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

  • Cell Mol Gastroenterol Hepatol. 2025 Feb 28:101486. doi: 10.1016/j.jcmgh.2025.101486.
Dong Zhen  1 ,  Songxue Wang  2 ,  Zhen Liu  2 ,  Yiyuan Xi  1 ,  Hanlin Du  1 ,  Ningrui Wang  3 ,  Xiaotang Gao  3 ,  Zhuofeng Lin  4 ,  Fan Wu  5
Affiliations
  • 1. Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • 2. Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
  • 3. School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
  • 4. Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China; The First Affiliated Hospital of Guangdong Medical University, Zhanjiang, China. Electronic address: [email protected].
  • 5. School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China. Electronic address: [email protected].
PMID: 40024533 DOI: 10.1016/j.jcmgh.2025.101486
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.

Keywords
FGF20; Macrophage Polarization; S100A9; Ulcerative Colitis.
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