Project Summary Type 2 diabetes (T2D) and inflammatory bowel disease (IBD) are among the most challenging and costly medical disorders of modern society. Both disease processes also share a common pathophysiology characterized by a chronic inflammatory state, altered gut microbiome, and dysfunctional intestinal barrier. Hyperglycemia is the primary cause of the many complications of diabetes, and recent studies have shown that hyperglycemia is capable of directly impairing intestinal barrier function independent of diet and obesity. Population-based studies have shown that patients with IBD also have an increased risk of T2D, which has important clinical consequences as comorbid T2D in patients with IBD is a predictor of poor disease-related outcomes, though the causative mechanisms remain unknown. In this proposal, we will investigate the novel hypothesis that diabetic hyperglycemia in the setting of diet-induced obesity (DIO) worsens IBD disease activity by increasing intestinal inflammation and associated barrier dysfunction. Specifically, we propose to characterize the effect of diabetic hyperglycemia on clinical and biochemical measures of intestinal inflammation and barrier function in murine models of IBD, and to determine the extent to which control of glycemia decreases intestinal inflammation and improves clinical outcomes in diabetic murine models of IBD. Diabetic-range hyperglycemia will be induced by administration of low-dose streptozotocin (STZ) in two independent models of IBD: 1) C57BL/6J wild-type (WT) mice treated with dextran sodium sulfate (DSS) and 2) Mdr1 knockout mice that spontaneously develop colitis, made obese by consumption of an obesogenic high-fat diet (HFD) or fed standard chow. The impact of hyperglycemia on intestinal barrier function and IBD pathology in the setting of DIO will be assessed using immunohistochemical staining, dextran-FITC permeability assays, and characterization of the components of the intestinal extracellular matrix. We will then investigate the translational potential of treating diabetic hyperglycemia to decrease IBD progression by administering a sodium-glucose cotransportor-2 (SGLT2) inhibitor to normalize glycemia in diabetic murine models of IBD. Lastly, SGLT2 inhibitors will be administered in combination with topical 5-aminosalysilic acids, which are standard first line therapy for mild-to-moderate ulcerative colitis but often fail to control more significant disease, to determine whether treating diabetic hyperglycemia improves the efficacy of introductory IBD therapies. The proposed project unites the clinical gastroenterology, hepatology and nutrition interests and research skills of the applicant as well as the considerable multi-disciplinary resources of the University of Washington Diabetes Institute to advance understanding of the mechanisms by which diabetic hyperglycemia influences intestinal inflammation, with the ultimate goal of understanding shared pathogenic mechanisms an...