Background: The increase in incidence of type 1 diabetes (T1D) is not solely a result of genetics and environmental factors, but also that of gut microbiota, which play a crucial role in disease onset.
Methods: We performed a longitudinal microbiome analysis (Illumina Hiseq2500) in children (0-3 years) with HLA-susceptibility to T1D, using an algorithm focusing on amyloid producing bacteria. This analysis revealed an overlooked association between autoimmunity and the dynamics of gut amyloid-producing E. coli.
Results: Our analysis revealed a statistically significant association between the development of autoantibodies in T1D HLA-susceptible children and (i) significantly (p<0.05) high initial (0-12 months of age) abundance of gut amyloid-producing E. coli, (ii) depletion of E. coli prior to seroconversion due to prophage induction, and (iii) triggering of islet autoimmunity and T1D development. Notably, alterations in E. coli abundance were identified only in children who further developed seroconversion and T1D. E. coli depletion was found before the appearance of antibodies, suggesting a role of E. coli in disease onset. Further, our in vitro study revealed a highly immunogenic complex (amyloid curli-DNA composites) released from E. coli biofilms upon prophage induction, which triggered the production of type I IFN through the TLR2/9 stimulation of β-cells and DCs, and autoimmune cascade through the TLR-2-MyD88-NF-kB pathway.
Conclusions: Our study suggests that E. coli biofilm-derived highly immunogenic amyloid curly-DNA complexes might be involved in the activation of a pro-diabetic pathway in children who are at a risk of T1D. Besides, amyloid protein producing E. coli and their phages are the factors associated with T1D development that were previously overlooked.
G. Tetz: None.
