Influence of obesity on the mechanisms of peripheral tolerance and on the modulation of immune response in the small intestine of mice.

Abstract

Epidemiological studies have shown an association between obesity and autoimmune diseases. However, the immunologic mechanisms that explain this association have not been elucidated. The small intestine is one of the most important organs for the induction of peripheral tolerance; the intestinal immune system maintains the function of the organ while it responds to antigens from diet, pathogens and microbiota. Thus, our hypothesis is that obesity impacts the intestinal homeostasis and lead to the loss of peripheral tolerance that can be associated with the triggering of autoimmune diseases. To investigate this hypothesis, the aim of the project is to evaluate whether obesity exerts influence on the mechanisms of peripheral tolerance in a murine model of oral tolerance. OT-II mice will be fed with high-fat diet and submitted to a protocol of oral tolerance to ovalbumin (OVA). They will be challenged with OVA-expressing bacteria to evaluate whether peripheral tolerance is altered. Quantification and characterization of the main cells involved in oral tolerance (dendritic cells and regulatory T cells) will be performed and we will study the specific effects of regulatory FOXP3+ T cells and microbiota in this context of loss of peripheral tolerance. To further investigate the mechanisms involved in the crosstalk among diet, microbiota, epithelium and intestinal immune system we will focus on the incretin GLP-1 as a possible modulator of immune activity in the small intestine. We hope that the results will contribute to a better understanding of the complex interactions in intestinal mucosa that can be involved with autoimmune diseases.