The Role of the Intestinal Immune System in Diet-induced Obesity and Insulin Resistance

Chronic low-grade inflammation of metabolic tissues is thought to be a major driver of obesity related insulin resistance and metabolic disease. While changes to the immune profile in adipose tissue during obesity has been extensively studied, alterations to the intestinal immune system and the contribution of these cells to metabolic disease remain largely unknown. This thesis aims to elucidate the immunological changes within the intestine during obesity-related insulin resistance with focus on the adaptive component of the intestinal immune system. Indeed, our main findings indicated a shift towards a pro-inflammatory environment within the intestine during high fat diet feeding in mice mainly characterized by increased IFNγ producing Th1 and CD8+ T cells, and reductions in regulatory T cells and IgA+ B and plasma cells. Mechanistic interactions between diet, gut microbiota, intestinal barrier and the intestinal immune system were also explored to delineate the implication of the intestinal network on the overall manifestation of metabolic disease. Existing therapies for metabolic disease such as metformin and bariatric surgery protocols were shown to influence the immunological environment within the intestine, while gut-specific anti-inflammatory therapies, namely 5-aminosalicylic acid, demonstrated promise in ameliorating obesity-related insulin resistance in preclinical models.Ph.D