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

Abstract

Proton pump inhibitors [PPIs] are widely used to treat a number of gastro-oesophageal disorders. PPI-induced elevation in intragastric pH may alter gastrointestinal physiology. The tight junctions [TJs] residing at the apical intercellular contacts act as a paracellular barrier. TJ barrier dysfunction is an important pathogenic factor in inflammatory bowel disease [IBD]. Recent studies suggest that PPIs may promote disease flares in IBD patients. The role of PPIs in intestinal permeability is not clear. The aim of the present study was to study the effect of PPIs on the intestinal TJ barrier function. Human intestinal epithelial cell culture and organoid models and mouse IBD models of dextran sodium sulphate [DSS] and spontaneous enterocolitis in IL-10-/- mice were used to study the role of PPIs in intestinal permeability. PPIs increased TJ barrier permeability via an increase in a principal TJ regulator, myosin light chain kinase [MLCK] activity and expression, in a p38 MAPK-dependent manner. The PPI-induced increase in extracellular pH caused MLCK activation via p38 MAPK. Long-term PPI administration in mice exaggerated the increase in intestinal TJ permeability and disease severity in two independent models of DSS colitis and IL-10-/- enterocolitis. The TJ barrier disruption by PPIs was prevented in MLCK-/- mice. Human database studies revealed increased hospitalizations associated with PPI use in IBD patients. Our results suggest that long-term use of PPIs increases intestinal TJ permeability and exaggerates experimental colitis via an increase in MLCK expression and activity.