Fibroblast Growth Factor 21 Deficiency Attenuates DSS‐induced Acute Colitis Through Activation Of Intestinal Epithelial Cell Stat3‐mediated Pathway

Background Fibroblast growth factor 21 (FGF21) is a novel metabolic regulator in glucose and lipid metabolism. Recent studies showed that FGF21 is also induced by inflammatory stimuli. However, its role in inflammatory bowel disease (IBD) has not been examined. Methods Experimental IBD model was induced by adding 2.5% (wt/vol) dextran sulfate sodium (DSS) into drinking water for 3, 5 and 7 days, respectively, in FGF21 knockout (KO) and wide type (WT) mice. Mouse colon tissues were analyzed for colitis severity and inflammatory cell infiltration. FGF21 and inflammatory makers were determined in serum and tissues samples. The T84 intestinal epithelial cell line was used for additional in vitro studies. Results In WT mice treated with DSS induced an elevation in serum FGF21 and a significant body weight loss in a time dependent manner. Gene expression studies showed that liver and epididymal white adipose tissues were the major sources of circulation FGF21. Surprisingly, the body weight loss and colitis severity were significantly attenuated in FGF21 KO mice. Further analysis showed that FGF21 KO mice had less colon shortening, histological damage, less neutrophil infiltration compared to WT mice. FGF21 deficiency decreased DSS treatment‐increased serum concentrations of IL‐6, TNF‐α and IL‐1β and their mRNA levels in colon tissues. Colonic epithelial cell proliferation, examined by BrdU staining, was increased in the KO mice. DSS treatment caused a decrease in epithelial cell proliferation and Paneth and Goblet cell numbers in WT mice, which were attenuated in the KO mice. Importantly, FGF21 depletion dramatically increased signal transducer and activator of transcription‐3 (STAT3) activation in intestinal epithelial cells, along with a decreased suppressor of cytokine signaling‐3 (Socs3) expression. FGF21 pretreatment inhibited IL6‐induced STAT3 phosphorylation in human intestine epithelial T84 cells. Conclusion Circulating levels of FGF21 were increased in acute colitis in mice. FGF21 deficiency attenuated DSS induced acute colitis, which is likely mediated by the inhibitory effect of FGF21 on IL‐6‐induced‐STAT3 activation in intestinal epithelial cells. Support or Funding Information This research was supported by the NIH and Veterans Administration.