| 1. |
- Håkansson, Åsa, et al.
(författare)
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Immunological alteration and changes of gut microbiota after dextran sulfate sodium (DSS) administration in mice
- 2015
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Ingår i: Clinical and Experimental Medicine. - : Springer Science and Business Media LLC. - 1591-9528. ; 15:1, s. 107-120
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Tidskriftsartikel (refereegranskat)abstract
- Ulcerative colitis (UC) is characterized bychronic inflammation of the colonic mucosa. Administrationof dextran sulfate sodium (DSS) to animals is a frequentlyused model to mimic human colitis. Deregulationof the immune response to the enteric microflora orpathogens as well as increased intestinal permeability havebeen proposed as disease-driving mechanisms. To enlargethe understanding of the pathogenesis, we have studied theeffect of DSS on the immune system and gut microbiota inmice. Intestinal inflammation was verified through histologicalevaluation and myeloperoxidase activity. Immunologicalchanges were assessed by flow cytometry inspleen, Peyer0s patches and mesenteric lymph nodes andthrough multiplex cytokine profiling. In addition, quantificationof the total amount of bacteria on colonic mucosaas well as the total amount of lactobacilli, Akkermansia,Desulfovibrio and Enterobacteriaceae was performed bythe use of quantitative PCR. Diversity and communitystructure were analysed by terminal restriction fragmentlength polymorphism (T-RFLP) patterns, and principalcomponent analysis was utilized on immunological andT-RFLP patterns. DSS-induced colitis show clinical andhistological similarities to UC. The composition of thecolonic microflora was profoundly changed and correlatedwith several alterations of the immune system. The resultsdemonstrate a relationship between multiple immunologicalchanges and alterations of the gut microbiota after DSSadministration. These data highlight and improve the definitionof the immunological basis of the disease andsuggest a role for dysregulation of the gut microbiota in thepathogenesis of colitis.
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| 2. |
- Kalis, Martins, et al.
(författare)
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Beta-cell specific deletion of dicer1 leads to defective insulin secretion and diabetes mellitus
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:12, s. e29166-
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Tidskriftsartikel (refereegranskat)abstract
- Mature microRNAs (miRNAs), derived through cleavage of pre-miRNAs by the Dicer1 enzyme, regulate protein expression in many cell-types including cells in the pancreatic islets of Langerhans. To investigate the importance of miRNAs in mouse insulin secreting beta-cells, we have generated mice with a beta-cells specific disruption of the Dicer1 gene using the Cre-lox system controlled by the rat insulin promoter (RIP). In contrast to their normoglycaemic control littermates (RIP-Cre(+/-) Dicer1(Delta/wt)), RIP-Cre(+/-) Dicer1(flox/flox) mice (RIP-Cre Dicer1(Delta/Delta)) developed progressive hyperglycaemia and full-blown diabetes mellitus in adulthood that recapitulated the natural history of the spontaneous disease in mice. Reduced insulin gene expression and concomitant reduced insulin secretion preceded the hyperglycaemic state and diabetes development. Immunohistochemical, flow cytometric and ultrastructural analyses revealed altered islet morphology, marked decreased beta-cell mass, reduced numbers of granules within the beta-cells and reduced granule docking in adult RIP-Cre Dicer1(Delta/Delta) mice. beta-cell specific Dicer1 deletion did not appear to disrupt fetal and neonatal beta-cell development as 2-week old RIP-Cre Dicer1(Delta/Delta) mice showed ultrastructurally normal beta-cells and intact insulin secretion. In conclusion, we have demonstrated that a beta-cell specific disruption of the miRNAs network, although allowing for apparently normal beta-cell development, leads to progressive impairment of insulin secretion, glucose homeostasis and diabetes development.
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| 3. |
- Tormo-Badia, Neivis, et al.
(författare)
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Antibiotic treatment of pregnant non-obese diabetic (NOD) mice leads to altered gut microbiota and intestinal immunological changes in the offspring.
