Objective: To explore the molecular mechanism by which emodin improves inflammatory bowel disease (IBD) by regulating gut microbiota and its metabolites, with a focus on analyzing its regulatory effect on the “microbiota immune epithelial regeneration” network. Method: A colitis model was induced in C57BL/6 mice using 3% sodium dextran sulfate (DSS). A control group, a model group, a low/high dose group of emodin (20/40 mg/kg), and a positive control group of 5-aminosalicylic acid (5-ASA) were established. Evaluate inflammatory phenotype through Disease Activity Index (DAI), colon length, and histopathology;16S rRNA sequencing was used to analyze the composition of gut microbiota, and metabolomics was used to detect the levels of short chain fatty acids (SCFAs); Epithelial regeneration markers; Flow cytometry was used to detect the proportion of Th17/Treg cells. Result: Emodin significantly improved the IBD phenotype, with a 43.9% decrease in DAI score in the high-dose group compared to the model group (2.3 ± 0.5 vs 4.1 ± 0.3), and a 97.6% recovery in colon length compared to the normal group (8.3 ± 0.2 vs 8.5 ± 0.3 cm).Microbial analysis showed that emodin inhibited the abundance of Enterobacteriaceae by 96.5% (1.09% vs 31.6%) and increased the abundance of Lactobacillus (+65.1%) and Bifidobacterium (+59.7%).Metabolomics confirmed that the level of butyric acid increased by 3.2 times (P<0.001), while activating FOXO1 nuclear translocation (3.7 times) and SOX9 expression (2.9 times), promoting a 2.3-fold increase in SOX9+crypt basal columnar cell density (P<0.01).Mechanistically, butyric acid enhances FOXO1/FOX9 signaling by inhibiting AKT phosphorylation, upregulates tight junction protein ZO-1 (+110%), and regulates Th17/Treg balance (Th17 decreased by 58.3%, Treg increased by 37.2%). Conclusion: Emodin provides a multi-target intervention strategy for IBD treatment by reshaping the structure of gut microbiota, increasing butyric acid production, synergistically activating the FFAR1/FOXO1-SOX9 pathway, promoting mucosal regeneration, and restoring immune homeostasis.
