Irisin reverses intestinal epithelial barrier dysfunction during intestinal injury via binding to the integrin αVβ5 receptor

Disruption of the gut barrier results in severe clinical outcomes with no specific treatment. Metabolic disorders and destruction of enterocytes play key roles in gut barrier dysfunction. Irisin is a newly identified exercise hormone that regulates energy metabolism. However, the effect of irisin on gut barrier function remains unknown. The therapeutic effect of irisin on gut barrier dysfunction was evaluated in gut ischemia reperfusion (IR). The direct effect of irisin on gut barrier function was studied in Caco‐2 cells. Here, we discovered that serum and gut irisin levels were decreased during gut IR and that treatment with exogenous irisin restored gut barrier function after gut IR in mice. Meanwhile, irisin decreased oxidative stress, calcium influx and endoplasmic reticulum (ER) stress after gut IR. Moreover, irisin protected mitochondrial function and reduced enterocyte apoptosis. The neutralizing antibody against irisin significantly aggravated gut injury, oxidative stress and enterocyte apoptosis after gut IR. Further studies revealed that irisin activated the AMPK‐UCP 2 pathway via binding to the integrin αVβ5 receptor. Inhibition of integrin αVβ5, AMPK or UCP 2 abolished the protective role of irisin in gut barrier function. In conclusion, exogenous irisin restores gut barrier function after gut IR via the integrin αVβ5‐AMPK‐UCP 2 pathway.