Daikenchuto ameliorates dextran sulfate sodium-induced acute and chronic ulcerative colitis by regulating gut microbiota-derived indoles to activate AhR signaling.

BACKGROUND: Ulcerative colitis (UC), a chronic-relapsing inflammatory disease with rising prevalence worldwide, is primarily driven by intestinal epithelial barrier dysfunction resulting from gut microbial dysbiosis and metabolic disturbances. Daikenchuto (DKT), a traditional Chinese medicine formulation, is commonly used for digestive disorders. Although DKT has demonstrated therapeutic potential for gut inflammation by modulating gut microbiota, its therapeutic effects on chronic ulcerative colitis (CUC) and the related mechanisms remain elusive. METHODS: The main components of DKT were tentatively identified using ultra-performance liquid chromatography-quadrupole-time of flight-mass spectrometry (UPLC-Q-TOF-MS), and the therapeutic effects of DKT were evaluated in the mouse models of acute colitis (AC) and CUC induced using dextran sulfate sodium. The models were validated based on alterations in the disease activity index (DAI), colonic inflammatory status, and intestinal barrier integrity. The impact of DKT on the dysbiosis of gut microbiota was evaluated using the 16S rRNA gene and metagenomic sequencing. Targeted metabolomics was conducted to quantify shifts in short-chain fatty acids and tryptophan (Trp) metabolites. To further elucidate the underlying mechanisms of DKT, key pathways were analyzed using Western blotting, immunohistochemistry, and real-time quantitative polymerase chain reaction. RESULTS: The principal constituents of DKT were tentatively identified. DKT administration significantly alleviated the symptoms of AC and CUC, reduced inflammation, and maintained intestinal barrier function. Furthermore, DKT modulated the structure and abundance of gut microbiota. Metagenomic sequencing analysis demonstrated that DKT significantly enriched the relative abundance of Ligilactobacillus murinus, Lactobacillus taiwanensis, and Lactobacillus johnsonii. Moreover, Trp metabolism and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathways might be the therapeutic mechanisms of DKT. Targeted metabolomics confirmed that Trp/indole was the major pathway during the therapeutic process of DKT on CUC. Further mechanistic studies demonstrated that activation of the aryl hydrocarbon receptor (AhR) signaling enhanced proliferation in the colonic crypts by stimulating IL-22 secretion and promoting STAT3 phosphorylation. CONCLUSIONS: DKT alleviated AC and CUC in mouse models by modulating gut microbiota, restoring Trp metabolism, and activating the AhR/IL-22/STAT3 signaling pathway. These findings provide a basis for the clinical application of DKT in UC patients.