Gut barrier disruption caused by enteric pathogen infection results in activated diabetogenic T cells and accelerated type 1 diabetes (T1D). Cathelicidin-related antimicrobial peptide (CRAMP) maintains intestinal barrier integrity, regulates the microbiome, and exerts positive immune-modulatory effects on pancreatic diseases.The model enteric pathogenwas adopted to represent clinical colonic infection with gut barrier disruption. The protective role and gut-pancreas pathophysiological mechanism of CRAMP in enteric pathogen-accelerated T1D were investigated in spontaneous non-obese diabetic (NOD) mice and streptozotocin-induced diabetic mice.Colonic CRAMP production was defective ininfection-accelerated T1D.infection triggered the recruitment of interferon-gamma (IFN-γ)T cells and accelerated T1D. In the-accelerated T1D mice, CRAMP deficiency further aggravated gut barrier disruption, gut dysbiosis, and diabetic phenotype, which could be reversed by CRAMP treatment. The protective effect of CRAMP may be due to CRAMP inhibiting-aggravated gut immune dysregulation, gut dysbiosis, and migration of gut-primed IFN-γT cells to the pancreas, thus contributing to gut barrier protection and pancreatic-intestinal immune homeostasis.CRAMP plays a pivotal role in pancreatic-gut crosstalk during-accelerated T1D by gut barrier-protective, immune- and microbial-modulatory mechanisms. Cathelicidin supplementation to restore a healthy gut barrier may represent a novel therapeutic strategy for T1D.