Fibroblast Growth Factor 20 Attenuates Colitis by Restoring Impaired Intestinal Epithelial Barrier Integrity and Modulating Macrophage Polarization via S100A9 in an NF-κB-Dependent Manner

Abstract

Background & Aims

Exogenous recombinant fibroblast growth factor 20 (FGF20) protein has been proved to 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. FGF20 knockout mice and Adenoassociated 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 subjects and mice with colitis. FGF20 deficiency exacerbated dextran sodium sulfate–induced colitis; in contrast, FGF20 replenishment alleviated colitis through 2 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 pharmacologic inhibition and overexpression experiments of S100A9 using paquinimod (a specific inhibitor of S100A9) and AAV-S100A9 in FGF20 knockout and AAV-FGF20 mice with colitis, respectively. Additionally, the nuclear factor-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 nuclear factor-κB, thereby inhibiting M1 macrophage polarization and restoring intestinal epithelial barrier integrity in mice with dextran sodium sulfate–induced colitis. FGF20 may serve as a potential therapeutic target for the treatment of ulcerative colitis.