scholarly journals Polysaccharide A-dependent opposing effects of mucosal and systemic exposures to human gut commensalBacteroides fragilisin type 1 diabetes

2018 ◽  
Author(s):  
M. Hanief. Sofi ◽  
Benjamin M. Johnson ◽  
Radhika R. Gudi ◽  
Amy Jolly ◽  
Marie-Claude Gaudreau ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Oral Administration ◽  
Disease Progression ◽  
Inflammatory Responses ◽  
Nod Mice ◽  
Gut Permeability ◽  
Opposing Effects ◽  
The Impact ◽  
Systemic Compartment

AbstractBacteroides fragilis(BF) is an integral component of the human colonic commensal microbiota. BF is also the most commonly isolated organism from clinical cases of intra-abdominal abscesses suggesting its potential to induce pro-inflammatory responses, upon accessing the systemic compartment. Hence, we examined the impact of mucosal and systemic exposures to BF on type 1 diabetes (T1D) incidence in non-obese diabetic (NOD) mice. The impact of intestinal exposure to BF under chemically-induced enhanced gut permeability condition, which permits microbial translocation, in T1D was also examined. While oral administration of pre-diabetic mice with heat-killed (HK) BF caused enhanced immune regulation and suppression of autoimmunity resulting in delayed hyperglycemia, mice that received HK BF by i.v. injection showed rapid disease progression. Importantly, polysaccharide-A deficient (ΔPSA) BF failed to produce these opposing effects upon oral and systemic deliveries. Further, BF induced modulation of disease progression was observed in WT, but not TLR2-deficient, NOD mice. Interestingly, oral administration of BF under enhanced gut permeability condition resulted in accelerated disease progression and rapid onset of hyperglycemia in NOD mice. Overall, these observations suggest that BF-like gut commensals can cause pro-inflammatory responses upon gaining access to systemic compartment and contribute to T1D in at-risk subjects.

scholarly journals Spatial variations in gut permeability are linked to type 1 diabetes development in non-obese diabetic mice

2019 ◽  
Vol 7 (1) ◽  
pp. e000793
Author(s):  
William C Joesten ◽  
Audrey H Short ◽  
Michael A Kennedy
Keyword(s):  
Type 1 Diabetes ◽  
Large Intestine ◽  
Nod Mice ◽  
Spatial Variations ◽  
Gut Permeability ◽  
Spatially Resolved ◽  
Diabetes Development ◽  
End Stage ◽  
Design And Methods

ObjectivesTo determine if spatial variations in gut permeability play a role in regulating type 1 diabetes (T1D) progression.Research design and methodsSpatially resolved duodenum, jejunum, ileum, and large intestine sections from end-stage T1D non-obese diabetic (NOD) mice were probed by immunohistochemistry to quantify zonulin levels as a measure of gut permeability in early-progressor and late-progressor NOD mice in comparison with non-progressor NOD mice and healthy NOR/LtJ control mice.ResultsZonulin levels were elevated in the small and large intestines in early-progressor and late-progressor NOD mice in comparison with non-progressor NOD mice and healthy NOR control mice. In early-onset mice, elevated zonulin levels were maximum in the duodenum and jejunum and decreased in the ileum and large intestine. In late-progressor mice, zonulin levels were elevated almost evenly along the small and large intestines. In non-progressor NOD mice, zonulin levels were comparable with NOR control levels in both the small and large intestines.ConclusionsElevated zonulin expression levels indicated that gut permeability was increased both in the small and large intestines in NOD mice that progressed to end-stage T1D in comparison with non-progressor NOD mice and healthy NOR control mice. Highest elevations in zonulin levels were observed in the duodenum and jejunum followed by the ileum and large intestines. Spatial variations in gut permeability appeared to play a role in regulating the rate and severity of T1D progression in NOD mice indicating that spatial variations in gut permeability should be investigated as a potentially important factor in human T1D progression.

scholarly journals Complex dietary-polysaccharide modulates gut immune function and microbiota, and promotes protection from autoimmune diabetes

