N‐Trans Caffeoyltyramine Alleviates Ulcerative Colitis by Targeting FXR to Promote Epithelial Barrier Protection and M2 Macrophage Polarization

BACKGROUND AND AIM: Ulcerative colitis (UC) remains a clinical challenge owing to the complex pathogenesis and lack of curative therapies. Although Cannabis sativa has been associated with alleviating inflammatory bowel disease, the specific active constituents and underlying mechanisms remain poorly defined. The present study aimed to systematically evaluate the anti-UC effects and mechanisms of two structurally related compounds from C. sativa extracts, N-trans caffeoyltyramine (NCT), and N-trans feruloyltyramine (NFT). EXPERIMENTAL PROCEDURE: We compared the therapeutic efficacy of NCT and NFT in an acute UC mice model, and investigated the underlying mechanisms using both colonic epithelial cells and macrophages. To validate the involvement of the nuclear receptor FXR, we performed genetic loss-of-function approaches to assess the impact on epithelial barrier integrity and macrophage polarization. KEY RESULTS: NCT is proven superior to NFT in alleviating acute UC. Remarkably, NCT exerts therapeutic efficacy by coordinating two pivotal aspects of UC pathogenesis. It improves tight junction structural integrity through upregulation of tight junction proteins while simultaneously promoting a protective M2 macrophage polarization. Mechanistically, FXR was identified as a key mediator of the effects of NCT, contributing to both barrier enhancement and macrophage phenotype switching. CONCLUSIONS AND IMPLICATIONS: The results provide a molecular rationale for the anti-UC activity of C. sativa and suggest that NCT alleviates UC, at least in part through FXR-mediated pathways. These findings support further preclinical development of NCT as a potential therapeutic candidate for UC.