Journal
THERANOSTICS
Volume 12, Issue 7, Pages 3438-3455Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.61433
Keywords
antimicrobial peptides; gut barrier; type 1 diabetes; gut-pancreas crosstalk; intestinal IFN gamma(+) T cell migration
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Funding
- National Natural Science Foundation of China [82122068, 81901670]
- Natural Science Foundation for Distinguished Young Scholars of Jiangsu Province [BK20200026]
- Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province
- Project of Wuxi Taihu Talent
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This study investigated the protective role of cathelicidin-related antimicrobial peptide (CRAMP) and its mechanisms in enteric pathogen-accelerated type 1 diabetes (T1D). The findings showed that CRAMP plays a crucial role in gut barrier protection, immune modulation, and microbial regulation, and it can inhibit gut immune dysregulation, gut dysbiosis, and migration of T cells to the pancreas.
Rationale: 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. Methods: The model enteric pathogen Citrobacter rodentium (C. rodentium) was 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. Results: Colonic CRAMP production was defective in C. rodentium infection-accelerated T1D. C. rodentium infection triggered the recruitment of interferon-gamma (IFN gamma)(+) T cells and accelerated T1D. In the C. rodentium-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 C. rodentium-aggravated gut immune dysregulation, gut dysbiosis, and migration of gut-primed IFN gamma(+) T cells to the pancreas, thus contributing to gut barrier protection and pancreatic-intestinal immune homeostasis. Conclusion: CRAMP plays a pivotal role in pancreatic-gut crosstalk during C. rodentium-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.
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