Type 1 diabetes susceptibility alleles are associated with distinct alterations in the gut microbiota

Mullaney, Jane A.; Stephens, J.; Costello, Mary Ellen; Fong, Cai; Geeling, Brooke E.; Gavin, Patrick G.; Wright, Casey M.; Spector, Timothy D.; Brown, Matthew A.; Hamilton‐Williams, Emma E.

doi:10.1186/s40168-018-0417-4

Cited by 64 publications

(73 citation statements)

References 60 publications

(82 reference statements)

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“…The study examined the gut microbiota of NOD mice, transgenic mice that mimic T1DM, and has shown distinct differences in the microbial composition between NOD and control C57BL/6 mice. Moreover, similarities of gut microbiomes were observed in NOD mice purchased from various animal facilities (Mullaney et al, ). Many studies have also described impaired glucose tolerance together with alterations of the gut microbiota composition in T2DM mouse models (Cani et al, ; Serino et al, ), disturbance of the metabolic system in adipose tissues, and subsequent inflammation caused by high‐fat diet associated with this phenomenon.…”

Section: Discussionmentioning

confidence: 97%

Influence of Porphyromonas gingivalis in gut microbiota of streptozotocin‐induced diabetic mice

et al. 2019

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Objectives Increasing evidence suggests that periodontitis can exacerbate diabetes, and gut bacterial dysbiosis appears to be linked with the diabetic condition. The present study examined the effects of oral administration of the periodontopathic bacterium, Porphyromonas gingivalis, on the gut microbiota and systemic conditions in streptozotocin‐induced diabetic mice. Materials and Methods Diabetes was induced by streptozotocin injection in C57BL/6J male mice (STZ). STZ and wild‐type (WT) mice were orally administered P. gingivalis (STZPg, WTPg) or saline (STZco, WTco). Feces were collected, and the gut microbiome was examined by 16S rRNA gene sequencing. The expression of genes related to inflammation, epithelial tight junctions, and glucose/fatty acid metabolism in the ileum or liver were examined by quantitative PCR. Results The relative abundance of several genera, including Brevibacterium, Corynebacterium, and Facklamia, was significantly increased in STZco mice compared to WTco mice. The relative abundances of Staphylococcus and Turicibacter in the gut microbiome were altered by oral administration of P. gingivalis in STZ mice. STZPg mice showed higher concentrations of fasting blood glucose and inflammatory genes levels in the ileum, compared to STZco mice. Conclusions Oral administration of P. gingivalis altered the gut microbiota and aggravated glycemic control in streptozotocin‐induced diabetic mice.

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Section: Discussionmentioning

confidence: 97%

Influence of Porphyromonas gingivalis in gut microbiota of streptozotocin‐induced diabetic mice

et al. 2019

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“…Interestingly, we detected an increased expression of the bacterial 16S rRNA gene in the PLNs of the AIM2 −/− mice at 15 days after the STZ injections ( Figure 4A), which suggests that the lack of AIM2 increases gut microbiota translocation to PLNs during T1D. Given the fact that gut microbiota dysbiosis is associated with bacterial translocation in T1D development, both in humans and mice [9,11,14,21,34,35], we next assessed whether diabetic AIM2 −/− mice have gut microbiota with an altered composition. First, we observed a significant increase in the abundance of Bacteroidetes, Firmicutes, Actinobacteria, and Verrucomicrobia bacterial phyla, but a significant decrease in Proteobacteria, in the feces of the AIM2 −/− mice, compared to the WT mice ( Figure 4B).…”

Section: Aim2 Receptor Controls Gut Microbiota Translocation To Plnsmentioning

confidence: 90%

The DNA Sensor AIM2 Protects against Streptozotocin-Induced Type 1 Diabetes by Regulating Intestinal Homeostasis via the IL-18 Pathway

