Gut microbiota from voluntary exercised mice protects the intestinal barrier by inhibiting neutrophil extracellular trap formation.

Ulcerative colitis is an inflammatory bowel disease characterized by impaired intestinal barrier function, dysregulated immune responses, and alterations in the gut microbiota. Excessive formation of neutrophil extracellular traps (NETs), driven by peptidyl arginine deiminase 4 (PAD4) activity, contributes to inflammation modulated by the gut microbiota. In this study, we used a mouse model of dextran sulfate sodium-induced colitis to investigate the effects of voluntary exercise and its underlying mechanisms. Exercise preconditioning attenuated colitis severity, maintained intestinal barrier integrity, normalized gut microbiota composition, and suppressed NET formation. PAD4 inhibition further enhanced these effects. By contrast, the depletion of the gut microbiota by antibiotics largely abolished the benefits of exercise. Additionally, fecal microbiota transplantation from exercised mice recapitulated these protective effects. These findings elucidate the interplay among exercise, gut microbiota, and PAD4-mediated NET formation. Targeting these pathways may offer promising therapeutic strategies for colitis.