A GLP‐1 Mimetic Alleviates Irritable Bowel Syndrome‐like Symptoms in the Wistar Kyoto Rat
Authors: O'Brien Rebecca , Buckley Maria M , O'Halloran Ken D , O'Malley Dervla 
Published: November 2023

BackgroundIrritable Bowel Syndrome (IBS), a common functional bowel disorder affecting approximately 10–20% of the population, is characterised by abdominal pain, altered bowel habit and bloating. No mortality is associated with IBS, however there is a heavy economic burden with an estimated annual cost of $20 billion. Although a full understanding of IBS pathophysiology remains elusive, research to date has implicated immune activation, dysfunctional endocrine signalling and altered brain‐gut communication. Glucagon‐like peptide −1 (GLP‐1) is an incretin hormone secreted, from enteroendocrine cells in the gastrointestinal tract, in response to food. GLP‐1 is currently used to enhance insulin secretion in diabetes patients who cannot achieve complete glycaemic control with Metformin (a glucophage used to lower blood glucose concentration) treatment alone. However, research using a rat model with IBS‐like symptoms such as altered bowel habit and visceral hypersensitivity, has shown that GLP‐1, GLP‐1R and GLP‐1R mRNA expression is altered and GLP‐1 has pain‐relieving effects in IBS patients, leading to our study aims.Aim of StudyInvestigate the role of GLP‐1 in IBS‐like pathophysiology and the potential use of a GLP‐1 mimetic as a suitable treatment option.MethodsWistar Kyoto (WKY) rats exhibit IBS‐like symptoms such as visceral hypersensitivity and stress‐induced faecal output. Male WKY rats (n=12 per treatment group) received an intraperitoneal (IP) injection of the GLP‐1 mimetic, exendin‐4 only (1.0mg/kg, 1 hour prior to behavioural assessment), or exendin‐4 with anti‐ IL‐6 receptor monoclonal antibodies (initial dose of 1.0mg/kg and subsequently 0.5mg/kg, twice weekly IP injections) over three weeks and were compared with saline‐treated controls. Stress‐induced defecation was assessed using an anxiogenic open field arena and visceral pain sensitivity was assessed by monitoring pain responses to colorectal distension (CRD; 0mmHg‐80mmHg over 8 minutes). Faecal pellets collected from the open field study were analysed for faecal water content (%) among treatment groups and controls. The animals’ weight gain was monitored throughout the study.ResultsCombined exendin‐4 & xIL‐6R treatment reduced faecal water content (p<0.05), compared with exendin‐4 and saline treated WKY. Combined exendin‐4 & xIL‐6R treatment and exendin‐4 alone had no effect on colon length, weight gain and pain threshold to CRD. Exendin‐4 treatment significantly reduced stress‐induced defecation (p<0.001) and the number of pain responses (p<0.05) compared with saline‐treated WKY rats.DiscussionPeripheral administration of a GLP‐1 mimetic has beneficial effects on bowel symptoms in the WKY rat model of IBS. The number of pain responses and the threshold at which the first pain response was noted were improved. Stress‐induced defecation in this anxious rat strain was also normalised. The faecal water content, which is increased compared with control Sprague Dawley rats, was normalised following combined Exendin‐4 and anti‐IL‐6R treatment. The findings support a potential therapeutic role for GLP‐1 in the treatment of visceral pain and altered bowel habit in IBS.Support or Funding InformationDepartment of Physiology, University College of Cork.