The gut microbiota has been suggested to be an important factor in the development of autoimmune diseases such as type 1 diabetes (T1D). Priming of islet specific T cells in the pancreatic lymph nodes (PaLN) and their migration to the pancreatic islets are critical steps in the destruction of insulin producing β-cells that leads the development of autoimmune diabetes. Perturbation of gut homeostasis by pathogenic microbes or imbalance of the gut microbiota during dysbiosis may provoke the autoimmune reactions that are associated with T1D. However, the mechanisms by which altered gut microbiota and its interaction with the immune system affect autoimmune diabetes development are unclear. In this thesis, we investigated how gut microbiota composition influences the progression of autoimmune diabetes in nonobese (NOD) mice and whether dysbiosis aggravates the immunological events associated with T1D pathogenesis.

This thesis will show how compromised intestinal barrier integrity and dysbiosis promote islet-specific T cell activation and their attraction to pancreatic islets. First, we show that healthy microbiota is associated with enhanced intestinal integrity and has a beneficial effect on the progression of autoimmune diabetes. We show that induction of dysbiosis with pathogenic microbes impairs intestinal barrier function, where among other factors plasmacytoid dendritic cells (pDCs) have an important regulatory role, and promote the autoimmune responses associated with the β-cell destruction. We describe a novel shared lymphatic drainage between the gut and pancreas that allows dendritic cell and bacterial migration to PaLNs during dysbiosis. Dysbiosis enhances the activation of islet-specific T cells and their priming with chemokine receptor CXCR3 in PaLNs. Additionally, we show that dysbiosis, followed by elevated endotoxin levels, enhances CXCL10 production within the pancreatic islets, which leads to enhanced attraction of CXCR3+ lymphocytes into pancreatic islets. Our results indicate that dysbiosis may be the initial factor that promotes lymphocyte infiltration into healthy pancreatic islets.

This thesis will give new insight into the effects of gut microbiota on the development of autoimmune diabetes and the role of dysbiosis in actuating the autoimmune responses associated with T1D pathogenesis.