GLP-2 Receptor Agonism Ameliorates Inflammation and Gastrointestinal Stasis in Murine Postoperative Ileus

Moore, Beverley A.; Peffer, Nancy J.; Pirone, Allison; Bassiri, Ashlyn E.; Sague, Sarah; Palmer, Jeffrey M.; Johnson, Dana L.; Nesspor, Tom; Kliwinski, Connie; Hornby, Pamela J.

doi:10.1124/jpet.109.161497

Cited by 24 publications

(19 citation statements)

References 38 publications

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“…Exogenous GLP-2 helps heal mucosal injury in inflammatory models of chemical-induced colitis [9], NSAID-induced enteropathy [12], radiation-induced enteritis [28] and post-operative ileus [29], consistent with our results. The effects of endogenous GLP-2 on refeeding-induced intestinal adaptation model were studied using the GLP-2R antagonist GLP-2(3–33) or in GLP-2R knockout (KO) mice [30–32].…”

Section: Discussionsupporting

confidence: 89%

Dipeptidyl Peptidase IV Inhibition Prevents the Formation and Promotes the Healing of Indomethacin-Induced Intestinal Ulcers in Rats

et al. 2013

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Backgrounds & Aims We studied the intestinotrophic hormone glucagon-like peptide-2 (GLP-2) as a possible therapy for non-steroidal anti-inflammatory drug (NSAID)-induced intestinal ulcers. Luminal nutrients release endogenous GLP-2 from enteroendocrine L cells. Since GLP-2 is degraded by dipeptidyl peptidase IV (DPPIV), we hypothesized that DPPIV inhibition combined with luminal administration of nutrients potentiates the effects of endogenous GLP-2 on intestinal injury. Methods Intestinal injury was induced by indomethacin (10 mg/kg, sc) in fed rats. The long-acting DPPIV inhibitor K579 was intragastrically (ig) or intraperitoneally (ip) given before or after indomethacin treatment. L-alanine (L-Ala) and 5′-inosine monophosphate (IMP) were co-administered ig after the treatment. Results Indomethacin treatment induced intestinal ulcers which gradually healed after treatment. Pretreatment with ig or ip K579 given either at 1 mg/kg reduced total ulcer length, whereas K579 at 3 mg/kg had no effect. Exogenous GLP-2 also reduced intestinal ulcers. The preventive effect of K579 was dose-dependently inhibited by a GLP-2 receptor antagonist. Daily treatment with K579 (1 mg/kg), GLP-2, or L-Ala + IMP after indomethacin treatment reduced total ulcer length. Co-administration (ig) of K579 and L-Ala + IMP further accelerated intestinal ulcer healing. Conclusion DPPIV inhibition and exogenous GLP-2 prevented the formation and promoted the healing of indomethacin-induced intestinal ulcers, although high-dose DPPIV inhibition reversed the preventive effect. Umami receptor agonists also enhanced the healing effects of the DPPIV inhibitor. The combination of DPPIV inhibition and luminal nutrient-induced GLP-2 release may be a useful therapeutic tool for the treatment of NSAIDs-induced intestinal ulcers.

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Section: Discussionsupporting

confidence: 89%

Dipeptidyl Peptidase IV Inhibition Prevents the Formation and Promotes the Healing of Indomethacin-Induced Intestinal Ulcers in Rats

et al. 2013

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“…Similarly, GLP-2R activation suppressed intestinal leukocyte infiltration and reduced the expression of genes regulating inflammation and barrier function in a murine model of surgical ileus (46) and in mice with experimental ileitis and colitis (40). Taken together, our findings establish the importance of the intestinal Glp2r for the regulation of host bacterial interactions and reveal a new role for GLP-2 in Paneth cell-derived enteric defense, and control of gut microbial communities.…”

Section: Consistent With Findings Of Enhanced Bacterial Translocationmentioning

confidence: 55%

Disruption of the Murine Glp2r Impairs Paneth Cell Function and Increases Susceptibility to Small Bowel Enteritis

