Centrally administered GLP-1 analogue improves intestinal barrier function through the brain orexin and the vagal...

Leaky gut, an altered intestinal barrier function, has been described in many diseases such as irritable bowel syndrome (IBS). We have recently demonstrated that orexin in the brain blocked leaky gut in rats, suggesting that the brain plays a role in regulation of intestinal barrier function. In the present study, we tried to clarify whether GLP-1 acts centrally in the brain to regulate intestinal barrier function and its mechanism. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Intracisternal injection of GLP-1 analogue, liraglutide dose-dependently abolished increased colonic permeability in response to lipopolysaccharide. Either atropine or surgical vagotomy blocked the central GLP-1-induced improvement of colonic hyperpermeability. Intracisternal GLP-1 receptor antagonist, exendin (9-39) prevented the central GLP-1-induced blockade of colonic hyperpermeability. In addition, intracisternal injection of orexin receptor antagonist, SB-334867 blocked the GLP-1-induced improvement of intestinal barrier function. On the other hand, subcutaneous liraglutide also improved leaky gut but larger doses of liraglutide were needed to block it. In addition, neither atropine nor vagotomy blocked subcutaneous liraglutide-induced improvement of leaky gut, suggesting that central or peripheral GLP-1 system works separately to improve leaky gut in a vagal-dependent or independent manner, respectively. These results suggest that GLP-1 acts centrally in the brain to reduce colonic hyperpermeability. Brain orexin signaling and the vagal cholinergic pathway play a vital role in the process. We would therefore suggest that activation of central GLP-1 signaling may be useful for leaky gut-related diseases such as IBS.