2018 ◽  
Author(s):  
Radhika Gudi ◽  
Nicolas Perez ◽  
Benjamin M. Johnson ◽  
M.Hanief Sofi ◽  
Robert Brown ◽  
...  
Keyword(s):  
Oral Administration ◽  
Immune Function ◽  
Ex Vivo ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Prolonged Treatment ◽  
Gut Mucosa ◽  
The Impact ◽  
Pro Inflammatory Cytokines

ABSTRACTSince the dietary supplement and prebiotic value of β-glucan-rich products have been widely recognized and the dietary approaches for modulating autoimmunity have been increasingly explored, we assessed the impact of oral administration of high-pure yeast β-glucan (YBG) on gut immune function, microbiota and type 1 diabetes (T1D) using mouse models. Oral administration of this non-digestible complex polysaccharide caused a Dectin-1-dependent immune response involving increased expression of IL10, retinaldehyde dehydrogenase (Raldh) and pro-inflammatory cytokines in the gut mucosa. YBG-exposed intestinal DCs induced/expanded primarily Foxp3+, IL10+ and IL17+ T cells, ex vivo. Importantly, prolonged oral administration of low-dose YBG at pre-diabetic stage suppressed insulitis and significantly delayed the T1D incidence in non-obese diabetic (NOD) mice. Further, prolonged treatment with YBG showed increased Foxp3+ T cell frequencies, and a significant change in the gut microbiota, particularly an increase in the abundance of Bacteroidetes and a decrease in the Firmicute members. Oral administration of YBG, together with Raldh-substrate and β-cell antigen, resulted in a better protection of NOD mice from T1D. These observations suggest that YBG not only has a prebiotic property, but also has an oral tolerogenic-adjuvant-like effect, and these features could be exploited for modulating autoimmunity in T1D.

scholarly journals Coxsackievirus B Vaccines Prevent Infection-Accelerated Diabetes in NOD Mice and Have No Disease-Inducing Effect

2021 ◽  
Author(s):  
Virginia M Stone ◽  
Marta Butrym ◽  
Minna M Hankaniemi ◽  
Amir-Babak Sioofy-Khojine ◽  
Vesa P Hytönen ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Disease Progression ◽  
Neutralizing Antibodies ◽  
Disease Model ◽  
Disease Onset ◽  
Nod Mice ◽  
Disease Etiology ◽  
Established Disease ◽  
Islet Inflammation

Enteroviruses, including the Coxsackievirus Bs (CVB), have been implicated as causal agents in human type 1 diabetes. Immunization of at-risk individuals with a CVB vaccine provides an attractive strategy for elucidating the role of CVBs in the disease etiology. Previously we have shown that an inactivated whole-virus vaccine covering all CVB serotypes (CVB1-6) is safe to administer and highly immunogenic in preclinical models, including non-human primates. Before initiating clinical trials with this type of vaccine it was also important to address whether a) the vaccine itself induces adverse immune reactions including accelerating diabetes onset in a diabetes prone host and b) the vaccine can prevent CVB induced diabetes in a well-established disease model. Here we present results from studies in which female NOD mice were left untreated, mock-vaccinated or vaccinated with CVB1-6 vaccine and monitored for insulitis occurrence or diabetes development. We demonstrate that vaccination induces virus neutralizing antibodies without altering insulitis scores or the onset of diabetes. We also show that NOD mice vaccinated with a CVB1 vaccine are protected from CVB-induced accelerated disease onset. Taken together, these studies show that CVB vaccines do not alter islet inflammation or accelerate disease progression in an animal model that spontaneously develops autoimmune type 1 diabetes. However, they can prevent CVB-mediated disease progression in the same model. <b></b>

scholarly journals Chromogranin A Deficiency Confers Protection from Autoimmune Diabetes Via Multiple Mechanisms

