Decreased glucagon-like peptide-1 correlates with abdominal pain in patients with constipation-predominant irritable bowel syndrome

O’Brien

Neurogastroenterology Motil

et al. 2019

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.

Section: Discussioncontrasting

confidence: 99%

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?

O’Brien

Neurogastroenterology Motil

et al. 2019

“…Administration of a GLP‐1 mimetic to female patients with IBS showed efficacy in reducing spasmodic and visceral pain symptoms . Moreover, in constipation‐predominant IBS (IBS‐C) patients, decreased circulating GLP‐1 and decreased mucosal expression of GLP‐1Rs was correlated with the severity of abdominal pain . Animal models of IBS suggest differential receptor expression levels in colons from animals with diarrhea or constipation …”

Section: Introductionmentioning

confidence: 99%

“…Mechanistically, the modulatory effects of GLP‐1 on GI function may be centrally orchestrated, with high levels of expression of GLP‐1 receptors (GLP‐1Rs) in the nucleus tractus solitarius, the ventrolateral medulla, the area postrema and the hypothalamus . Central administration of GLP‐1 increased colonic transit, also through vagal signaling, whereas peripherally applied GLP‐1 has a mollifying effect on GI motility, which is likely to be mediated through local release of nitric oxide, regulated by myenteric neurons …”

Section: Introductionmentioning

confidence: 99%

“…Indeed, specific commensal bacteria increase intestinal and circulating GLP‐1 . In the context of IBS pathophysiology, altered microbial profiles have been reported, which could result in modified circulating GLP‐1 . However, few studies have been carried out on the cellular mechanisms underlying the inhibitory effects of GLP‐1 in the colon and how this may be impacted by other hormones in the context of bowel dysfunction.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

PI 3‐kinase‐ and ERK‐MAPK‐dependent mechanisms underlie Glucagon‐Like Peptide‐1‐mediated activation of Sprague Dawley colonic myenteric neurons

O’Brien

Neurogastroenterology Motil

Kelliher

et al. 2019

Background Glucagon‐like peptide (GLP‐1) can modify colonic function, with beneficial effects reported in the functional bowel disorder, irritable bowel syndrome (IBS). IBS pathophysiology is characterized by hyper‐activation of the hypothalamic‐pituitary‐adrenal stress axis and altered microbial profiles. This study aims to characterize the neuronal and functional effects of GLP‐1 in healthy rat colons to aid understanding of its beneficial effects in moderating bowel dysfunction. Methods Immunofluorescent and calcium imaging of myenteric neurons prepared from Sprague Dawley rat colons was carried out to elucidate the neuromodulatory actions of the GLP‐1 receptor agonist, exendin‐4 (Ex‐4). Colonic contractile activity was assessed using organ bath physiological recordings. Key results Ex‐4 induced an elevation of intracellular calcium arising from store release and influx via voltage‐gated calcium channels. Ex‐4 activated both ERK‐MAPK and PI 3‐kinase signaling cascades. Neuronal activation was found to underlie suppression of contractile activity in colonic circular muscle. Although the stress hormone, corticotropin‐releasing factor (CRF) potentiated the neuronal response to Ex‐4, and the functional effects of Ex‐4 on colonic circular muscle activity were not altered. Conclusions and inferences Ex‐4 evoked neurally regulated suppression of rat colonic circular muscle activity. In myenteric neurons, the neurostimulatory effects of Ex‐4 were dependent upon activation of PI 3‐kinase and ERK‐MAPK signaling cascades. No further change in circular muscle function was noted in the presence of CRF suggesting that stress does not impact on colonic function in health. Further studies in a model of IBS are needed to determine whether mechanisms are modified in the context of bowel dysfunction.

Experimental Physiology

“…Moreover, this was correlated with the severity of abdominal pain (Li et al., ). The authors suggested that lower GLP‐1 led to loss of the pro‐kinetic effects of GLP‐1 in the colon (Camilleri et al., ), resulting in constipation and abdominal pain (Li et al., ). Consistent with the supposition that decreased GLP‐1 contributes to pain‐related symptoms, circulating levels of bioactive GLP‐1 were also decreased in a rat model of visceral pain sensitivity (Yang et al., ).…”

Section: Glucagon‐like Peptide‐1 Modulates Gastrointestinal Functionmentioning

confidence: 99%

Endocrine regulation of gut function – a role for glucagon‐like peptide‐1 in the pathophysiology of irritable bowel syndrome

O’Malley

2018

New Findings What is the topic of this review?Pathophysiological changes linked to irritable bowel syndrome (IBS) include stress and immune activation, changes in gastrointestinal microbial and bile acid profiles and sensitization of extrinsic and intrinsic gut neurons. This review explores the potential role for L‐cells in these pathophysiological changes. What advances does it highlight?L‐cells, which secrete glucagon‐like peptide‐1 in response to nutrients, microbial factors, bile acids and short‐chain fatty acids, may sense IBS‐related changes in the luminal environment. Glucagon‐like peptide‐1 can act as a hormone, a paracrine factor or a neuromodulatory factor and, through its actions on central or peripheral neurons, may play a role in gastrointestinal dysfunction. Abstract The prevalent and debilitating functional bowel disorder, irritable bowel syndrome (IBS), is characterized by symptoms that include abdominal pain, bloating, diarrhoea and/or constipation. The heterogeneity of IBS underscores a complex multifactorial pathophysiology, which is not completely understood but involves dysfunction of the bi‐directional signalling axis between the brain and the gut. This axis incorporates efferent and afferent branches of the autonomic nervous system, circulating endocrine hormones and immune factors, local paracrine and neurocrine factors and microbial metabolites. L‐cells, which are electrically excitable biosensors embedded in the gastrointestinal epithelium, secrete glucagon‐like peptide‐1 (GLP‐1) in response to nutrients in the small intestine. However, they appear to function in a different manner more distally in the gastrointestinal tract, where they are activated by luminal factors including short‐chain fatty acids, bile acids and microbial metabolic products, all of which are altered in IBS patients. Glucagon‐like peptide‐1 can also interact with the hypothalamic–pituitary–adrenal stress axis and the immune system, both of which are activated in IBS. Given that a GLP‐1 mimetic has been found to alleviate acute pain symptoms in IBS patients, GLP‐1 might be important in the manifestation of IBS symptoms. This review assesses the current knowledge about the role of GLP‐1 in IBS pathophysiology and its potential role as a signal transducer in the microbiome–gut–brain signalling axis.