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

• Published in: Cellular and molecular gastroenterology and hepatology Vol. 19; no. 6; p. 101486
• Main Authors: Zhen, Dong, Wang, Songxue, Liu, Zhen, Xi, Yiyuan, Du, Hanlin, Wang, Ningrui, Gao, Xiaotang, Lin, Zhuofeng, Wu, Fan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2025; Elsevier
• Subjects: Animals; Calgranulin B - genetics; Calgranulin B - metabolism; Colitis - chemically induced; Colitis, Ulcerative - chemically induced; Colitis, Ulcerative - drug therapy; Colitis, Ulcerative - immunology; Colitis, Ulcerative - metabolism; Colitis, Ulcerative - pathology; Dextran Sulfate - toxicity; Disease Models, Animal; FGF20; Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - metabolism; Fibroblast Growth Factors - pharmacology; Gastroenterology and Hepatology; Humans; Intestinal Mucosa - drug effects; Intestinal Mucosa - immunology; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Macrophage Polarization; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B - metabolism; Original Research; S100A9; Signal Transduction; Ulcerative Colitis; PBS; PAS; KO; DSS; IBD; DAI; LPS; UC; Macrophage Polarization; NF-κB; FITC; IL6; TNF-α; Ulcerative Colitis; AAV; FGF20; iNOS; S100A9; WT; PCR; fibroblast growth factor 20; nuclear factor kappa B; phosphate-buffered saline; interleukin-6; inducible nitric oxide synthase; tumor necrosis factor alpha; fluorescein isothiocyanate; polymerase chain reaction; knockout; dextran sulfate sodium; adenoassociated virus; periodic acid–Schiff; inflammatory bowel disease; disease activity index; lipopolysaccharide; wild-type
• ISSN: 2352-345X; 2352-345X
• DOI: 10.1016/j.jcmgh.2025.101486

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. 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. 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. 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. [Display omitted]