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Background Shedding of intestinal epithelial cells (IECs) is a potent cause of barrier loss that plays an important role in the pathogenesis of inflammatory bowel disease (IBD). TNFα can induce IEC shedding, but little is known about this process. Methods To investigate the molecular mechanism regulating IEC shedding, mice lacking interferon regulatory factor1 (IRF1), caspase-3 or gasdermin E (GSDME) and their control wild-type (WT) littermates were intravenously injected with TNFα to establish an IEC shedding model. A dual-luciferase reporter assay and a chromatin immunoprecipitation assay were used to determine the role of IRF1 in regulating caspase-3 expression. Results TNFα administration induced obvious IEC shedding in WT mice, but IRF1  -/- and caspase-3  -/-mice were completely protected from TNFα-induced IEC shedding. As a critical transcription factor, IRF1 was found to be required for caspase-3 expression in IECs by binding to IRF1-binding sites in the caspase-3 promoter. In WT mice, plasma membrane integrity was disrupted in shed IECs; these cells were swollen and contained GSDME-N terminal (NT) fragments, which are responsible for the induction of pyroptosis. However, in Gsdme  -/- mice, plasma membrane integrity was not disrupted in shed IECs, which were not swollen and did not contain GSDME-NT, indicating that GSDME converted TNFα-induced IEC shedding into a pyroptotic cell death process. In addition, IRF1 deficiency resulted in decreases in mucosal inflammation and mucosal bacteria levels in TNFα-challenged colons. Conclusions IRF1 deficiency maintains intestinal barrier integrity by restricting TNFα-induced IEC shedding.