2021 ◽  
Author(s):  
Virginia M Stone ◽  
Marta Butrym ◽  
Minna M Hankaniemi ◽  
Amir-Babak Sioofy-Khojine ◽  
Vesa P Hytönen ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Disease Progression ◽  
Neutralizing Antibodies ◽  
Autoimmune Diabetes ◽  
Disease Model ◽  
Disease Onset ◽  
Nod Mice ◽  
Disease Etiology ◽  
Islet Inflammation

Enteroviruses, including the Coxsackievirus Bs (CVB), have been implicated as causal agents in human type 1 diabetes. Immunization of at-risk individuals with a CVB vaccine provides an attractive strategy for elucidating the role of CVBs in the disease etiology. Previously we have shown that an inactivated whole-virus vaccine covering all CVB serotypes (CVB1-6) is safe to administer and highly immunogenic in preclinical models, including non-human primates. Before initiating clinical trials with this type of vaccine it was also important to address whether a) the vaccine itself induces adverse immune reactions including accelerating diabetes onset in a diabetes prone host and b) the vaccine can prevent CVB induced diabetes in a well-established disease model. Here we present results from studies in which female NOD mice were left untreated, mock-vaccinated or vaccinated with CVB1-6 vaccine and monitored for insulitis occurrence or diabetes development. We demonstrate that vaccination induces virus neutralizing antibodies without altering insulitis scores or the onset of diabetes. We also show that NOD mice vaccinated with a CVB1 vaccine are protected from CVB-induced accelerated disease onset. Taken together, these studies show that CVB vaccines do not alter islet inflammation or accelerate disease progression in an animal model that spontaneously develops autoimmune type 1 diabetes. However, they can prevent CVB-mediated disease progression in the same model. <b></b>

Neutrophil elastase triggers the development of autoimmune diabetes by exacerbating innate immune responses in pancreatic islets of non-obese diabetic mice

2020 ◽  
Vol 134 (13) ◽  
pp. 1679-1696 ◽  
Author(s):  
Lingling Shu ◽  
Ling Zhong ◽  
Yang Xiao ◽  
Xiaoping Wu ◽  
Yang Liu ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Neutrophil Elastase ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Islet Inflammation ◽  
The Impact

Abstract Type 1 diabetes is an autoimmune disease resulted from self-destruction of insulin-producing pancreatic β cells. However, the pathological pathways that trigger the autoimmune destruction remain poorly understood. Clinical studies have demonstrated close associations of neutrophils and neutrophil elastase (NE) with β-cell autoimmunity in patients with Type 1 diabetes. The present study aims to investigate the impact of NE inhibition on development of autoimmune diabetes in NOD mice. NE pharmacological inhibitor (sivelestat) or biological inhibitor (elafin) was supplemented into NOD mice to evaluate their effects on islet inflammation and diabetogenesis. The impact of NE inhibition on innate and adaptive immune cells was measured with flow cytometry and immunohistochemistry. A significant but transient increase in neutrophil infiltration accompanied with elevated NE activity was observed in the neonatal period of NOD mice. Treatment of NOD mice with sivelestat or elafin at the early age led to a marked reduction in spontaneous development of insulitis and autoimmune diabetes. Mechanistically, inhibition of NE significantly attenuated infiltration of macrophages and islet inflammation, thus ameliorating cytotoxic T cell-mediated autoimmune attack of pancreatic β cells. In vitro studies showed that NE directly induced inflammatory responses in both min6 β cells and RAW264.7 macrophages, and promoted macrophage migration. These findings support an important role of NE in triggering the onset and progression of β-cell autoimmunity, and suggest that pharmacological inhibition of NE may represent a promising therapeutic strategy for treatment of autoimmune diabetes.

scholarly journals Gene Expression Analysis of the Pre-Diabetic Pancreas to Identify Pathogenic Mechanisms and Biomarkers of Type 1 Diabetes

2020 ◽  
Vol 11 ◽  
Author(s):  
Linda Yip ◽  
Rebecca Fuhlbrigge ◽  
Reem Alkhataybeh ◽  
C. Garrison Fathman
Keyword(s):  
Gene Expression ◽  
Type 1 Diabetes ◽  
Disease Progression ◽  
Expression Analysis ◽  
Peripheral Blood ◽  
Gene Expression Analysis ◽  
Nod Mice ◽  
Human Pancreas ◽  
Blood Samples

