Glucagon-Like Peptide-2 and Common Therapeutics in a Murine Model of Ulcerative Colitis

L’Heureux, Marie-Claude; Brubaker, Patricia L.

doi:10.1124/jpet.103.051771

Cited by 75 publications

(54 citation statements)

References 42 publications

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“…GLP-2 has been shown to improve mucosal healing accompanied by an increased crypt cell proliferation rate. 28,29) We did not find any obvious difference in the amounts of mucus demonstrated by PAS staining (data not shown). The BrdU incorporation commonly observed in the colonic epithelial cells of DPPIVdeficient rats on day 4 of DSS exposure might indicate the increased crypt cell proliferation.…”

Section: Discussionmentioning

confidence: 70%

Contribution of Dipeptidyl Peptidase IV to the Severity of Dextran Sulfate Sodium-Induced Colitis in the Early Phase

Iwaya

Fujii

Hagio

et al. 2013

Bioscience, Biotechnology, and Biochemistry

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Section: Discussionmentioning

confidence: 70%

Contribution of Dipeptidyl Peptidase IV to the Severity of Dextran Sulfate Sodium-Induced Colitis in the Early Phase

Iwaya

Fujii

Hagio

et al. 2013

Bioscience, Biotechnology, and Biochemistry

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“…Recently, the important role of Glucagon-like-peptide-2 (GLP-2), which is secreted from local neuroendocrine epithelial cells and promotes epithelial cell proliferation via stimulation of enteric neurons [54] , has received more attention. GLP-2 demonstrating ability to ameliorate murine short bowel syndrome and experimental colitis [55,56] has consequently lead to clinical studies, evaluating the effect of GLP-2 in patients with short bowel syndrome.…”

Section: The Role Of Regulatory Peptides For Intestinal Epithelial Womentioning

confidence: 99%

Epithelial restitution and wound healing in inflammatory bowel disease

Sturm¹,

Dignaß²

2008

WJG

292

260

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disorders including inflammatory bowel diseases and require constant repair of the epithelium. Enhancement of intestinal repair mechanisms by regulatory peptides or other modulatory factors may provide future approaches for the treatment of diseases that are characterized by injuries of the epithelial surface. THE MUCOSAL DEFENSE SYSTEMThe surface of the digestive tract is covered by epithelial cells that constitute an efficient physical barrier between the dietary and enteric flora pathogens found in the intestinal lumen and the individuum, but also allows an exchange between nutrients and the systemic circulation [1] . The epithelial defense mechanism can be categorized into three key components: pre-epithelial, epithelial and post-epithelial, the latter is represented by the lamina propria [2] . The pre-epithelial mucus barrier is composed of mucin associated with other proteins and lipids and forms a continuous gel into which a bicarbonate-rich fluid is secreted, maintaining a neutralizing pH at the epithelial surface. Phosphatidylcholine is the predominant surface bioactive phospholipid found within the gastrointestinal tract [3] . Intestinal epithelial cells secrete mucins and glycocalyx, which contain membrane-anchored negatively charged mucin-like glycoproteins and hydrophobic phospholipids [4] . The tight adherence of mucin to the apical surfaces of epithelia is owed to the existence of the specific complex between mucin oligosaccharides and the mucin binding protein of the apical mucosal membrane [5] . AbstractInflammatory bowel disease is characterized by a chronic inflammation of the intestinal mucosa. The mucosal epithelium of the alimentary tract constitutes a key element of the mucosal barrier to a broad spectrum of deleterious substances present within the intestinal lumen including bacterial microorganisms, various dietary factors, gastrointestinal secretory products and drugs. In addition, this mucosal barrier can be disturbed in the course of various intestinal disorders including inflammatory bowel diseases. Fortunately, the integrity of the gastrointestinal surface epithelium is rapidly reestablished even after extensive destruction. Rapid resealing of the epithelial barrier following injuries is accomplished by a process termed epithelial restitution, followed by more delayed mechanisms of epithelial wound healing including increased epithelial cell proliferation and epithelial cell differentiation. Restitution of the intestinal surface epithelium is modulated by a range of highly divergent factors among them a broad spectrum of structurally distinct regulatory peptides, variously described as growth factors or cytokines. S e ve ra l re g u l a t or y pe pt ide fac t or s ac t from t he basolateral site of the epithelial surface and enhance epithelial cell restitution through TGF-β-dependent pathways. In contrast, members of the trefoil factor family (TFF peptides) appear to stimulate epithelial restitution in conjunction with mucin glycoproteins through a TGF-β-independent mechanism from...

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“…Because germline loss of the Glp2r was not associated with a demonstrable intestinal phenotype in nonstressed mice, we subjected Glp2r ϩ/ϩ , Glp2r ϩ/Ϫ , and Glp2r Ϫ/Ϫ mice to experimental dextran sulfate (DS)-induced colitis, a controlled inflammatory insult responsive to exogenous GLP-2 administration (22,30). Oral administration of 3% DS for 9 d produced comparable weight loss and similar changes in colon weight and length in Glp2r ϩ/ϩ vs.…”

mentioning

confidence: 99%

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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Glucagon-Like Peptide-2 and Common Therapeutics in a Murine Model of Ulcerative Colitis

Abstract: The intestinal hormone glucagon-like peptide-2 (GLP-2) enhances bowel growth and reduces the severity of colonic injury in dextran sulfate sodium

Cited by 75 publications

References 42 publications

Contribution of Dipeptidyl Peptidase IV to the Severity of Dextran Sulfate Sodium-Induced Colitis in the Early Phase

Contribution of Dipeptidyl Peptidase IV to the Severity of Dextran Sulfate Sodium-Induced Colitis in the Early Phase

Epithelial restitution and wound healing in inflammatory bowel disease

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

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