Fibroblast growth factor 21 depletion attenuates acute experimental colitis in mice through epithelial STAT3 activation
Authors: Feng Wenke , Dryden Gerald , McClain Craig 
Published: November 2023

AimsFibroblast growth factor 21 (FGF21) is a novel metabolic regulator produced primarily in the liver under conditions of energy crisis to regulate glucose and lipid metabolism. Recent studies showed that FGF21 is also induced by inflammatory response, which is a hallmark of inflammatory bowel disease (IBD). However, whether IBD alters FGF21 expression and the role of FGF21 in IBD development have not been examined. In this study, we aimed to determine the role of FGF21 in an acute experimental colitis murine model and investigate the underlying mechanisms.MethodsThe serum levels of FGF21 in colitis patients were analyzed. Experimental acute IBD was induced by adding 2.5% (wt/vol) dextran sulfate sodium (DSS) into drinking water for 7 days to FGF21 knockout (KO) mice and wide type (WT) control mice. Blood was collected for measuring FGF21 concentrations and inflammatory cytokine levels using commercial kits. Small intestine and colon tissue samples were processed for histopathological analysis. Tissue mRNA levels of inflammatory cytokines were measured by real‐time RT‐PCR. Intestinal inflammatory cell infiltration was analyzed by flow cytometry. Tissue protein levels of target genes were analyzed by Western blotting.ResultsSerum FGF21 concentrations were significantly higher in patients with colitis than healthy controls, implying a role of FGF21 in IBD. Plasma levels and liver expression of FGF21 were significantly increased in mice treated with DSS. White adipose tissue also showed an elevation of FGF21 protein upon DSS treatment. However, DSS did not increase intestinal FGF21 expression. DSS treatment induced a significant body weight loss in WT mice. Surprisingly, in FGF21 KO mice, this body weight loss was significantly attenuated. Further analysis showed that FGF21 KO mice had less colon shortening, histological damage, crypt loss and less neutrophil infiltration compared to WT mice. Depletion of FGF21 also decreased DSS treatment‐increased serum concentrations of IL‐6, TNF‐α and IL‐1β and their mRNA levels in colon tissues. FGF21 deficiency markedly increased colon STAT3 phosphorylation and blocked SOCS2/3 expression upon DSS treatment, indicating that FGF21 mediates the SOCS2/3 inhibition of STAT3 activation in colon. Furthermore, FGF21 depletion significantly increased intestinal Goblet cell numbers. Goblet cells are responsible for gut lumen microbiota regulation by increasing antimicrobial peptides, and this process is regulated by epithelial STAT3 activation. In addition, in vitro study using Caco‐2 cells showed that recombinant FGF21 treatment blocked IL‐6‐induced STAT3 phosphorylation.ConclusionsFGF21 deletion protects mice form DSS‐induced acute colitis by multiple mechanisms, including decrease of the intestinal inflammation, increase of epithelial STAT3 activation and Goblet cell differentiation. Our results indicate the hepatic FGF21 elevation by acute colitis induction contributes to the progression of colitis. Targeting FGF21 signaling pathway may provide a therapeutic strategy for IBD.Support or Funding InformationSupported by NIH and Veterans Administration.