Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection

Area of Science:

• Metabolic disorders
• Gastroenterology
• Immunology

Background:

• Obesity and diabetes increase susceptibility to infections and inflammation.
• The mechanisms linking metabolic dysfunction to compromised mucosal immunity are not fully understood.

Purpose of the Study:

• To investigate how hyperglycemia affects intestinal barrier function and systemic inflammation in obesity and diabetes.
• To identify molecular targets for restoring intestinal barrier integrity.

Main Methods:

• Utilized mouse models of obesity and diabetes.
• Examined the role of glucose transporter 2 (GLUT2) in intestinal epithelial cells.
• Assessed intestinal barrier permeability, tight junction integrity, and systemic microbial translocation.
• Correlated microbial product influx with glycemic control (hemoglobin A1c) in humans.

Main Results:

• Hyperglycemia, mediated by GLUT2, disrupts intestinal epithelial cells and tight junctions, increasing barrier permeability.
• This barrier disruption facilitates the systemic influx of microbial products and exacerbates enteric infections.
• Treatments targeting hyperglycemia, GLUT2, or glucose metabolism restored barrier function and bacterial containment.
• In humans, systemic microbial product levels correlate with glycemic control.

Conclusions:

• Hyperglycemia is a key driver of intestinal barrier dysfunction in obesity and diabetes.
• Restoring glycemic control or inhibiting glucose metabolism can repair the gut barrier and reduce infection risk.
• These findings mechanistically link metabolic health to intestinal barrier integrity and systemic immunity.