BACKGROUND & AIMS: Exogenous recombinant Fibroblast growth factor 20 (FGF20) protein has been proved that can treat ulcerative colitis, however, its mechanism of action remains unclear. This study aimed to explore the role and mechanism of action of FGF20 in ulcerative colitis. METHODS: Data from patients with ulcerative colitis were analyzed using the Gene Expression Omnibus dataset. A murine colitis model was established by administering 2% dextran sodium sulfate (DSS). FGF20 knockout (KO) mice and Adeno-associated viruses (AAV)-FGF20 treated-mice were used to elucidate the specific mechanisms. Proteomic analysis was conducted to identify differentially expressed genes. RESULTS: FGF20 levels were significantly elevated in the colonic tissues of both subjects and mice with colitis. FGF20 deficiency exacerbated DSS-induced colitis
in contrast, FGF20 replenishment alleviated colitis through two principal mechanisms-restoration of impaired intestinal epithelial barrier integrity and inhibition of M1 macrophage polarization. Notably, S100A9 was identified as a pivotal downstream target of FGF20, which was further demonstrated by pharmacological inhibition and overexpression experiments of S100A9 using paquinimod (a specific inhibitor of S100A9) and AAV-S100A9 in FGF20 KO and AAV-FGF20 mice with colitis, respectively. Additionally, the NF-κB pathway was found to be involved in the process by which FGF20 regulates S100A9 to counteract colitis. CONCLUSIONS: These results suggest that FGF20 acts as a negative regulator of S100A9 and NF-κB, thereby inhibiting M1 macrophage polarization and restoring intestinal epithelial barrier integrity in mice with DSS-induced colitis. FGF20 may serve as a potential therapeutic target for the treatment of ulcerative colitis.