Leite

Pessenda²,

Guerra-Gomes³

et al. 2020

Cells

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Pattern recognition receptors (PRRs), such as Nod2, Nlrp3, Tlr2, Trl4, and Tlr9, are directly involved in type 1 diabetes (T1D) susceptibility. However, the role of the cytosolic DNA sensor, AIM2, in T1D pathogenesis is still unknown. Here, we demonstrate that C57BL/6 mice lacking AIM2 (AIM2−/−) are prone to streptozotocin (STZ)-induced T1D, compared to WT C57BL/6 mice. The AIM2−/− mice phenotype is associated with a greater proinflammatory response in pancreatic tissues, alterations in gut microbiota and bacterial translocation to pancreatic lymph nodes (PLNs). These alterations are related to an increased intestinal permeability mediated by tight-junction disruption. Notably, AIM2−/− mice treated with broad-spectrum antibiotics (ABX) are protected from STZ-induced T1D and display a lower pancreatic proinflammatory response. Mechanistically, the AIM2 inflammasome is activated in vivo, leading to an IL-18 release in the ileum at 15 days after an STZ injection. IL-18 favors RegIIIγ production, thus mitigating gut microbiota alterations and reinforcing the intestinal barrier function. Together, our findings show a regulatory role of AIM2, mediated by IL-18, in shaping gut microbiota and reducing bacterial translocation and proinflammatory response against insulin-producing β cells, which ultimately results in protection against T1D onset in an STZ-induced diabetes model.

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“…Critical B cell specificities, such as our anti-insulin V H 125 SD , reside in B cell subsets that are programmed to respond to innate signals; therefore, modifications to the innate environment could alter their response potential. For example, gut microbiota are recognized to alter T1D outcomes (72,73), and their innate signals may be expected to modify the responses of T2-and MZ-like B cells. Further, not all anti-insulin B cells are pathogenic.…”

Section: Discussionmentioning

confidence: 99%

Anti-Insulin B Cells Are Poised for Antigen Presentation in Type 1 Diabetes

Felton

Maseda

Bonami

et al. 2018

The Journal of Immunology

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Early breaches in B cell tolerance are central to type 1 diabetes progression in mouse and man. Conventional BCR transgenic mouse models (VH125.Tg NOD) reveal the power of B cell specificity to drive disease as APCs. However, in conventional fixed IgM models, comprehensive assessment of B cell development is limited. To provide more accurate insight into the developmental and functional fates of anti-insulin B cells, we generated a new NOD model (V125NOD) in which anti-insulin VDJH125 is targeted to the IgH chain locus to generate a small (1-2%) population of class switch-competent insulin-binding B cells. Tracking of this rare population in a polyclonal repertoire reveals that anti-insulin B cells are preferentially skewed into marginal zone and late transitional subsets known to have increased sensitivity to proinflammatory signals. Additionally, IL-10 production, characteristic of regulatory B cell subsets, is increased. In contrast to conventional models, class switch-competent anti-insulin B cells proliferate normally in response to mitogenic stimuli but remain functionally silent for insulin autoantibody production. Diabetes development is accelerated, which demonstrates the power of anti-insulin B cells to exacerbate disease without differentiation into Ab-forming or plasma cells. Autoreactive T cell responses in V125NOD mice are not restricted to insulin autoantigens, as evidenced by increased IFN-γ production to a broad array of diabetes-associated epitopes. Together, these results independently validate the pathogenic role of anti-insulin B cells in type 1 diabetes, underscore their diverse developmental fates, and demonstrate the pathologic potential of coupling a critical β cell specificity to predominantly proinflammatory Ag-presenting B cell subsets.

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Type 1 diabetes susceptibility alleles are associated with distinct alterations in the gut microbiota

Cited by 64 publications

References 60 publications

Influence of Porphyromonas gingivalis in gut microbiota of streptozotocin‐induced diabetic mice

Influence of Porphyromonas gingivalis in gut microbiota of streptozotocin‐induced diabetic mice

The DNA Sensor AIM2 Protects against Streptozotocin-Induced Type 1 Diabetes by Regulating Intestinal Homeostasis via the IL-18 Pathway

Anti-Insulin B Cells Are Poised for Antigen Presentation in Type 1 Diabetes

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