Emerging evidence suggests that priming intestinal stem cells (ISCs) towards secretory progenitor cells is beneficial for maintaining gut homeostasis against inflammatory bowel disease (IBD). However, the mechanism driving such biased lineage commitment remains elusive. Here we show that MG53, also named as TRIM72, prompts ISCs to secretory lineages via upregulating peroxisome proliferator-activated receptor alpha (PPARalpha), thus maintaining intestinal epithelium integrity against noxious insults. Using genetic mouse models, we found that MG53 deficiency leads to exacerbated intestinal damage caused by various injuries in mice, whereas MG53 overexpression in ISCs is sufficient to ameliorate such damage. Mechanistically, MG53 promoted asymmetric division of ISCs to generate more progenitor cells of secretory lineages via activating PPARalpha signaling. Specifically, MG53 overexpression induced PPARalpha expression at transcriptional level and concomitantly increased PPARalpha activity by elevating the contents of a panel of unsaturated fatty acids in the intestine that serve as potent endogenous agonists of PPARalpha. Furthermore, genetic ablation or pharmacological inhibition of PPARalpha abolished the protective effects of MG53. These findings reveal a crucial role of MG53-PPARalpha axis in driving the secretory lineage commitment of ISCs, especially during injury response, highlighting the important therapeutic potential of targeting MG53-PPARalpha signaling for IBD treatment and marking PPARalpha agonists as novel therapies for IBD caused by various etiologies.