Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection. Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection

Obesity, diabetes and related manifestations are associated with an enhanced, but poorly understood risk for mucosal infection. Here, we show in mouse models of obesity and diabetes that hyperglycemia drives intestinal barrier permeability, through GLUT2-dependent transcriptional reprogramming of intestinal epithelial cells and alteration of tight and adherence junction formation. In turn, hyperglycemia-mediated barrier disruption leads to steady-state influx of microbial products and enhanced systemic dissemination of enteric infection. Treatment of hyperglycemia, intestinal epithelial-specific GLUT2 deletion, or inhibition of epithelial glucose metabolism restores barrier function and bacterial containment. In humans, systemic influx of intestinal microbiome products correlates with individualized glycemic control, as manifested by glycated hemoglobin levels. Together, our results mechanistically link hyperglycemia, regulation of intestinal barrier function, and systemic infectious consequences of obesity and diabetes.