Lgr4, one of the newly identified R-Spondinl receptors, potentiates Wnt signaling which is critical for intestinal epithelial homeostasis.However,how Lgr4 functions in intestinal homeostasis and inflammation are largely unknown.Here we show that mice deficient for Lgr4 were highly susceptible to dextran sodium sulfate (DSS)-induced colitis.Inactivation of Lgr4 led to hypoactivation of Wnt signaling, resulting in reduced cell proliferation, dramatic Paneth ceils loss, and significant reduction of both fast-cycling Lgr5+ and quiescent Bmi1+ stem cells.We also revealed that Lgr5+ stem cell responses to DSS-induced injury suggesting its vital role in response to tissue damage signals during intestinal inflammation.When Wnt/β-catenin signaling is reactivated by crossing with APCmin/+ mice or by treating with GSK-3β inhibitor,the number of Paneth cell was partially restored and the mortality caused by DSS-induced IBD was strikingly reduced in Lgr4 mutant mice.Thus, Lgr4 is critically involved in the maintenance of intestinal homeostasis and protection against inflammatory bowel disease through the modulation of Wnt/β-catenin signaling pathway.