The Gut Microbiota‐Xanthurenic Acid‐Aromatic Hydrocarbon Receptor Axis Mediates the Anticolitic Effects of Trilobatin

Abstract Current treatments for ulcerative colitis (UC) remain limited, highlighting the need for novel therapeutic strategies. Trilobatin (TLB), a naturally derived food additive, exhibits potential anti‐inflammatory properties. In this study, a dextran sulfate sodium (DSS)‐induced animal model is used to investigate the effects of TLB on UC. It is found TLB significantly alleviates DSS‐induced UC in mice, as evidenced by a reduction in the disease activity index, an increase in colon length, improvement in histopathological lesions. Furthermore, TLB treatment results in a decrease in proinflammatory cytokines and an increase in anti‐inflammatory cytokines. TLB mitigates UC by modulating the intestinal microbiota, particularly Akkermansia , which enhances tryptophan metabolism and upregulates the production of xanthurenic acid (XANA). To confirm the role of TLB‐induced microbiota changes, experiments are performed with pseudogerm‐free mice and fecal transplantation. It is also identified XANA as a key metabolite that mediates TLB's protective effects. Both TLB and XANA markedly activate the aromatic hydrocarbon receptor (AhR). Administration of an AhR antagonist abrogates their protective effects, thereby confirming the involvement of AhR in the underlying mechanism. In conclusion, the study reveals a novel mechanism through which TLB alleviates UC by correcting microbiota imbalances, regulating tryptophan metabolism, enhancing XANA production, and activating AhR.