title: 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.
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.
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO.
authors.forename: Aimon K
authors.initials: AK
authors.lastname: Alkanani
authors.forename: Naoko
authors.initials: N
authors.lastname: Hara
authors.forename: Egil
authors.initials: E
authors.lastname: Lien
authors.forename: Diana
authors.initials: D
authors.lastname: Ir
authors.forename: Cassandra V
authors.initials: CV
authors.lastname: Kotter
authors.forename: Charles E
authors.initials: CE
authors.lastname: Robertson
authors.forename: Brandie D
authors.initials: BD
authors.lastname: Wagner
authors.forename: Daniel N
authors.initials: DN
authors.lastname: Frank
authors.forename: Danny
authors.initials: D
authors.lastname: Zipris
mesh_terms: D000818:Animals; D001419:Bacteria / Q000145:classification; D003920:Diabetes Mellitus / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D007422:Intestines / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D011070:Poly I-C; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism
chemical_list: C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C519703:TLR3 protein, mouse; C495370:Tlr9 protein, mouse; D051196:Toll-Like Receptor 3; D051217:Toll-Like Receptor 9; D011070:Poly I-C