Astragaloside IV Alleviates DSS-Induced Ulcerative Colitis by Modulating Host–Gut Tryptophan Metabolism

Astragaloside IV (AS-IV), a principal bioactive constituent of the medicinal and edible herb Radix Astragali, exerts protective effects against ulcerative colitis (UC). This study investigated its underlying mechanisms in dextran sulfate sodium (DSS)-induced colitis using 16S rRNA sequencing, untargeted fecal metabolomics, and label-free proteomics. AS-IV intervention remodeled intestinal microbiota composition by markedly increasing Akkermansia abundance. Fecal metabolomic analysis revealed enhanced tryptophan (Trp) metabolism and elevated levels of kynurenic acid, 5-hydroxyindoleacetic acid and indole-3-acetic acid, which were significantly positively correlated with Akkermansia abundance. Proteomic analysis further identified Trp metabolism as a key pathway. Indoleamine 2,3-dioxygenase 1 (IDO1) and dopa decarboxylase (DDC) were recognized as differentially expressed proteins in colonic tissues. AS-IV ameliorated colitis by downregulating IDO1 expression, while upregulating the expression of tryptophan hydroxylase 1 (TPH1), DDC, monoamine oxidase A (MAO-A), and the aryl hydrocarbon receptor (AhR), as well as inhibiting NF-κB p65 phosphorylation. Collectively, these findings indicate that AS-IV enhances intestinal barrier function and mitigates colonic inflammation in DSS-induced UC. These beneficial effects are associated with the regulation of host–gut Trp metabolism, altered AhR expression, and suppressed NF-κB p65 activation. This study underscores the potential of AS-IV as a candidate functional food ingredient for the management of UC.