Antibiotic-induced acceleration of type 1 diabetes alters maturation of innate intestinal immunity

The early-life intestinal microbiota plays a key role in shaping host immune system development. We found that a single early-life antibiotic course (1PAT) accelerated type 1 diabetes (T1D) development in male NOD mice. The single course had deep and persistent effects on the intestinal microbiome, leading to altered cecal, hepatic, and serum metabolites. The exposure elicited sex-specific effects on chromatin states in the ileum and liver and perturbed ileal gene expression, altering normal maturational patterns. The global signature changes included specific genes controlling both innate and adaptive immunity. Microbiome analysis revealed four taxa each that potentially protect against or accelerate T1D onset, that were linked in a network model to specific differences in ileal gene expression. This simplified animal model reveals multiple potential pathways to understand pathogenesis by which early-life gut microbiome perturbations alter a global suite of intestinal responses, contributing to the accelerated and enhanced T1D development.

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Proinsulin 2 Knockout NOD Mice: A Model for Genetic Variation of Insulin Gene Expression in Type 1 Diabetes

Diabetes ◽

10.2337/diabetes.51.2007.s489 ◽

2002 ◽

Vol 51 (Supplement 3) ◽

pp. S489-S493 ◽

Cited By ~ 16

Author(s):

D. Dubois-Lafforgue ◽

L. Mogenet ◽

K. Thebault ◽

J. Jami ◽

P. Krief ◽

...

Keyword(s):

Gene Expression ◽

Type 1 Diabetes ◽

Genetic Variation ◽

Nod Mice ◽

Insulin Gene ◽

Insulin Gene Expression

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IFN Regulatory Factors 4 and 8 Expression in the NOD Mouse

Clinical and Developmental Immunology ◽

10.1155/2011/374859 ◽

2011 ◽

Vol 2011 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Gilles Besin ◽

Simon Gaudreau ◽

Émilie Dumont-Blanchette ◽

Michael Ménard ◽

Chantal Guindi ◽

...

Keyword(s):

Gene Expression ◽

Bone Marrow ◽

Type 1 Diabetes ◽

Nod Mice ◽

Nod Mouse ◽

Dc Functions ◽

Gm Csf ◽

Diabetes Progression ◽

Islet Inflammation

Dendritic cells (DCs) contribute to islet inflammation and its progression to diabetes in NOD mouse model and human. DCs play a crucial role in the presentation of autoantigen and activation of diabetogenic T cells, and IRF4 and IRF8 are crucial genes involved in the development of DCs. We have therefore investigated the expression of these genes in splenic DCs during diabetes progression in NOD mice. We found that IRF4 expression was upregulated in splenocytes and in splenic CD11c+DCs of NOD mice as compared to BALB/c mice. In contrast, IRF8 gene expression was higher in splenocytes of NOD mice whereas its expression was similar in splenic CD11c+DCs of NOD and BALB/c mice. Importantly, levels of IRF4 and IRF8 expression were lower in tolerogenic bone marrow derived DCs (BMDCs) generated with GM-CSF as compared to immunogenic BMDCs generated with GM-CSF and IL-4. Analysis of splenic DCs subsets indicated that high expression of IRF4 was associated with increased levels of CD4+CD8α−IRF4+CD11c+DCs but not CD4−CD8α+IRF8+CD11c+DCs in NOD mice. Our results showed that IRF4 expression was up-regulated in NOD mice and correlated with the increased levels of CD4+CD8α−DCs, suggesting that IRF4 may be involved in abnormal DC functions in type 1 diabetes in NOD mice.

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N-Acetyl-l-Cysteine Supplement in Early Life or Adulthood Reduces Progression of Diabetes in Nonobese Diabetic Mice

Current Developments in Nutrition ◽

10.1093/cdn/nzy097 ◽

2018 ◽

Vol 3 (4) ◽

Author(s):

Lital Argaev Frenkel ◽

Hava Rozenfeld ◽

Konstantin Rozenberg ◽

Sanford R Sampson ◽

Tovit Rosenzweig

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Type 1 Diabetes ◽

Antioxidant Enzymes ◽

Early Life ◽

Nod Mice ◽

Morbidity Rate ◽

Nonobese Diabetic ◽

Total Antioxidant

ABSTRACT Background Oxidative stress contributes to the pathologic process leading to the development, progression, and complications of type 1 diabetes (T1D). Objective The aim of this study was to investigate the effect of the antioxidant N-acetyl-l-cysteine (NAC), supplemented during early life or adulthood on the development of T1D. Methods NAC was administered to nonobese diabetic (NOD) female mice during pregnancy and lactation, and the development of diabetes was followed in offspring. In an additional set of experiments, offspring of untreated mice were given NAC during adulthood, and the development of T1D was followed. Morbidity rate, insulitis and serum cytokines were measured in the 2 sets of experiments. In addition, markers of oxidative stress, glutathione, lipid peroxidation, total antioxidant capacity and activity of antioxidant enzymes, were followed. Results Morbidity rate was reduced in both treatment protocols. A decrease in interferon γ, tumor necrosis factor α, interleukin 1α, and other type 1 diabetes-associated proinflammatory cytokines was found in mice supplemented with NAC in adulthood or during early life compared with control NOD mice. The severity of insulitis was higher in control NOD mice than in treated groups. NAC administration significantly reduced oxidative stress, as determined by reduced lipid peroxidation and increased total antioxidant capacity in serum and pancreas of mice treated in early life or in adulthood and increased pancreatic glutathione when administrated in adulthood. The activity of antioxidant enzymes was not affected in mice given NAC in adulthood, whereas an increase in the activity of superoxide dismutase and catalase was demonstrated in the pancreas of their offspring. Conclusion NAC decreased morbidity of NOD mice by attenuating the immune response, presumably by eliminating oxidative stress, and might be beneficial in reducing morbidity rates of T1D in high-risk individuals.

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

Frontiers in Endocrinology ◽

10.3389/fendo.2020.609271 ◽

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.

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Gene expression profiling in type 1 diabetes prone NOD mice immunized with a disease protective autoantigenic peptide

Journal of Autoimmunity ◽

10.1016/j.jaut.2004.09.002 ◽

2004 ◽

Vol 23 (4) ◽

pp. 311-321 ◽

Cited By ~ 3

Author(s):

Ashish Rajput ◽

Bhagirath Singh

Keyword(s):

Gene Expression ◽

Type 1 Diabetes ◽

Gene Expression Profiling ◽

Expression Profiling ◽

Nod Mice

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Role of Nutritional Factors at the Early Life Stages in the Pathogenesis and Clinical Course of Type 1 Diabetes

BioMed Research International ◽

10.1155/2015/382165 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 6

Author(s):

Yukiko Kagohashi ◽

Hiroki Otani

Keyword(s):

Type 1 Diabetes ◽

Early Life ◽

Nod Mice ◽

Allergic Diseases ◽

Lactation Period ◽

Life Stages ◽

Early Life Stages ◽

Acid Ratio ◽

Pregnancy And Lactation

Nutrition has been suggested as an important environmental factor other than viruses and chemicals in the pathogenesis of type 1 diabetes (T1D). Whereas various maternal dietary nutritional elements have been suggested and examined in T1D of both humans and experimental animals, the results largely remain controversial. In a series of studies using T1D model nonobese diabetic (NOD) mice, maternal dietary n-6/n-3 essential fatty acid ratio during pregnancy and lactation period, that is, early life stages of the offspring, has been shown to affect pathogenesis of insulitis and strongly prevent overt T1D of the offspring, which is consistent with its preventive effects on other allergic diseases.

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