To read the full abstract: Science 2018;359:1376-1383
The metabolic syndrome (MetS) is associated with dysfunctions of the intestinal barrier, leading to increased permeability and translocation of microbial molecules into the intestinal lamina propria and to circulation. The entry of pathogens through an impaired barrier leads to an increased risk of infection, as well as to chronic inflammation in obese and diabetic individuals.
In a series of elegant experiments, Thaiss et al. here defined the molecular and cellular disruptors of intestinal barrier function. Studying leptin deficient and leptin resistant mice, they first demonstrated elevated amounts of microbial pattern recognition receptor ligands, indicative of influx of microbial products. Then they demonstrated that tight and adherence junction structures were among the genes whose expression was most strongly abrogated. Neither leptin signaling nor obesity per se explained the severity of barrier dysfunction. Studying other components of the MetS that may contribute to barrier dysfunction, the authors revealed that hyperglycemia per se resulted in dysfunction of intestinal epithelial adherence junctions in a mouse model of type 1 diabetes. Treatment with insulin prevented the loss of adherence junction integrity. Isolated intestinal epithelial cells from hyperglycemic mice featured elevated amounts of metabolites along the glycolytic cascade and GLUT2 was discovered as the molecule involved in the intestinal epithelial cell barrier dysfunction. Hyperglycemia causes retrograde transport of glucose into intestinal epithelial cells via GLUT2, followed by alterations in intracellular glucose metabolism and transcriptional reprogramming. The authors suggest that the impact of hyperglycemia on epithelial barrier function might be relevant beyond the gastrointestinal tract and affect other mucosal surfaces, such as the respiratory tract.