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01-09-2020 | Original Article

GLP-2 Acutely Prevents Endotoxin-Related Increased Intestinal Paracellular Permeability in Rats

Authors: Koji Maruta, Takeshi Takajo, Yasutada Akiba, Hyder Said, Emi Irie, Ikuo Kato, Atsukazu Kuwahara, Jonathan D. Kaunitz

Published in: Digestive Diseases and Sciences | Issue 9/2020

Abstract

Background

Circulating endotoxin (lipopolysaccharide, LPS) increases the gut paracellular permeability. We hypothesized that glucagon-like peptide-2 (GLP-2) acutely reduces LPS-related increased intestinal paracellular permeability by a mechanism unrelated to its intestinotrophic effect.

Methods

We assessed small intestinal paracellular permeability in vivo by measuring the appearance of intraduodenally perfused FITC-dextran 4000 (FD4) into the portal vein (PV) in rats 1–24 h after LPS treatment (5 mg/kg, ip). We also examined the effect of a stable GLP-2 analog teduglutide (TDG) on FD4 permeability.

Results

FD4 movement into the PV was increased 6 h, but not 1 or 3 h after LPS treatment, with increased PV GLP-2 levels and increased mRNA expressions of proinflammatory cytokines and proglucagon in the ileal mucosa. Co-treatment with a GLP-2 receptor antagonist enhanced PV FD4 concentrations. PV FD4 concentrations 24 h after LPS were higher than FD4 concentrations 6 h after LPS, reduced by exogenous GLP-2 treatment given 6 or 12 h after LPS treatment. FD4 uptake measured 6 h after LPS was reduced by TDG 3 or 6 h after LPS treatment. TDG-associated reduced FD4 uptake was reversed by the VPAC1 antagonist PG97-269 or L-NAME, not by EGF or IGF1 receptor inhibitors.

Conclusions

Systemic LPS releases endogenous GLP-2, reducing LPS-related increased permeability. The therapeutic window of exogenous GLP-2 administration is at minimum within 6–12 h after LPS treatment. Exogenous GLP-2 treatment is of value in the prevention of increased paracellular permeability associated with endotoxemia.

Ammori BJ, Leeder PC, King RF, et al. Early increase in intestinal permeability in patients with severe acute pancreatitis: correlation with endotoxemia, organ failure, and mortality. J Gastrointest Surg. 1999;3:252–262.PubMed

Gäbele E, Dostert K, Hofmann C, et al. DSS induced colitis increases portal LPS levels and enhances hepatic inflammation and fibrogenesis in experimental NASH. J Hepatol. 2011;55:1391–1399.PubMed

Sorkine P, Szold O, Halpern P, et al. Gut decontamination reduces bowel ischemia-induced lung injury in rats. Chest. 1997;112:491–495.PubMed

Cohen J, Vincent JL, Adhikari NK, et al. Sepsis: a roadmap for future research. Lancet Infect Dis. 2015;15:581–614.PubMed

Drucker DJ, Erlich P, Asa SL, Brubaker PL. Induction of intestinal epithelial proliferation by glucagon-like peptide 2. Proc Natl Acad Sci U S A. 1996;93:7911–7916.PubMedPubMedCentral

Cani PD, Possemiers S, Van de WT, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut. 2009;58:1091–1103.PubMed

Rowland KJ, Trivedi S, Lee D, et al. Loss of glucagon-like peptide-2-induced proliferation following intestinal epithelial insulin-like growth factor-1-receptor deletion. Gastroenterology. 2011;141:2166–2175.PubMed

Bahrami J, Yusta B, Drucker DJ. ErbB activity links the glucagon-like peptide-2 receptor to refeeding-induced adaptation in the murine small bowel. Gastroenterology. 2010;138:2447–2456.PubMed

Orskov C, Hartmann B, Poulsen SS, Thulesen J, Hare KJ, Holst JJ. GLP-2 stimulates colonic growth via KGF, released by subepithelial myofibroblasts with GLP-2 receptors. Regul Pept. 2005;124:105–112.PubMed

10.

