Induction of Diabetes in the RIP-B7.1 Mouse Model Is Critically Dependent on TLR3 and MyD88 Pathways and Is Associated With Alterations in the Intestinal Microbiome

  1. Danny Zipris1
  1. 1Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO
  2. 2Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA
  3. 3Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, CO
  4. 4Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO
  5. 5University of Colorado Microbiome Research Consortium, Aurora, CO
  6. 6Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Denver, Aurora, CO
  1. Corresponding author: Danny Zipris, danny.zipris{at}ucdenver.edu.

Abstract

RIP-B7.1 transgenic mice express B7.1 costimulatory molecules in pancreatic islets and develop diabetes after treatment with polyinosinic:polycytidylic acid (poly I:C), a synthetic double-stranded RNA and agonist of Toll-like receptor (TLR) 3 and retinoic acid–inducible protein I. We used this model to investigate the role of TLR pathways and intestinal microbiota in disease progression. RIP-B7.1 mice homozygous for targeted disruption of TLR9, TLR3, and myeloid differentiation factor-88 (MyD88), and most of the wild-type RIP-B7.1 mice housed under normal conditions remained diabetes-free after poly I:C administration. However, the majority of TLR9-deficient mice and wild-type animals treated with poly I:C and an antibiotic developed disease. In sharp contrast, TLR3- and MyD88-deficient mice were protected from diabetes following the same treatment regimen. High-throughput DNA sequencing demonstrated that TLR9-deficient mice treated with antibiotics plus poly I:C had higher bacterial diversity compared with disease-resistant mice. Furthermore, principal component analysis suggested that TLR9-deficient mice had distinct gut microbiome compared with the diabetes-resistant mice. Finally, the administration of sulfatrim plus poly I:C to TLR9-deficient mice resulted in alterations in the abundance of gut bacterial communities at the phylum and genus levels. These data imply that the induction of diabetes in the RIP-B7.1 model is critically dependent on TLR3 and MyD88 pathways, and involves modulation of the intestinal microbiota.

Footnotes

  • Received June 27, 2013.
  • Accepted October 7, 2013.

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  1. Diabetes vol. 63 no. 2 619-631
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