What question did this study set out to answer?

To explore how chronic intestinal inflammation affects gut bacterial translocation and its link to metabolic dysfunction in a mouse model of Crohn disease.

February 8, 2026Open Access

The role of gut bacterial translocation in the development of glucose intolerance and insulin resistance

Key Points

To explore how chronic intestinal inflammation affects gut bacterial translocation and its link to metabolic dysfunction in a mouse model of Crohn disease.
Used the SHIP-/- mouse model to examine intestinal inflammation and bacterial translocation.
Assessed intestinal barrier function, adipose tissue inflammation, and pancreatic cytokine levels.
Evaluated susceptibility to glucose intolerance and responses to a Western diet and prebiotic supplementation.
SHIP-/- mice showed intestinal barrier dysfunction and adipose tissue inflammation but did not develop glucose intolerance.
Pancreatic IL-1β levels were elevated in SHIP-/- mice compared to controls.
Diet-induced metabolic stress resistance was observed in SHIP-/- mice after a Western diet.
Inulin supplementation improved intestinal barrier function in SHIP-/- mice, especially in females, but did not consistently reduce extra-intestinal inflammation.

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.

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