Kaunitz JD, Akiba Y. Control of intestinal epithelial proliferation and differentiation: the microbiome, enteroendocrine L cells, telocytes, enteric nerves, and GLP, too. Dig Dis Sci. 2019;64:2709–2716. https://doi.org/10.1007/s10620-019-05778-1.CrossRefPubMedPubMedCentral

11.

Guan X, Karpen HE, Stephens J, et al. GLP-2 receptor localizes to enteric neurons and endocrine cells expressing vasoactive peptides and mediates increased blood flow. Gastroenterology. 2006;130:150–164.PubMed

12.

Sugamoto S, Kawauch S, Furukawa O, Mimaki TH, Takeuchi K. Role of endogenous nitric oxide and prostaglandin in duodenal bicarbonate response induced by mucosal acidification in rats. Dig Dis Sci. 2001;46:1208–1216. https://doi.org/10.1023/A:1010603026913.CrossRefPubMed

13.

Eklund S, Jodal M, Lundgren O, Sjoqvist A. Effects of vasoactive intestinal polypeptide on blood flow, motility and fluid transport in the gastrointestinal tract of the cat. Acta Physiol Scand. 1979;105:461–468.PubMed

14.

Yao B, Hogan DL, Bukhave K, Koss MA, Isenberg JI. Bicarbonate transport by rabbit duodenum in vitro: effect of vasoactive intestinal peptide, prostaglandin E₂, and cyclic adenosine monophosphate. Gastroenterology. 1993;104:732–740.PubMed

15.

Nylander O, Hällgren A, Holm L. Duodenal mucosal alkaline secretion, permeability, and blood flow. Am J Physiol. 1993;265:G1029–G1038.PubMed

16.

Neunlist M, Toumi F, Oreschkova T, et al. Human ENS regulates the intestinal epithelial barrier permeability and a tight junction-associated protein ZO-1 via VIPergic pathways. Am J Physiol Gastrointest Liver Physiol. 2003;285:G1028–G1036.PubMed

17.

Takeuchi K, Kagawa S, Mimaki H, Aoi M, Kawauchi S. COX and NOS isoforms involved in acid-induced duodenal bicarbonate secretion in rats. Dig Dis Sci. 2002;47:2116–2124. https://doi.org/10.1023/A:1019601702559.CrossRefPubMed

18.

Kahles F, Meyer C, Mollmann J, et al. GLP-1 secretion is increased by inflammatory stimuli in an IL-6-dependent manner, leading to hyperinsulinemia and blood glucose lowering. Diabetes. 2014;63:3221–3229.PubMed

19.

Nguyen AT, Mandard S, Dray C, et al. Lipopolysaccharides-mediated increase in glucose-stimulated insulin secretion: involvement of the GLP-1 pathway. Diabetes. 2014;63:471–482.PubMed

20.

Lebrun LJ, Lenaerts K, Kiers D, et al. Enteroendocrine L cells sense LPS after gut barrier injury to enhance GLP-1 secretion. Cell Rep. 2017;21:1160–1168.PubMed

21.

Wang JH, Inoue T, Higashiyama M, et al. Umami receptor activation increases duodenal bicarbonate secretion via glucagon-like peptide-2 release in rats. J Pharmacol Exp Ther. 2011;339:464–473.PubMedPubMedCentral

22.

Williams JM, Duckworth CA, Watson AJ, et al. A mouse model of pathological small intestinal epithelial cell apoptosis and shedding induced by systemic administration of lipopolysaccharide. Dis Model Mech. 2013;6:1388–1399.PubMedPubMedCentral

23.

Yue C, Wang W, Tian WL, et al. Lipopolysaccharide-induced failure of the gut barrier is site-specific and inhibitable by growth hormone. Inflamm Res. 2013;62:407–415.PubMed

24.

Volynets V, Reichold A, Bardos G, Rings A, Bleich A, Bischoff SC. Assessment of the intestinal barrier with five different permeability tests in healthy C57BL/6J and BALB/cJ mice. Dig Dis Sci. 2016;61:737–746. https://doi.org/10.1007/s10620-015-3935-y.CrossRefPubMed

25.

Gourlet P, Vandermeers A, Vertongen P, et al. Development of high affinity selective VIP1 receptor agonists. Peptides. 1997;18:1539–1545.PubMed

26.

