A gut microbial peptide and molecular mimicry in the pathogenesis of type 1 diabetes

Abstract

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of pancreatic β-cells. One of the earliest aspects of this process is the development of autoantibodies and T cells directed at an epitope in the B-chain of insulin (insB:9–23). Analysis of microbial protein sequences with homology to the insB:9–23 sequence revealed 17 peptides showing >50% identity to insB:9–23. Of these 17 peptides, the hprt4–18 peptide, found in the normal human gut commensal Parabacteroides distasonis , activated both human T cell clones from T1D patients and T cell hybridomas from nonobese diabetic (NOD) mice specific to insB:9–23. Immunization of NOD mice with P. distasonis insB:9–23 peptide mimic or insB:9–23 peptide verified immune cross-reactivity. Colonization of female NOD mice with P. distasonis accelerated the development of T1D, increasing macrophages, dendritic cells, and destructive CD8 + T cells, while decreasing FoxP3 + regulatory T cells. Western blot analysis identified P. distasonis –reacting antibodies in sera of NOD mice colonized with P. distasonis and human T1D patients. Furthermore, adoptive transfer of splenocytes from P. distasonis –treated mice to NOD/SCID mice enhanced disease phenotype in the recipients. Finally, analysis of human children gut microbiome data from a longitudinal DIABIMMUNE study revealed that seroconversion rates (i.e., the proportion of individuals developing two or more autoantibodies) were consistently higher in children whose microbiome harbored sequences capable of producing the hprt4–18 peptide compared to individuals who did not harbor it. Taken together, these data demonstrate the potential role of a gut microbiota-derived insB:9–23-mimic peptide as a molecular trigger of T1D pathogenesis.

Effect of Phorate on the Development of Hyperglycaemia in Mouse and Resistance Genes in Intestinal Microbiota

“…However, the abundances of Parabacteroides and Alistipes were increased in the phorate-exposed groups compared with those in the control group. Parabacteroides can accelerate the development of diabetes in non-obese diabetic mice as well as increase the macrophage, dendritic cell, and destructive CD8+ T cell levels and reduce the Treg cell levels [ 22 ]. Feeding on HFDs increases the abundance of Alistipes [ 23 ].…”

Host-microbiota interactions shaping T-cell response and tolerance in type 1 diabetes

“…P. distasonis colonization in NOD mice has been demonstrated to accelerate diabetes. A molecular mimic of the insulin peptide B:9-23, derived from P. distasonis , previously identified in a DIABIMMUNE study, was shown to activate insulin specific T-cells ex vivo with similar potency ( 29 , 147 ). An integrase derived peptide expressed by several Bacteroides species was found to encode a low avidity mimetope of IGRP 206-214 that can recruit IGRP specific CD8+ T-cells to the GALTs and activate them.…”

Pathophysiology of Type 1 Diabetes and Gut Microbiota Role

“…Interestingly, T-cell clones against preproinsulin peptides have shown high cross-reactivity to the peptides of Bacteroides and Clostridium species [ 72 ]. In a NOD mouse model, a peptide produced by Parabacteroides distasonis with homology to β-chain of insulin has been identified [ 73 ]. This peptide can be recognized by T-cells, cross-stimulating an immune response to this chain of insulin [ 73 ].…”

“…In a NOD mouse model, a peptide produced by Parabacteroides distasonis with homology to β-chain of insulin has been identified [ 73 ]. This peptide can be recognized by T-cells, cross-stimulating an immune response to this chain of insulin [ 73 ].…”