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

Abstract

ObjectivesTo determine if spatial variations in gut permeability play a role in regulating type 1 diabetes (T1D) progression.Research design and methodsSpatially 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.ResultsZonulin 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.ConclusionsElevated 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.

Gut microbiota, key to unlocking the door of diabetic kidney disease

“…Intestinal bacteria may pass through the leaky intestinal barrier and act as dietary pathogens, or antigens, to elicit an immune response. 49 , 50 According to an experiment performed on db/db mice, a high‐fat diet could alter gut microbiota composition and reduce the expression of epithelial tight junction proteins (ZO‐1 and occludin). These changes increased intestinal permeability and enhanced LPS absorption, thereby promoting visceral adipose tissue inflammation, oxidative stress and macrophage infiltration.…”

The Role of Intestinal Mucosal Barrier in Autoimmune Disease: A Potential Target

“…In addition, the altered composition of the intestinal microbiome is also involved in the onset of T1D (88)(89)(90), which is related to the impaired intestinal mucosal barrier or accelerates the disruption of the intestinal mucosal barrier directly. Zonulin as a regulator of tight junction in the intestinal mucosal barrier has been reported to participate in the pathogenesis of T1D (91)(92)(93). The increased serum concentration of zonulin was found in the diabetic rat model, and the elevated zonulin levels were detected in the intestinal tissue of T1D patients, which was positively correlated with the disease progression (91).…”

“…Zonulin as a regulator of tight junction in the intestinal mucosal barrier has been reported to participate in the pathogenesis of T1D (91)(92)(93). The increased serum concentration of zonulin was found in the diabetic rat model, and the elevated zonulin levels were detected in the intestinal tissue of T1D patients, which was positively correlated with the disease progression (91). Besides that, the study found that patients with T1D and their relatives had the high level zonulin (92), which indicated that the high zonulin increased the susceptibility to T1D and its pathways have a pathogenic effect on T1D.…”

The role and mechanism of gut microbiota-derived short-chain fatty in the prevention and treatment of diabetic kidney disease

“…Notably, these unfavorable changes could be attenuated by employing antibiotic therapy. The underlying mechanism of these beneficial effects may be associated with some agents’ capacity for improving the gut barricade and reducing intestinal permeability by regulating gut microbiota and alleviating DKD-related complications ( 84 ).…”