Insights from Bacteroides Species in Children with Type 1 Diabetes

Abstract

In our previous study the enrichment of the intestinal proteome of type 1 diabetes (T1D) children with Bacteroides proteins was observed, which led us to our current study that aimed to isolate and characterize Bacteroides species from fecal samples of T1D and control children. Repetitive sequence-based PCR (rep-PCR) was used for typing the isolated Bacteroides species. The antibiotic susceptibility and mucinolytic activity of the isolates was determined. The quantification of specific bacterial groups in the fecal samples was determined by qPCR. The ability to adhere and invade the human colonic cell line HT29-MTX-E12 of strains of P. dorei, B. uniformis and P. distasonis was determined and their whole genome sequencing was performed. The results showed similar numbers of Bacteroides species in T1D and control samples, but unique Bacteroides species and a higher recovery of P. distasonis from T1D samples was observed. Rep-PCR grouped the different Bacteroides species, but no discrimination by origin was achieved. T1D children showed a significant increase in Proteobacteria and a depletion in Lactobacillus sp. All tested P. dorei, B. uniformis and P. distasonis were able to adhere to HT29-MTX-E12 cells but significant differences (p < 0.05) in the ability to invade was observed. The highest ability to invade was exhibited by P. distasonis PtF D14MH1 and P. dorei PtFD16P1, while B. uniformis strains were unable to invade. The damage to tight junctions was also observed. The presence of Lactobacillus sp. inhibited the invasion ability of P. distasonis PtF D14MH1 but not P. dorei PtFD16P1. Sequences of agonist peptides of the human natural preproinsulin and the insulin B chain insB:9-23 peptide mimics were identified. The results reported in our study stresses the continued efforts required to clarify the link between T1D and gut microbiota.

Islet‐specific CD8+ T cells gain effector function in the gut lymphoid tissues via bystander activation not molecular mimicry

“…productively activate IGRP 206-214 and InsB 15-23 specific CD8 + T cells were either not present in the gut microbiota of the NOD or B16A-NOD mice or were not transported to the GALT for antigen presentation to T cells, perhaps due to exclusion by the mucous barrier.While we did not find evidence of molecular mimicry leading to activation of IGRP 206-214 and InsB[15][16][17][18][19][20][21][22][23] …”

“…For example, a human preproinsulin‐reactive, MHC class‐I restricted CD8 + T‐cell clone (1E6) was found to recognize over a million different peptides 21 . Several studies have identified the presence of epitopes within the gut microbiota peptidome that are cross‐reactive with known islet antigens of relevance to T1D progression 6,10,20,23 . However, the high inter‐individual variability in the gut microbiota and different population groups plus the highly variable relative abundance of individual species means that it is hard to know whether the presence of such peptide mimics will impact the activation of islet‐specific T cells in vivo .…”

“…InsB 15–23 has been shown to be amongst the earliest detected epitopes targeted by CD8 + T cells in young NOD mice, 18 and is very similar to the human InsB 15‐24 epitope targeted by islet‐reactive CD8 + T cells in diabetes‐susceptible HLA‐A24*02 positive individuals 19 . Evidence for bacterial mimics for insulin epitopes including insulin B9‐23 has been reported, although it has not been directly shown whether the bacterial derived peptides can activate insulin‐specific T cells in vivo 20,21 . Furthermore, T‐cell receptor (TCR) cross‐reactive between islet and gut commensal epitopes have been discovered in human type 1 diabetes, but their role in disease pathogenesis is unknown 22,23 .…”

High-risk genotypes for type 1 diabetes are associated with the imbalance of gut microbiome and serum metabolites

“…They treated obese mice with live Parabacteroides distasonis , resulting in less food intake and ameliorating glucose homeostasis ( 46 ). However, several studies have suggested that Parabacteroides distasonis 33B can mimic the human insulin B:9–23 peptide and may stimulate T1D onset ( 47 ). Different Parabacteroides distasonis strains and host genetic background may be the potential decisive factors of those contrasting findings.…”

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

“…Interestingly, the mimic peptide had a stronger agonist potency than the ZnT8 186-194 peptide ( 27 ). The gut commensal Parabacteroides distasonis has been positively correlated with T1D cases ( 13 , 146 ). P. distasonis colonization in NOD mice has been demonstrated to accelerate diabetes.…”