- 2014
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 1365-3083 .- 0300-9475. ; 80:4, s. 250-260
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Tidskriftsartikel (refereegranskat)abstract
- The intestinal microbiota is important for tolerance induction through mucosal immunological responses. The composition of the gut microbiota of an infant is affected by environmental factors like diet, disease and antibiotic treatment. However, already in utero these environmental factors can affect the immunological development of the fetus and influence the future gut microbiota of the infant. To investigate the effects of antibiotic treatment of pregnant mothers on the offspring's gut microbiome and diabetes development, we treated non-obese diabetic (NOD) mice with a cocktail of antibiotics during gestation and the composition of the gut microbiota, diabetes incidence and major gut-related T lymphocyte populations were investigated in the offspring. We observed a persistent reduction in the general diversity of the gut microbiota in the offspring from NOD mothers treated with antibiotics during gestation compared to offspring from control mothers. In addition, by clustering the present bacterial taxa with principal component analysis we found a differential clustering of gut microbiota in the offspring from NOD mothers treated with antibiotics during gestation compared to offspring from control mothers. Offspring from NOD mothers treated with antibiotics during gestation also showed some immunological alterations in the gut immune system, which could be related to the diversity of the gut microbiome and influence modulation of diabetes development at 20 weeks. Our data point out maternal derangement of the intestinal microbiota as a potential environmental risk factor for T1D development. This article is protected by copyright. All rights reserved.
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| 4. |
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| 5. |
- Tormo-Badia, Neivis
(författare)
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Regulation of Autoimmunity and Inflammation by microRNAs and Environmental Factors
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Tolerance is crucial for maintaining immunological balance and avoid autoimmune diseases like type 1 diabetes and the inflammatory bowel disease, ulcerative colitis (UC). In Study I, we have investigated the regulatory role of a class of noncoding RNAs, the miRNAs, during thymocyte development of the where central tolerance is established. We used the non-obese diabetic mouse (NOD) which is spontaneously developing T1D and have been described to have defects in the T cell maturation. By studying the apoptosis response of NOD lymphocytes (which activates similar cell-cycle checkpoints and apoptosis pathways as during thymocyte maturation) we showed differential expression of the miRNA-34a/b/c gene family, miR-125 and miR-155 in the DNA damage response between NOD and wild-type mice. We believe that these differentially expressed miRNAs may contribute to defect p53 expression in NOD thymocytes after DNA damage, which we also demonstrated in this study. In Study II, we studied the importance of global canonical miRNA regulation in the NOD mice for the development of T1D development by deleting Dicer1 (an enzyme needed for miRNA maturation) early in thymocyte development. We showed that these NOD.Lck-Cre Dicer KO mice had phenotype alterations including markedly decreased amount of αβ CD4+ and CD8+ T cells in the secondary lymph nodes but not a similarly large decrease in nTregs. No difference in diabetes incidence between female NOD.Lck-Cre Dicer KO mice and control littermates could be found as a result of these phenotypic changes but surprisingly a significant increase in the male mice diabetes incidence. In Study III, we investigated whether the maternal intestinal microbiota is an environmental factor influencing T1D development in the offspring. By modulating the intestinal gut microbiota with antibiotics during pregnancy of NOD mice we showed decreased diversity and a persistent modulation of the intestinal microbial pattern in the offspring. Possibly resulting in the immunological alterations of CD8+ and CD4+CD25+ T cell frequencies in the mesenteric lymph nodes respectively Peyer’s patches, which we demonstrated. The diabetes incidence seems to have increased in the offspring to treated mothers at 20 weeks of age but the effect was not persistent. In study IV, the relationship between the global intestinal microbiota and the immune system was investigated in the dextran sulfate sodium induced UC mouse model. We demonstrated changes in the colonic intestinal microbiota pattern and immunological alterations of different populations of T cells, dendritic cells and natural killer cells after UC induction.
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