Hyperglycemia and Obesity Play a Different Role in the Pathogenesis of Colitis in Diabetic Mice

Abstract

Obesity, diabetes, and related manifestations have a large impact on global health. Evidence shows that these pathological disorders are highly associated with gastrointestinal (GI) diseases such as colitis. However, the impact of diabetes‐related hyperglycemia and obesity in the development of colitis is uncertain. In this study, we aimed to study the role of hyperglycemia with or without obesity condition in the pathogenesis of colitis in diabetic mice. For this purpose, we designed two mouse models of diabetes in male mice (9 weeks old). In the first model, B6 db/db mice with diabetic and obese phenotype or wild‐type B6 mice were subjected to dextran sulfate sodium (DSS, 40 kDa) treatment in drinking water for one week to induce colitis. In another model, we treated wild‐type B6 mice with streptozotocin (STZ, 175 mg/kg) or saline (control) to induce a hyperglycemia/diabetic phenotype without obesity. Eight weeks after induction of diabetes by STZ, mice were given DSS in their drinking water to examine whether prolonged hyperglycemia condition affects colitis development. The blood glucose, disease activity index (DAI, incorporating weight loss, stool consistency, and GI bleeding) of colitis and intestinal histological changes were monitored throughout the study. Interestingly, we found that DSS treated db/db mice with both diabetic and obese phenotype showed very mild symptoms (DAI 4.5 vs DAI 8.5, P<0.05), and significantly less body weight loss (1.87 % vs 19.04 %, P<0.01) compared to the DSS treated wild‐type B6 mice. In meanwhile, DSS treated STZ‐induced hyperglycemia mice without obese phenotype exhibited severe symptoms of colitis compared to DSS treated wild‐type B6 mice (DAI 2.4 vs DAI 0.64, P<0.01) beginning at day 3 of DSS treatment. They were found to have a delayed recovery from the intestinal injury and an increase in mortality rate after the withdrawal of DSS compared to control groups, suggesting that the long‐term hyperglycemia predisposes diabetic mice to gut inflammation. Collectively, prolonged hyperglycemia/diabetes enhances the susceptibility to intestinal injury. In contrast, the obese condition seems to have a different role or delaying the development of colitis in diabetic individuals. The underlying mechanisms by which diabetes and obesity affect the pathogenesis of colitis in diabetic mice are to be studied in the future.