Codonopsis pilosula (Dangshen) Alleviates Ulcerative Colitis Through Activation of the Aromatic Hydrocarbon Receptor Signaling Pathway by the Gut Bacterium Alistipes onderdonkii and Its Metabolite, 5-HIAA

Ulcerative colitis (UC) is a growing global health concern, but there remains a lack of natural food sources and multi-targeted drugs to effectively it. Codonopsis pilosula (dangshen, DS), a medicinal food used in traditional Chinese medicine, offers more comprehensive benefits than conventional drugs due to the numerous active compounds, such as lobetyolin, tangshenoside I, codonopsine, succinic acid, and raffinose, it contains. DS can be safely incorporated into diets to enhance UC treatment compliance and continuous management. This study explored the therapeutic effects and mechanisms of DS using microbial sequencing, metabolomics, and experimental validation. DS alleviated UC symptoms in mice to ultimately achieve reduced weight loss, colon shortening, disease activity, and histopathology scores. It lowered pro-inflammatory cytokine levels (IL-6, IL-1β, TNF-[Formula: see text], balanced Th17 and Treg cells, and enhanced the intestinal barrier integrity by upregulating tight junction proteins (ZO-1, occludin, E-cadherin). In addition, DS significantly reduced the abundance of pathogenic Escherichia-Shigella by modulating the composition of the intestinal flora and increasing the production of tryptophan metabolites (5-hydroxyindole-3-acetic acid (5-HIAA) and kynurenic acid (KYNA)) through probiotic bacteria, like Alistipes and Lactobacillus, which act as aromatic hydrocarbon receptor (AhR) ligands. We found that Alistipes onderdonkii cultured in vitro produced 5-HIAA, and that DS could further increase 5-HIAA levels. In addition, both 5-HIAA and DS activated AhR in turn. The diminished efficacy of DS in UC after colony clearance was accompanied by a decrease in the level of AhR, which suggests the importance of bacterial-derived metabolites as mediators of the efficacy of DS. The metabolomics results showed that DS mainly exerted its regulatory effects by modulating arachidonic acid metabolism and tryptophan metabolism. Based on our data, which elucidated the relationship between AhR and anti-inflammatory effects, we identified the AhR/NF-κBp65 signaling pathway as a potential pharmacological mechanism by which DS is associated with UC amelioration.