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
- Aimon K. Alkanani1,
- Naoko Hara1,
- Egil Lien2,
- Diana Ir3,
- Cassandra V. Kotter3,
- Charles E. Robertson4,5,
- Brandie D. Wagner5,6,
- Daniel N. Frank3,5 and
- Danny Zipris1⇑
- 1Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO
- 2Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA
- 3Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, CO
- 4Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO
- 5University of Colorado Microbiome Research Consortium, Aurora, CO
- 6Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Denver, Aurora, CO
- Corresponding author: Danny Zipris, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-1007/-/DC1.
- Received June 27, 2013.
- Accepted October 7, 2013.
- © 2014 by the American Diabetes Association.
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