The Role of Gastrointestinal Mucosal Immunity in Diabetes

A person dies every 7 seconds from complications of type 2 diabetes (T2D). Fueled by the obesity epidemic, T2D affects 29 million people in the United States and 400 million worldwide. Aberrant systemic inflammation that develops in the obese contributes to insulin resistance and the development of T2D. Growing evidence suggest that the gastrointestinal (GI) tract may be an important organ that drives systemic inflammation and the pathogenesis of diabetes. Changes in intestinal permeability to inflammatory antigens derived from the microbiome have been shown to lead to insulin resistance and adipose tissue inflammation. Further supporting the importance of the GI tract in diabetes, alteration of intestinal anatomy with bariatric surgery reverse systemic markers of inflammation, alters the gut microbiome, and is the most effective current therapy for diabetes. We hypothesize that diabetes alters the GI mucosal immune response, leading to impaired intestinal metabolic and barrier function. To test this hypothesis, we propose the following specific aims: Aim 1. Quantify changes in GI leukocyte phenotype and function in diabetes. The mucosal immune system maintains homeostasis with the gut microbiota; therefore, we believe sustained changes in the GI immune response must occur that lead to altered intestinal permability and systemic inflammation. We will use the novel technique of mass cytometry to perform single cell immune profiles of gastric, small intestine, and colonic leukocytes in mouse models of diabetes and obesity. We will simultaneously collect human intestinal tissue for validation of animal results. Aim 2. Study the influence of mucosal immunity on intestinal glucose regulation. Intestinal inflammation has been linked to altered intestinal epithelial metabolic function. We will employ an unique portal-systemic catherization model to directly measure the impact of altered intestinal inflammation on intestinal glucose utilization, absorption, incretin hormone secretion, and gut permeability. The goal of this work is to identify targets in the gut immune system for the treatment of diabetes. This pilot study will also provide a foundation for future studies looking at the impact of bariatric surgery on mucosal and systemic immunity.