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. K E Y W O R D S colorectal distension, exendin-4, glucagon-like peptide-1, interleukin-6, open field, stress, Wister Kyoto

Probiotics Alleviate the Progressive Deterioration of Motor Functions in a Mouse Model of Parkinson’s Disease

“…It has been hypothesized that GI dysfunctions could reflect the disruptions of the microbiome-gut-brain axis, leading to serious GI inflammatory diseases (e.g., acute pancreatitis or inflammatory bowel disease), endothelial dysfunction, altered immune functioning and regulation of appetite control, neural inflammation, subsequent neurodegeneration, cognitive or psychoneurological disorders (e.g., depression, anxiety, autism, dementia), and disease progression of PD [8][9][10][11][12][13][14][15][16][17][18][19]. In addition to the use of peptides for the improvement of gastrointestinal or digestive dysfunctions [13,[20][21][22], and in order to improve GI function and the balance of microbiota, probiotics could be one of the powerful tools to be used for altering the PD-associated microbiota composition and mitigating the related inflammatory process [12,23]. It could, therefore, inhibit the harmful gut bacteria and decrease the bacterial translocation, gut leakiness, and the associated neural inflammation in the enteric nervous system (ENS) [24][25][26][27].…”

Insights into a possible role of glucagon-like peptide-1 receptor agonists in the treatment of depression

“…Similar results were found in a clinical study in patients with T2DM, where administration of liraglutide, but not metformin, increased the relative abundance of Akkermansia , which is often associated with the improvement of gastric mucosa and also becomes severely depleted in diabetic patients [ 115 ]. Administration of exendin-4 ameliorated stress-induced defecation, decreased visceral pain sensitivity and increased the serum level of anti-inflammatory cytokine: interleukin-13 in the Wistar–Kyoto rat strain, which was considered a model for irritable bowel syndrome [ 116 ]. However, this particular rat strain is also widely regarded as a valid model of endogenous depression [ 117 ].…”

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

“…Circulating levels of pro-inflammatory cytokinessuchasinterleukin(IL)-1β,IL-6,IL-8,andTNFα 3,5,6 are altered. We have elucidated the neuromodulatory actions of IL-6 in entericneurons, [7][8][9] which underpins changes in intestinal secretion and smooth muscle contractile activity. [8][9][10][11][12][13] However,changesinhormonal secretion also contribute to the etiology of IBS.…”

“…We have elucidated the neuromodulatory actions of IL-6 in entericneurons, [7][8][9] which underpins changes in intestinal secretion and smooth muscle contractile activity. [8][9][10][11][12][13] However,changesinhormonal secretion also contribute to the etiology of IBS. 1,14,15 Indeed, inthecontextofelevatedcirculatinglevelsofpro-inflammatorycytokines,wehaveobservedadditiveeffectsofthestresshormone, corticotrophin-releasingfactoroncolonicfunction.…”

“…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. We found that exendin 4 (Ex-4), a longer-lasting GLP-1 receptor agonist, 29 decreased the amplitude of circular smooth muscle contractions, increased theamplitudeofcolonicsecretorycurrents,anddecreasedbarrier permeability.…”