Download Toll-like Receptors and Intestinal Microbiome in Type 1 Diabetes

 Faculty of Medicine, Health & Molecular Sciences
School of Pharmacy and Molecular Science
Biochemistry/Biotechnology
- Molecular Immunology Group -
Degree: Honours / PhD
Prof Alan Baxter
Bldg. 21; Room CH012
Tel: +61 7 4781 6265
Email: [email protected]
Toll-like Receptors and Intestinal Microbiome in Type 1 Diabetes
Type 1 diabetes (T1D) accounts for 13% of diabetes in Australia but >90% of diabetes in
children under 14 y; the incidence is increasing by 6% annually. Children with T1D have
altered mucosal immunity, changes in intestinal microbiome, and increased intestinal
permeability - changes we have found in Toll-like receptor (TLR)-deficient Nonobese
Diabetic (NOD) mice with increased T1D. This provides a model in which these putative
causes can be tested with a view to identifying new targets for therapy. The NOD mouse
strain is the best available animal model of T1D - it shares with the human disease over
20 genetic loci and autoantigens for both B and T cells.
Preliminary data: 1). Deletion of Tlr2 or Myd88 from NOD mice reduced T1D while
deletion of Tlr1 or Tlr4 exacerbated disease. NOD.Tlr6-/- and NOD.Tlr9-/- mice were
unaffected. 2). The intestinal microbiomes of NOD wild-type (WT), NOD.Tlr1-/-,
NOD.Tlr2-/- and NOD.Tlr4-/- mice were compared by high throughput sequencing (HTS)
of 16S rDNA. Analysis of 16S sequences derived from the microbiota in caecum mucosa
clearly resolved the lines; the most T1D-susceptible mice had reduced microbiome
diversity; about half of sequences from NOD.Tlr1-/- and NOD.Tlr4-/- mice were from
Helicobacter and Bacteroides species respectively. 3). Microarray gene expression
comparisons of WT NOD, NOD.Tlr1-/- and NOD.Tlr2-/- mice identified highly significant
differential expression in multiple pathways affecting the differentiation and integrity of
the intestinal mucosa.
Hypotheses: 1). TLR expression affects the composition of the intestinal microbiome. 2).
The intestinal microbiome affects gut integrity. 3). The intestinal microbiome and gut
integrity affect T1D.
Specific Aims: 1). To identify how TLR signalling controls the microbiome. 2). To
determine causes of decreased intestinal integrity. H&E- and immuno-histology and
electron microscopy will be performed on stomach, duodenum, ileum, caecum and colon
of WT and mutant NOD and B6 mice. 3). To determine how the microbiome and
intestinal integrity affect T1D.
Publications:
Jordan MA, Poulton LD, Fletcher JM, Baxter AG. Allelic variation of Ets1 does not
contribute to NK and NKT cell deficiencies in type 1 diabetes susceptible NOD mice. Rev
Diabet Stud. 2009. 6:104-16.
Fletcher MT, Baxter AG. Clinical application of NKT cell biology in type I (autoimmune)
diabetes mellitus. Immunol Cell Biol. 2009. 87:315-23.