Role of CB 1 receptors in the acute regulation of small intestinal permeability: Effects of high-fat diet

The endocannabinoid system of the gastrointestinal tract is involved in the control of intestinal barrier function. Whether the cannabinoid 1 (CB₁) receptor is expressed on the intestinal epithelium and acutely regulates barrier function has not been determined. Here we tested the hypothesis that ligands of the CB₁ receptor acutely modulate small intestinal permeability and that this is associated with altered distribution of tight junction proteins. We examined the acute effects of CB₁ receptor ligands on small intestinal permeability both in chow fed and 2-week high-fat diet (HFD) fed mice using Ussing chambers. We assessed the distribution of CB₁ receptor and tight junction proteins using immunofluorescence and the expression of CB₁ receptor using PCR. A low level of CB₁ expression was found on the intestinal epithelium. CB₁ receptor was highly expressed on enteric nerves in the lamina propria. Neither the CB₁/CB₂ agonist CP55,940 nor the CB₁ neutral antagonist AM6545 altered the flux of 4Kda FITC dextran (FD4) across the jejunum or ileum of chow-fed mice. Remarkably, both CP55,940 and AM6545 reduced FD4 flux across the jejunum and ileum in HFD-fed mice that have elevated baseline intestinal permeability. These effects were absent in CB₁ knockout mice. CP55,940 reduced the expression of claudin-2, while AM6545 had little effect on claudin-2 expression. Neither ligand altered the expression of ZO-1. Our data suggest that CB₁ receptor on the intestinal epithelium regulates tight junction protein expression and restores barrier function when it is increased following exposure to a HFD for 2 weeks.