Long-Term Use of Proton Pump Inhibitors Disrupts Intestinal Tight Junction Barrier and Exaggerates Experimental...

Area of Science:

• Gastroenterology
• Molecular Biology
• Immunology

Background:

• Proton pump inhibitors (PPIs) are frequently prescribed for gastroesophageal conditions.
• Elevated intragastric pH from PPIs may impact gut physiology.
• Tight junction (TJ) barrier dysfunction is implicated in inflammatory bowel disease (IBD), with PPIs potentially exacerbating flares.

Purpose of the Study:

• To investigate the impact of PPIs on intestinal TJ barrier function and permeability.

Main Methods:

• Utilized human intestinal cell and organoid models.
• Employed mouse models of IBD, including dextran sodium sulfate (DSS) colitis and IL-10 knockout enterocolitis.
• Assessed TJ permeability, myosin light chain kinase (MLCK) activity and expression, and p38 MAPK signaling.

Main Results:

• PPIs elevated TJ barrier permeability by increasing MLCK activity and expression in a p38 MAPK-dependent manner.
• Long-term PPI administration worsened intestinal permeability and colitis severity in mouse models.
• Mice lacking MLCK were protected from PPI-induced TJ barrier disruption.
• Human data indicated increased hospitalizations with PPI use in IBD patients.

Conclusions:

• Long-term PPI use increases intestinal TJ permeability and exacerbates experimental colitis.
• This effect is mediated by increased MLCK expression and activity.
• PPIs may pose a risk for IBD patients due to compromised intestinal barrier function.