| Type 1 diabetes (T1D) is an autoimmune disease the development of which is highly susceptible to environmental influence. I utilized non-obese diabetic (NOD) mice as a model of spontaneous T1D to address the impact of environmental factors in modulating disease. Specifically, how microbiota is able to naturally protect male mice from T1D development but not female mice, and the role of dietary manipulation in prevention of the disease in female mice. In the first part of this work we wanted to under why female NOD mice in specific pathogen free conditions have a 1.3-4.4 times higher incidence of T1D compared to male mice. We identified that microbiota differed in male and female mice post-puberty, and that this trend is reversed by male castration, confirming that androgens influence gut microbiota. Colonization of germ free (GF) NOD mice with defined microbiota revealed that some, but not all, lineages of overrepresented bacteria in male mice were able to lead to specific protection of male mice but not female mice. Gene expression analysis identified a key pathway mediated by IFNgamma that is specifically upregulated in male mice by the presence of protective microbiota and is involved in protection of male mice from T1D. Thus, in SPF conditions microbiota and androgens act in concert to trigger protective pathways exclusively in male mice.;Previous work has suggested that dietary intervention could lead to protection of NOD female mice in SPF conditions and that this protection correlated with changes in microbiota. We were able to utilize germ free mice to show that protection mediated by diet was independent of the presence of microbiota, and that changes in microbiota are secondary to the effect of diet on disease development. No gross changes in the ability of the immune compartments ability to induce disease were observed in response to protective diet, as there was still heavy infiltration of the islet by lymphocytes, and the diet did not affect disease development in transfer models of the disease. Finally, we found that dietary exposure actually affected beta cell function and that even shortened exposure to the diet up until 4 weeks of age was enough to result in protection in mice even at 30 weeks of age.;Many environmental factors have a significant impact on development of T1D in NOD mice. We identified protective pathways which were microbiota dependent and independent and which target different steps necessary for development of T1D. This suggests that diverse intervention strategies need to specifically target stages in development of T1D which are susceptible to such modulation. |
