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 identified by an ultra-performance liquid chromatography-quadrupole-time of flight-mass spectrometry (UPLC-Q-TOF-MS) and the therapeutic effect of DKT was evaluated in mouse models of acute colitis (AC) and CUC model induced by dextran sulfate sodium. The model was validated based on alterations in the disease activity index (DAI), colonic inflammatory status, and intestinal barrier integrity. To evaluate the impact of DKT on dysbiosis of gut microbiota, 16S rRNA and metagenomic sequencing were performed. Targeted metabolomics was conducted to quantify shifts in short-chain fatty acids and tryptophan (Trp) metabolites in all groups. To further elucidate the underlying mechanisms of DKT, key pathways were analyzed by Western blotting, immunohistochemistry, and real-time quantitative PCR. Results The principal constituents of DKT were systematically identified. Administration of DKT 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 DKT significantly enriched 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 action of DKT. Targeted metabolomics study 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, restorating Trp metabolic, and acting AhR/IL-22/STAT3 signaling pathway. These findings provided a basis for applying DKT in UC patients.