Abstract
The etiopathogenesis of type 1 diabetes (T1D), a common autoimmune disorder, is not completely understood. Recent studies suggested the gut microbiome plays a role in T1D. We have used public longitudinal microbiome data from T1D patients to analyze amyloid-producing bacterial composition and found a significant association between initially high amyloid-producing Escherichia coli abundance, subsequent E. coli depletion prior to seroconversion, and T1D development. In children who presented seroconversion or developed T1D, we observed an increase in the E. coli phage/E. coli ratio prior to E. coli depletion, suggesting that the decrease in E. coli was due to prophage activation. Evaluation of the role of phages in amyloid release from E. coli biofilms in vitro suggested an indirect role of the bacterial phages in the modulation of host immunity. This study for the first time suggests that amyloid-producing E. coli, their phages, and bacteria-derived amyloid might be involved in pro-diabetic pathway activation in children at risk for T1D.
Highlights
type 1 diabetes (T1D) is generally associated with a long pre-diabetic seroconversion period, during which autoantibodies to antigens of pancreatic β-cells or insulin are produced[9]
This study revealed an association between the dynamics of intestinal amyloid-producing E. coli prior to seroconversion in HLA-matched children and the development of T1D-associated autoimmunity
There are multiple factors that could lead to E. coli depletion within the gut microbiome, including interplay with other gut microorganisms, which constantly change during infancy
Summary
T1D is generally associated with a long pre-diabetic seroconversion period, during which autoantibodies to antigens of pancreatic β-cells or insulin are produced[9]. The exact roles of these mechanisms in disease onset remain poorly understood[1] Pancreatotropic viruses, such as enterovirus, coxsackie B, mumps, rubella, and cytomegalovirus, have been evaluated as triggers of T1D since the discovery of antiviral antibodies in diabetic patients and because of the role of viral infection in elevated levels of type I interferon (IFN), which is known to play a role in T1D progression[17,18,19]. In that work, the authors showed that bacterial curli fibers triggered T-cell immunity through the TLR-2-MyD88-NF-kB signaling pathway, which is known to be associated with T1D progression; no microbiome studies have been conducted to reveal the association of amyloid-producing bacteria with diabetes[36]. We have previously shown that bacteriophages can alter the mammalian microbiota, leading to increased intestinal permeability and triggering chronic inflammation, which potentially participate in protein misfolding and might contribute to the onset of Parkinson’s disease[40,41]
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