Type 1 Diabetes (T1D) occurs as a result of the autoimmune destruction of pancreatic β-cells by self-reactive T cells. The etiology of this disease is complex and difficult to study due to a lack of disease-relevant tissues from pre-diabetic individuals. In this study, we performed gene expression analysis on human pancreas tissues obtained from the Network of Pancreatic Organ Donors with Diabetes (nPOD), and showed that 155 genes were differentially expressed by ≥2-fold in the pancreata of autoantibody-positive (AA+) at-risk individuals compared to healthy controls. Only 48 of these genes remained changed by ≥2-fold in the pancreata of established T1D patients. Pathway analysis of these genes showed a significant association with various immune pathways. We were able to validate the differential expression of eight disease-relevant genes by QPCR analysis: A significant upregulation of CADM2, and downregulation of TRPM5, CRH, PDK4, ANGPL4, CLEC4D, RSG16, and FCGR2B was confirmed in the pancreata of AA+ individuals versus controls. Studies have already implicated FCGR2B in the pathogenesis of disease in non-obese diabetic (NOD) mice. Here we showed that CADM2, TRPM5, PDK4, and ANGPL4 were similarly changed in the pancreata of pre-diabetic 12-week-old NOD mice compared to NOD.B10 controls, suggesting a possible role for these genes in the pathogenesis of both T1D and NOD disease. The loss of the leukocyte-specific gene, FCGR2B, in the pancreata of AA+ individuals, is particularly interesting, as it may serve as a potential whole blood biomarker of disease progression. To test this, we quantified FCGR2B expression in peripheral blood samples of T1D patients, and AA+ and AA- first-degree relatives of T1D patients enrolled in the TrialNet Pathway to Prevention study. We showed that FCGR2B was significantly reduced in the peripheral blood of AA+ individuals compared to AA- controls. Together, these findings demonstrate that gene expression analysis of pancreatic tissue and peripheral blood samples can be used to identify disease-relevant genes and pathways and potential biomarkers of disease progression in T1D.

scholarly journals Helminth Infection Can Reduce Insulitis and Type 1 Diabetes through CD25- and IL-10-Independent Mechanisms

2009 ◽  
Vol 77 (12) ◽  
pp. 5347-5358 ◽  
Author(s):  
Qian Liu ◽  
Krishnan Sundar ◽  
Pankaj K. Mishra ◽  
Gity Mousavi ◽  
Zhugong Liu ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Helminth Infection ◽  
Inflammatory Responses ◽  
Nod Mice ◽  
Interleukin 4 ◽  
Heligmosomoides Polygyrus ◽  
Nonobese Diabetic

ABSTRACT Parasitic helminth infection has been shown to modulate pathological inflammatory responses in allergy and autoimmune disease. The aim of this study was to examine the effects of infection with a helminth parasite, Heligmosomoides polygyrus, on type 1 diabetes (T1D) in nonobese diabetic (NOD) mice and to elucidate the mechanisms involved in this protection. H. polygyrus inoculation at 5 weeks of age protected NOD mice from T1D until 40 weeks of age and also inhibited the more aggressive cyclophosphamide-induced T1D. Moreover, H. polygyrus inoculation as late as 12 weeks of age reduced the onset of T1D in NOD mice. Following H. polygyrus inoculation of NOD mice, pancreatic insulitis was markedly inhibited. Interleukin-4 (IL-4), IL-10, and IL-13 expression and the frequency of CD4+ CD25+ FoxP3+ regulatory T cells were elevated in mesenteric and pancreatic lymph nodes. Depletion of CD4+ CD25+ T cells in vivo did not abrogate H. polygyrus-induced T1D protection, nor did anti-IL-10 receptor blocking antibody. These findings suggest that infection with H. polygyrus significantly inhibits T1D in NOD mice through CD25- and IL-10-independent mechanisms and also reduces the severity of T1D when administered late after the onset of insulitis.

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