Spatial variations in gut permeability are linked to type 1 diabetes development in non-obese diabetic mice.

Objectives: To determine if spatial variations in gut permeability play a role in regulating type 1 diabetes (T1D) progression. Research design and methods: Spatially resolved duodenum, jejunum, ileum, and large intestine sections from end-stage T1D non-obese diabetic (NOD) mice were probed by immunohistochemistry to quantify zonulin levels as a measure of gut permeability in early-progressor and late-progressor NOD mice in comparison with non-progressor NOD mice and healthy NOR/LtJ control mice. Results: Zonulin levels were elevated in the small and large intestines in early-progressor and late-progressor NOD mice in comparison with non-progressor NOD mice and healthy NOR control mice. In early-onset mice, elevated zonulin levels were maximum in the duodenum and jejunum and decreased in the ileum and large intestine. In late-progressor mice, zonulin levels were elevated almost evenly along the small and large intestines. In non-progressor NOD mice, zonulin levels were comparable with NOR control levels in both the small and large intestines. Conclusions: Elevated zonulin expression levels indicated that gut permeability was increased both in the small and large intestines in NOD mice that progressed to end-stage T1D in comparison with non-progressor NOD mice and healthy NOR control mice. Highest elevations in zonulin levels were observed in the duodenum and jejunum followed by the ileum and large intestines. Spatial variations in gut permeability appeared to play a role in regulating the rate and severity of T1D progression in NOD mice indicating that spatial variations in gut permeability should be investigated as a potentially important factor in human T1D progression.