Open Collections

Abstract

Crohn disease (CD) is a form of inflammatory bowel disease (IBD) characterized by chronic, relapsing and remitting, or progressive inflammation of the gastrointestinal tract. Mounting evidence suggests that individuals with CD have an elevated risk of developing metabolic disease, such as type 2 diabetes (T2D), though the mechanisms linking these conditions remain poorly understood. CD and T2D share several pathophysiological features, including microbial dysbiosis, intestinal barrier dysfunction, and adipose tissue (AT) dysfunction. The Sly laboratory has previously characterized the Src homology 2 domain-containing inositolphosphate 5'-phosphatase (SHIP-/-) mouse model of CD-like ileitis, providing a model to investigate these shared mechanisms. Based on this, I hypothesized that chronic ileal inflammation in SHIP-/- mice would disrupt intestinal barrier function, facilitating bacterial translocation to mesenteric AT (MAT), contributing to the development of metabolic dysfunction (or disease). I confirmed that SHIP-/- mice exhibit additional features relevant to human CD, including intestinal barrier dysfunction, systemic AT inflammation, and fibrosis in MAT. SHIP-/- mice also had elevated pancreatic IL-1β concentrations. Despite displaying characteristics associated with both CD and T2D, SHIP-/- mice did not develop glucose intolerance and maintained insulin sensitivity comparable to SHIP+/+ controls. Furthermore, a Western diet challenge revealed that SHIP-/- mice may be resistant to diet-induced metabolic stress. Finally, supplementation with the prebiotic fibre inulin modestly improved intestinal barrier function and CD-like ileitis in SHIP-/- mice, with more pronounced effects observed in female mice. However, extra-intestinal inflammation was not consistently reduced, and in some cases, was exacerbated. Overall, these findings indicate that chronic intestinal inflammation and AT inflammation do not necessarily lead to metabolic dysfunction, highlighting a complex and context-dependent relationship between intestinal and extra-intestinal inflammation and metabolic health in CD.