Evaluation of different mucosal microbiota leads to gut microbiota-based prediction of type 1 diabetes in NOD mice

ABSTRACTType 1 Diabetes (T1D) is an autoimmune disease characterized by destruction of pancreatic β-cells. Focusing on the main insulin epitope, insulin B-chain 9-23 (insB:9-23), we explored whether a microbial insB:9-23 mimic could modulate T1D. We now demonstrate that a microbial insB:9-23 mimic of Parabacteroides distasonis, a human gut commensal, exclusively stimulates non-obese diabetic (NOD) mouse T cells specific to insB:9-23. Indeed, immunization of NOD mice with either the bacterial mimic peptide or insB:9-23 further verified the cross-reactivity in vivo. Modeling P. distasonis peptide revealed a potential pathogenic register 3 binding. P. distasonis colonization of the female NOD mice gut accelerated T1D onset. In addition, adoptive transfer of splenocytes from NOD mice colonized with P. distasonis to NOD.SCID recipients conferred the enhanced disease phenotype. Integration analysis of published infant T1D gut microbiome data revealed that P. distasonis peptide is not present in the gut microbiota in the first year of life of infants that eventually develop T1D. Furthermore, P. distasonis peptide can stimulate human T cell clones specific to insB:9-23 and T1D patients demonstrated a strong humoral immune response to P. distasonis than controls. Taken together, our studies define a potential molecular mimicry link between T1D pathogenesis and the gut microbiota.One Sentence SummaryThe human gut commensal bacterium, Parabacteroides distasonis, accelerates type 1 diabetes in the NOD mouse model of the disease and involves expression of an insulin B:9-23 epitope mimic, supporting a potential disease mechanism involving molecular mimicry.

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IL-10 Deficiency Accelerates Type 1 Diabetes Development via Modulation of Innate and Adaptive Immune Cells and Gut Microbiota in BDC2.5 NOD Mice

Frontiers in Immunology ◽

10.3389/fimmu.2021.702955 ◽

2021 ◽

Vol 12 ◽

Author(s):

Juan Huang ◽

Qiyuan Tan ◽

Ningwen Tai ◽

James Alexander Pearson ◽

Yangyang Li ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

T Cell ◽

Gut Microbiota ◽

Spontaneous Diabetes ◽

Nod Mice ◽

Treg Cells ◽

Diabetes Development

Type 1 diabetes is an autoimmune disease caused by T cell-mediated destruction of insulin-producing β cells. BDC2.5 T cells in BDC2.5 CD4+ T cell receptor transgenic Non-Obese Diabetic (NOD) mice (BDC2.5+ NOD mice) can abruptly invade the pancreatic islets resulting in severe insulitis that progresses rapidly but rarely leads to spontaneous diabetes. This prevention of diabetes is mediated by T regulatory (Treg) cells in these mice. In this study, we investigated the role of interleukin 10 (IL-10) in the inhibition of diabetes in BDC2.5+ NOD mice by generating Il-10-deficient BDC2.5+ NOD mice (BDC2.5+Il-10-/- NOD mice). Our results showed that BDC2.5+Il-10-/- NOD mice displayed robust and accelerated diabetes development. Il-10 deficiency in BDC2.5+ NOD mice promoted the generation of neutrophils in the bone marrow and increased the proportions of neutrophils in the periphery (blood, spleen, and islets), accompanied by altered intestinal immunity and gut microbiota composition. In vitro studies showed that the gut microbiota from BDC2.5+Il-10-/- NOD mice can expand neutrophil populations. Moreover, in vivo studies demonstrated that the depletion of endogenous gut microbiota by antibiotic treatment decreased the proportion of neutrophils. Although Il-10 deficiency in BDC2.5+ NOD mice had no obvious effects on the proportion and function of Treg cells, it affected the immune response and activation of CD4+ T cells. Moreover, the pathogenicity of CD4+ T cells was much increased, and this significantly accelerated the development of diabetes when these CD4+ T cells were transferred into immune-deficient NOD mice. Our study provides novel insights into the role of IL-10 in the modulation of neutrophils and CD4+ T cells in BDC2.5+ NOD mice, and suggests important crosstalk between gut microbiota and neutrophils in type 1 diabetes development.

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Early-life exposure to gut microbiota from disease-protected mice does not impact disease outcome in type 1 diabetes susceptible NOD mice

Immunology and Cell Biology ◽

10.1111/imcb.12201 ◽

2018 ◽

Vol 97 (1) ◽

pp. 97-103 ◽

Cited By ~ 3

Author(s):

Jane A Mullaney ◽

Juliette E Stephens ◽

Brooke E Geeling ◽

Emma E Hamilton-Williams

Keyword(s):

Type 1 Diabetes ◽

Gut Microbiota ◽

Early Life ◽

Nod Mice ◽

Disease Outcome ◽

Early Life Exposure

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Akkermansia muciniphila induces gut microbiota remodelling and controls islet autoimmunity in NOD mice

Gut ◽

10.1136/gutjnl-2017-314508 ◽

2017 ◽

Vol 67 (8) ◽

pp. 1445-1453 ◽

Cited By ~ 102

Author(s):

Arno Hänninen ◽

Raine Toivonen ◽

Sakari Pöysti ◽

Clara Belzer ◽

Hubert Plovier ◽

...

Keyword(s):

Type 1 Diabetes ◽

Gut Microbiota ◽

Intestinal Microbiota ◽

Nod Mice ◽

Diabetes Incidence ◽

Potential Significance ◽

Akkermansia Muciniphila ◽

High Incidence ◽

Low Incidence

ObjectiveIntestinal microbiota is implicated in the pathogenesis of autoimmune type 1 diabetes in humans and in non-obese diabetic (NOD) mice, but evidence on its causality and on the role of individual microbiota members is limited. We investigated if different diabetes incidence in two NOD colonies was due to microbiota differences and aimed to identify individual microbiota members with potential significance.DesignWe profiled intestinal microbiota between two NOD mouse colonies showing high or low diabetes incidence by 16S ribosomal RNA gene sequencing and colonised the high-incidence colony with the microbiota of the low-incidence colony. Based on unaltered incidence, we identified a few taxa which were not effectively transferred and thereafter, transferred experimentally one of these to test its potential significance.ResultsAlthough the high-incidence colony adopted most microbial taxa present in the low-incidence colony, diabetes incidence remained unaltered. Among the few taxa which were not transferred, Akkermansia muciniphila was identified. As A. muciniphila abundancy is inversely correlated to the risk of developing type 1 diabetes-related autoantibodies, we transferred A. muciniphila experimentally to the high-incidence colony. A. muciniphila transfer promoted mucus production and increased expression of antimicrobial peptide Reg3γ, outcompeted Ruminococcus torques from the microbiota, lowered serum endotoxin levels and islet toll-like receptor expression, promoted regulatory immunity and delayed diabetes development.ConclusionTransfer of the whole microbiota may not reduce diabetes incidence despite a major change in gut microbiota, but single symbionts such as A. muciniphila with beneficial metabolic and immune signalling effects may reduce diabetes incidence when administered as a probiotic.

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