The Glucagon‐like peptide‐1 receptor agonist, exendin‐4, ameliorated gastrointestinal dysfunction in the Wistar Kyoto rat model of Irritable Bowel Syndrome

Abstract Background Glucagon‐like peptide‐1 (GLP‐1) is beneficial in relieving pain‐related symptoms of Irritable bowel syndrome (IBS), a prevalent, multi‐factorial functional bowel disorder characterized by diarrhea and/or constipation, abdominal bloating, and pain. Activation of myenteric neurons has been implicated in the inhibitory effects of GLP‐1 on gastrointestinal motility; however, the mechanisms of action underlying this are not clear. Methods A rat model of IBS was used to examine physiological changes evoked by intraperitoneal administration of a GLP‐1 receptor agonist, exendin‐4. Behavioral and physiological analysis of stress‐sensitive Wister Kyoto (WKY) rats was used to determine if administration of exendin‐4, in the presence or absence of neutralizing interleukin‐6 receptor monoclonal antibodies, modified IBS‐like symptoms. Immunofluorescence, calcium imaging, and Western blotting techniques were used to investigate the potential role of enteric neural plexi and tight junction protein expression in this effect. Key Results Consistent with the expression of GLP‐1 and interleukin‐6 receptors in both submucosal and myenteric ganglia, exendin‐4 and interleukin‐6 stimulated calcium responses in these neurons. In vivo administration of exendin‐4 normalized stress‐induced defecation and visceral pain sensitivity in WKY rats. No additional changes were noted in rats co‐treated with exendin‐4 and anti‐interleukin‐6 receptor antibodies. Mucosal expression of occludin, a tight junction protein, was decreased by exendin‐4. Centrally regulated anxiety‐like behaviors were not modified. Conclusions and Inferences These data suggest that intraperitoneal injection of exendin‐4 improves bowel dysfunction in WKY rats without impacting on centrally regulated anxiety‐like behaviors. Modulation of enteric neuronal function and tight junction expression appear to underlie the functional benefits of this intervention.