related signaling pathways in colitis mice. These findings position UA as a promising functional food component for managing colitis and its hepatic complications.