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Copenhagen, Denmark

Bangsgaard Bendtsen K.M.,Copenhagen University | Krych L.,Copenhagen University | Sorensen D.B.,Copenhagen University | Pang W.,Copenhagen University | And 5 more authors.
PLoS ONE | Year: 2012

Stress has profound influence on the gastro-intestinal tract, the immune system and the behavior of the animal. In this study, the correlation between gut microbiota composition determined by Denaturing Grade Gel Electrophoresis (DGGE) and tag-encoded 16S rRNA gene amplicon pyrosequencing (454/FLX) and behavior in the Tripletest (Elevated Plus Maze, Light/Dark Box, and Open Field combined), the Tail Suspension Test, and Burrowing in 28 female BALB/c mice exposed to two weeks of grid floor induced stress was investigated. Cytokine and glucose levels were measured at baseline, during and after exposure to grid floor. Stressing the mice clearly changed the cecal microbiota as determined by both DGGE and pyrosequencing. Odoribacter, Alistipes and an unclassified genus from the Coriobacteriaceae family increased significantly in the grid floor housed mice. Compared to baseline, the mice exposed to grid floor housing changed the amount of time spent in the Elevated Plus Maze, in the Light/Dark Box, and burrowing behavior. The grid floor housed mice had significantly longer immobility duration in the Tail Suspension Test and increased their number of immobility episodes from baseline. Significant correlations were found between GM composition and IL-1α, IFN-γ, closed arm entries of Elevated Plus Maze, total time in Elevated Plus Maze, time spent in Light/Dark Box, and time spent in the inner zone of the Open Field as well as total time in the Open Field. Significant correlations were found to the levels of Firmicutes, e.g. various species of Ruminococccaceae and Lachnospiraceae. No significant difference was found for the evaluated cytokines, except an overall decrease in levels from baseline to end. A significant lower level of blood glucose was found in the grid floor housed mice, whereas the HbA1c level was significantly higher. It is concluded that grid floor housing changes the GM composition, which seems to influence certain anxiety-related parameters. © 2012 Bangsgaard Bendtsen et al. Source


Adlercreutz E.H.,Skane University Hospital | Svensson J.,Herlev Hospital | Svensson J.,Copenhagen University | Hansen D.,University of Southern Denmark | And 5 more authors.
Pediatric Diabetes | Year: 2015

Objectives: The aim was to determine the prevalence of celiac disease autoimmunity in children with type 1 diabetes (T1D) diagnosed in Denmark and Sweden. Methods: A total of 662 Swedish children with T1D were matched with 1080 Danish children with T1D and 309 healthy children from Sweden and 283 from Denmark served as controls. Sera were analyzed for the presence of IgA and IgG (IgAG) autoantibodies against deamidated gliadin peptide (DGP) and tissue transglutaminase (tTG) with enzyme-linked immunosorbent assay (ELISA) and IgG-tTG separately in a radioligand binding assay (RBA). Human leukocyte antigen (HLA)-DQB1 and DQA1 genotyping were determined in the T1D cohorts. Results: In the Swedish T1D cohort, 17.2% (114/662) were IgAG-DGP/tTG positive compared with 11.7% (126/1080) in the Danish T1D cohort (p = 0.001) and with 9.4% (29/309) Swedish (p = 0.001) and 5.7% (16/283) Danish (p = 0.003) controls. In the Swedish T1D cohort, both levels of IgAG-DGP/tTG and IgG-tTG were higher compared with the levels in the Danish T1D (p < 0.001). In the control group, 2.8% of the Danish children were positive for both IgAG-DGP/tTG and IgG-tTG, compared to 0.3% of the Swedish. Presence of HLA-DQ2 was equally distributed among 89 children with T1D positive for both IgAG-DGP/tTG and IgG-tTG. Conclusion: The discrepancy in levels of IgAG-DGP/tTG and IgG-tTG between Swedish and Danish T1D cohorts was independent of HLA and suggests that regional variations in comorbidity of celiac disease in T1D is caused by difference in exposure to environmental factors. © 2015 John Wiley & Sons A/S. Source


Sorensen J.O.,The Bartholin Institute | Buschard K.,The Bartholin Institute | Brogren C.-H.,The Bartholin Institute
APMIS | Year: 2014

