GHSR‐1 agonist sensitizes rat colonic intrinsic and extrinsic neurons to exendin‐4: A role in the manifestation of postprandial gastrointestinal symptoms in irritable bowel syndrome?

Abstract

Background Patients with irritable bowel syndrome (IBS) may experience postprandial symptom exacerbation. Nutrients stimulate intestinal release of glucagon‐like peptide 1 (GLP‐1), an incretin hormone with known gastrointestinal effects. However, prior to the postprandial rise in GLP‐1, levels of the hunger hormone, ghrelin, peak. The aims of this study were to determine if ghrelin sensitizes colonic intrinsic and extrinsic neurons to the stimulatory actions of a GLP‐1 receptor agonist, and if this differs in a rat model of IBS. Methods Calcium imaging of enteric neurons was compared between Sprague Dawley and Wistar Kyoto rats. Colonic contractile activity and vagal nerve recordings were also compared between strains. Key Results Circulating GLP‐1 concentrations differ between IBS subtypes. Mechanistically, we have provided evidence that calcium responses evoked by exendin‐4, a GLP‐1 receptor agonist, are potentiated by a ghrelin receptor (GHSR‐1) agonist, in both submucosal and myenteric neurons. Although basal patterns of colonic contractility varied between Sprague Dawley and Wister Kyoto rats, the capacity of exendin‐4 to alter smooth muscle function was modified by a GHSR‐1 agonist in both strains. Gut‐brain signaling via GLP‐1–mediated activation of vagal afferents was also potentiated by the GHSR‐1 agonist. Conclusions & Inferences These findings support a temporal interaction between ghrelin and GLP‐1, where the preprandial peak in ghrelin may temporarily sensitize colonic intrinsic and extrinsic neurons to the neurostimulatory actions of GLP‐1. While the sensitizing effects of the GHSR‐1 agonist were identified in both rat strains, in the rat model of IBS, underlying contractile activity was aberrant.

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

“…The peak of circulating GLP-1 levels coincides with postprandial symptom manifestation in patients with IBS 12 and in addition to its role as an incretin hormone, GLP-1 also modifies GI function, 13 both in healthy controls 46 and in patients with IBS. [14][15][16] Given our previous work, 10 where we determined that fasting GLP-1 levels are decreased in diarrhea-predominant…”

“…Factors such as food, bile acids, antibiotics and infections, gender, and adverse psychosocial events, particularly in early childhood, are all implicated in alterations in the gut epithelial barrier. 10 Glucagon-like peptide-1 (GLP-1), which is released from intestinal L cells in response to the arrival of nutrients in the intestinal lumen, 11 is a circulating satiety hormone with a peak concentration that coincides with IBS postprandial symptom manifestation. Combined with microbial changes these results in abnormal gut secretory and sensorimotor function.…”

“…[4][5][6] Postprandial exacerbation of symptoms is problematic in many patients with IBS, 7-9 thus satiety-related hormones may have a role in IBS pathophysiology. 10 Glucagon-like peptide-1 (GLP-1), which is released from intestinal L cells in response to the arrival of nutrients in the intestinal lumen, 11 is a circulating satiety hormone with a peak concentration that coincides with IBS postprandial symptom manifestation. 12 In addition to being an incretin hormone, GLP-1 also modifies gut function, inhibiting small intestinal secretion, 13 gastrointestinal (GI) motility, gastric emptying, and the migrating motor complex in both healthy controls and in patients with IBS.…”

Divergent effects of exendin‐4 and interleukin‐6 on rat colonic secretory and contractile activity are associated with changes in regional vagal afferent signaling

“…13 Furthermore, in vivo investigations in Wistar-Kyoto rats found that Ex-4 alone normalized stress-induced defecation rates, but there were no additional effects of IL-6. 9 The current study has examined potential cross-communicationbetweenagonistsfortheIL-6andGLP-1receptors, both of which are expressed on intrinsic 12,26 and extrinsic 34 gut neurons. We also assessed how such interactions could modify colonic secretory and contractile function and we investigated if regional afferent signaling from the colon reflected the evoked changes in colonic function.…”

“…18 In contrast to the inhibitory effects in the proximal intestine,GLP-1hasbeenfoundtoenhancecolonictransitviaavagally mediated signaling mechanism. 19 Given the acute exacerbation of IBS symptoms in the post-prandial period, [20][21][22] and GLP-1-evoked changes in motility observed in patients with IBS as well as healthy individuals, [23][24][25] this gut hormone may be important in mechanisms underlyingboweldysfunction.Indeed,furtherevidencetosupport this supposition includes suppressed circulating levels of GLP-1 in diarrhea-predominant IBS patients 26 and the improvement in vis-ceralpainandgutspasmsinIBSpatientstreatedwithaGLP-1mimetic. 27,28 We have reproduced the positive effects of GLP-1 on gutfunctionintheWistar-KyotoratmodelofIBS 9 and used healthy Sprague-Dawley rats colons to further explore the mechanisms of action underlying these beneficial effects.…”