Lee

et al. 2012

Endocrinology

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Exogenous glucagon-like peptide-2 receptor (GLP-2R) activation elicits proliferative and cytoprotective responses in the gastrointestinal mucosa and ameliorates experimental small and large bowel gut injury. Nevertheless, the essential physiological role(s) of the endogenous GLP-2R remain poorly understood. We studied the importance of the GLP-2R for gut growth, epithelial cell lineage allocation, the response to mucosal injury, and host-bacterial interactions in Glp2r Ϫ/Ϫ and littermate control Glp2r ϩ/ϩ mice. Glp2r Ϫ/Ϫ mice exhibit normal somatic growth and preserved small and large bowel responses to IGF-I and keratinocyte growth factor. However, Glp2r Ϫ/Ϫ mice failed to up-regulate intestinal epithelial c-fos expression in response to acute GLP-2 administration and do not exhibit changes in small bowel conductance or small or large bowel growth after administration of GLP-2R agonists. The crypt and villus compartment and the numbers and localization of Paneth, enteroendocrine, and goblet cells were comparable in Glp2r ϩ/ϩ vs. Glp2r Ϫ/Ϫ mice.Although the severity and extent of colonic mucosal injury in response to 3% oral dextran sulfate was similar across Glp2r genotypes, Glp2r Ϫ/Ϫ mice exhibited significantly increased morbidity and mortality and increased bacterial translocation after induction of enteritis with indomethacin and enhanced mucosal injury in response to irinotecan. Moreover, bacterial colonization of the small bowel was significantly increased, expression of Paneth cell antimicrobial gene products was reduced, and mucosal bactericidal activity was impaired in Glp2r Ϫ/Ϫ mice. Although the Glp2r is dispensable for gut development and the response to colonic injury, Glp2r Ϫ/Ϫ mice exhibit enhanced sensitivity to small bowel injury, and abnormal host-bacterial interactions in the small bowel. (Endocrinology 153: 1141-1151, 2012)

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“…The therapeutic potential of GLP-2 during intestinal inflammation has been previously examined. Several studies have shown that agonism of GLP-2R or inhibition of DPPIV (dipeptidyl peptidase-4), the proteolytic enzyme responsible for cleaving active GLP-2 into its inactive metabolite could reduce intestinal inflammation in different models of colitis and ileitis (2,10,31,40,41,49). Here, we assessed the potential efficacy of GLP-2 in reducing the severity of already established colitis.…”

Section: Discussionmentioning

confidence: 99%

Glugacon-like peptide-2: broad receptor expression, limited therapeutic effect on intestinal inflammation and novel role in liver regeneration

El-Jamal

Erdual

Neunlist

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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The glucagon-like peptide 2 (GLP-2) is an intestinotrophic hormone with growth promoting and anti-inflammatory actions. However, the full biological functions of GLP-2 and the localization of its receptor (GLP-2R) remain controversial. Among cell lines tested, the expression of GLP-2R transcript was detected in human colonic myofibroblasts (CCD-18Co) and in primary culture of rat enteric nervous system but not in intestinal epithelial cell lines, lymphocytes, monocytes, or endothelial cells. Surprisingly, GLP-2R was expressed in murine (GLUTag), but not human (NCI-H716) enteroendocrine cells. The screening of GLP-2R mRNA in mice organs revealed an increasing gradient of GLP-2R toward the distal gut. An unexpected expression was detected in the mesenteric fat, mesenteric lymph nodes, bladder, spleen, and liver, particularly in hepatocytes. In two mice models of trinitrobenzene sulfonic acid (TNBS)- and dextran sulfate sodium (DSS)-induced colitis, the colonic expression of GLP-2R mRNA was decreased by 60% compared with control mice. Also, GLP-2R mRNA was significantly downregulated in intestinal tissues of inflammatory bowel disease patients. Therapeutically, GLP-2 showed a weak restorative effect on intestinal inflammation during TNBS-induced colitis as assessed by macroscopic score and inflammatory markers. Finally, GLP-2 treatment accelerated mouse liver regeneration following partial hepatectomy as assessed by histological and molecular analyses. In conclusion, the limited therapeutic effect of GLP-2 on colonic inflammation dampens its utility in the management of severe inflammatory intestinal disorders. However, the role of GLP-2 in liver regeneration is a novelty that might introduce GLP-2 into the management of liver diseases and emphasizes on the importance of elucidating other extraintestinal functions of GLP-2.

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GLP-2 Receptor Agonism Ameliorates Inflammation and Gastrointestinal Stasis in Murine Postoperative Ileus

Cited by 24 publications

References 38 publications

Dipeptidyl Peptidase IV Inhibition Prevents the Formation and Promotes the Healing of Indomethacin-Induced Intestinal Ulcers in Rats

Dipeptidyl Peptidase IV Inhibition Prevents the Formation and Promotes the Healing of Indomethacin-Induced Intestinal Ulcers in Rats

Disruption of the Murine Glp2r Impairs Paneth Cell Function and Increases Susceptibility to Small Bowel Enteritis

Glugacon-like peptide-2: broad receptor expression, limited therapeutic effect on intestinal inflammation and novel role in liver regeneration

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