FGF21 Depletion Attenuates Colitis through Intestinal Epithelial IL-22-STAT3 Activation in Mice

Area of Science:

• Gastroenterology
• Immunology
• Endocrinology

Background:

• Fibroblast growth factor 21 (FGF21) regulates metabolism and is induced by inflammation.
• The role of FGF21 in inflammatory bowel disease (IBD) remains unexplored.
• IBD is characterized by chronic inflammation of the gastrointestinal tract.

Purpose of the Study:

• To investigate the role of FGF21 in dextran sodium sulfate (DSS)-induced acute colitis, an experimental model of IBD.
• To determine the effects of FGF21 deficiency on colitis severity and associated inflammatory responses.
• To elucidate the underlying molecular mechanisms by which FGF21 influences intestinal inflammation.

Main Methods:

• An experimental IBD model was established in FGF21 knockout (KO) and wild-type (WT) mice using DSS administration.
• Colitis severity, body weight loss, and colon tissue inflammation were assessed.
• Plasma and colon levels of pro-inflammatory factors, cell proliferation (BrdU staining), and specific cell populations (Paneth and goblet cells) were analyzed.
• Mechanistic studies involved evaluating signal transducer and activator of transcription (STAT)-3 activation, IL-22 expression, and suppressor of cytokine signaling (SOCS) 2/3 expression in intestinal epithelial cells.

Main Results:

• WT mice treated with DSS exhibited elevated plasma FGF21, significant body weight loss, and severe colitis.
• FGF21 KO mice showed significantly attenuated body weight loss and reduced colitis severity compared to WT mice.
• FGF21 deficiency led to lower pro-inflammatory factors, increased colonic epithelial cell proliferation, and preserved Paneth and goblet cell numbers.
• Mechanistically, FGF21 deficiency enhanced STAT3 activation and IL-22 expression while inhibiting SOCS 2/3 in intestinal epithelial cells.

Conclusions:

• FGF21 deficiency ameliorates DSS-induced acute colitis in mice.
• The protective effect is associated with enhanced IL-22-STAT3 signaling in intestinal epithelial cells.
• These findings suggest FGF21 as a potential therapeutic target for IBD.