Ulcerative colitis (UC) is characterized by chronic inflammation of the colonic mucosa. Administration of dextran sulfate sodium (DSS) to animals is a frequently used model to mimic human colitis. Deregulation of the immune response to the enteric microflora or pathogens as well as increased intestinal permeability have been proposed as disease-driving mechanisms. To enlarge the understanding of the pathogenesis, we have studied the effect of DSS on the immune system and gut microbiota in mice. Intestinal inflammation was verified through histological evaluation and myeloperoxidase activity. Immunological changes were assessed by flow cytometry in spleen, Peyer′s patches and mesenteric lymph nodes and through multiplex cytokine profiling. In addition, quantification of the total amount of bacteria on colonic mucosa as well as the total amount of lactobacilli, Akkermansia, Desulfovibrio and Enterobacteriaceae was performed by the use of quantitative PCR. Diversity and community structure were analysed by terminal restriction fragment length polymorphism (T-RFLP) patterns, and principal component analysis was utilized on immunological and T-RFLP patterns. DSS-induced colitis show clinical and histological similarities to UC. The composition of the colonic microflora was profoundly changed and correlated with several alterations of the immune system. The results demonstrate a relationship between multiple immunological changes and alterations of the gut microbiota after DSS administration. These data highlight and improve the definition of the immunological basis of the disease and suggest a role for dysregulation of the gut microbiota in the pathogenesis of colitis.

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 β-cells, we have generated mice with a β-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 Δ/wt), RIP-Cre+/− Dicer1flox/flox mice (RIP-Cre Dicer1 Δ/Δ) 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 β-cell mass, reduced numbers of granules within the β-cells and reduced granule docking in adult RIP-Cre Dicer1 Δ/Δ mice. β-cell specific Dicer1 deletion did not appear to disrupt fetal and neonatal β-cell development as 2-week old RIP-Cre Dicer1 Δ/Δ mice showed ultrastructurally normal β-cells and intact insulin secretion. In conclusion, we have demonstrated that a β-cell specific disruption of the miRNAs network, although allowing for apparently normal β-cell development, leads to progressive impairment of insulin secretion, glucose homeostasis and diabetes development.

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 such as diet, disease and antibiotic treatment. However, already in utero, these environmental factors can affect the immunological development of the foetus 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 with 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 with 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.