In the last two decades, natural killer T (NKT) cells have emerged as an important factor in preventing type 1 diabetes (T1D) when investigated in the experimental non-obese diabetic (NOD) mouse model. So far, investigations have largely focused on type 1 NKT cells with invariant T-cell receptors, whereas the role of type 2 NKT cells with diverse T-cell receptors is less well understood. However, there have been several findings which indicate that in fact type 2 NKT cells may regulate the progression of type 1 diabetes in NOD mice, including a fraction of these cells which recognize β-cell-enriched sulfatide. Therefore, the focus for this review is to present the current evidence of the effect of type 2 NKT cells on the development of T1D. In general, there is still uncertainty surrounding the mechanism of activation and function of NKT cells. Here, we present two models of the effector mechanisms, respectively, Th1/Th2 polarization and the induction of tolerogenic dendritic cells (DC). In conclusion, this review points to the importance of immunoregulation by type 2 NKT cells in preventing the development of T1D and highlights the induction of tolerogenic DC as a likely mechanism. The possible therapeutic role of type 1 and type 2 NKT cells are evaluated and future experiments concerning type 2 NKT cells and T1D are proposed. © 2013 APMIS. Source


Weile C.,The Bartholin Institute | Josefsen K.,The Bartholin Institute | Buschard K.,The Bartholin Institute
Clinical and Experimental Immunology | Year: 2011

Toll-like receptors are pattern-recognition receptors of the innate immune system that are activated during viral, bacterial or other infections, as well as during disease progression of type 1 and type 2 diabetes. Toll-like receptor 5 (TLR-5) specifically recognizes bacterial infection through binding of flagellin from pathogenic bacteria such as Salmonella and Listeria species. We have found that the expression of TLR5 is up-regulated by glucose activation of isolated islets of Langerhans, in contrast to other investigated TLRs (TLR-2, -3, -4, -6 and -9. Stimulation of islets with 10mm glucose increased the levels of TLR5 mRNA 10-fold (P=0·03) and the TLR-5 protein levels twofold (P=0·04). Furthermore, the protein level of downstream signalling molecule myeloid differentiation primary response gene 88 (MyD88) increased 1·6-fold (P=0·01). Activation of TLR-5 in islets lead to a marked reduction of both stimulated and basal secretion of insulin, as well as an increase in production of nitric oxide, proinflammatory cytokines, anti-inflammatory heat-shock protein and major histocompatibility complex (MHC) class I transporter. We observe no effects of TLR-5 activation on islet survival. We suggest that this regulation by TLR-5 might be beneficial during serious infection such as sepsis by limiting the activity of beta cells during peaks of insulin demand to counteract beta cell damage. © 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for Immunology. Source


Antvorskov J.C.,The Bartholin Institute | Fundova P.,The Bartholin Institute | Fundova P.,Charles University | Fundova P.,Academy of Sciences of the Czech Republic | And 3 more authors.
Immunology | Year: 2013

Several studies have documented that dietary modifications influence the development of type 1 diabetes. However, little is known about the interplay of dietary components and the penetration of diabetes incidence. In this study we tested if wheat gluten is able to induce differences in the cytokine pattern of Foxp3+ regulatory T cells, as well as Foxp3- T cells, isolated from intestinal mucosal lymphoid tissue and non-mucosal lymphoid compartments in BALB/c mice. The gluten-containing standard diet markedly changed the cytokine expression within Foxp3- T cells, in all lymphoid organs tested, towards a higher expression of pro-inflammatory interferon-γ (IFN-γ), interleukin-17 (IL-17) and IL-2. In Foxp3+ regulatory T cells, gluten ingestion resulted in a mucosal increase in IL-17 and IL-2 and an overall increase in IFN-γ and IL-4. The gluten-free diet induced an anti-inflammatory cytokine profile with higher proportion of transforming growth factor-β (TGF-β)+ Foxp3- T cells in all tested lymphoid tissues and higher IL-10 expression within non-T cells in spleen, and a tendency towards a mucosal increase in TGF-β+ Foxp3+ regulatory T cells. Our data shows that the gluten-containing standard diet modifies the cytokine pattern of both Foxp3- T cells and Foxp3+ regulatory T cells towards a more inflammatory cytokine profile. This immune profile may contribute to the higher type 1 diabetes incidence associated with gluten intake. © 2012 Blackwell Publishing Ltd. Source

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