Mizumori M, Meyerowitz J, Takeuchi T, et al. Epithelial carbonic anhydrases facilitate PCO₂ and pH regulation in rat duodenal mucosa. J Physiol. 2006;573:827–842.PubMedPubMedCentral

27.

Akiba Y, Inoue T, Kaji I, et al. Short-chain fatty acid sensing in rat duodenum. J Physiol. 2015;593:585–599.PubMedPubMedCentral

28.

Thulesen J, Knudsen LB, Hartmann B, et al. The truncated metabolite GLP-2 (3-33) interacts with the GLP-2 receptor as a partial agonist. Regul Pept. 2002;103:9–15.PubMed

29.

Drucker DJ, DeForest L, Brubaker PL. Intestinal response to growth factors administered alone or in combination with human [Gly2]glucagon-like peptide 2. Am J Physiol. 1997;273:G1252–G1262.PubMed

30.

García-Echeverría C, Pearson MA, Marti A, et al. In vivo antitumor activity of NVP-AEW541-A novel, potent, and selective inhibitor of the IGF-IR kinase. Cancer Cell. 2004;5:231–239.PubMed

31.

Bos M, Mendelsohn J, Kim YM, Albanell J, Fry DW, Baselga J. PD153035, a tyrosine kinase inhibitor, prevents epidermal growth factor receptor activation and inhibits growth of cancer cells in a receptor number-dependent manner. Clin Cancer Res. 1997;3:2099–2106.PubMed

32.

Unno N, Wang H, Menconi MJ, et al. Inhibition of inducible nitric oxide synthase ameliorates endotoxin-induced gut mucosal barrier dysfunction in rats. Gastroenterology. 1997;113:1246–1257.PubMed

33.

Han X, Fink MP, Yang R, Delude RL. Increased iNOS activity is essential for intestinal epithelial tight junction dysfunction in endotoxemic mice. Shock. 2004;21:261–270.PubMed

34.

Buchholz BM, Chanthaphavong RS, Bauer AJ. Nonhemopoietic cell TLR4 signaling is critical in causing early lipopolysaccharide-induced ileus. J Immunol. 2009;183:6744–6753.PubMed

35.

Amato A, Baldassano S, Serio R, Mule F. Glucagon-like peptide-2 relaxes mouse stomach through vasoactive intestinal peptide release. Am J Physiol Gastrointest Liver Physiol. 2009;296:G678–G684.PubMed

36.

Wøjdemann M, Wettergren A, Hartmann B, Holst JJ. Glucagon-like peptide-2 inhibits centrally induced antral motility in pigs. Scand J Gastroenterol. 1998;33:828–832.PubMed

37.

Nagell CF, Wettergren A, Pedersen JF, Mortensen D, Holst JJ. Glucagon-like peptide-2 inhibits antral emptying in man, but is not as potent as glucagon-like peptide-1. Scand J Gastroenterol. 2004;39:353–358.PubMed

38.

Berg JK, Kim EH, Li B, Joelsson B, Youssef NN. A randomized, double-blind, placebo-controlled, multiple-dose, parallel-group clinical trial to assess the effects of teduglutide on gastric emptying of liquids in healthy subjects. BMC Gastroenterol. 2014;14:25.PubMedPubMedCentral

39.

Riegler M, Sedivy R, Sogukoglu T, et al. Epidermal growth factor promotes rapid response to epithelial injury in rabbit duodenum in vitro. Gastroenterology. 1996;111:28–36.PubMed

40.

Van Landeghem L, Santoro MA, Mah AT, et al. IGF1 stimulates crypt expansion via differential activation of 2 intestinal stem cell populations. FASEB J. 2015;29:2828–2842.PubMedPubMedCentral

41.

Conlin VS, Wu X, Nguyen C, et al. Vasoactive intestinal peptide ameliorates intestinal barrier disruption associated with Citrobacter rodentium-induced colitis. Am J Physiol Gastrointest Liver Physiol. 2009;297:G735–750.PubMed

42.

Clayburgh DR, Barrett TA, Tang Y, et al. Epithelial myosin light chain kinase-dependent barrier dysfunction mediates T cell activation-induced diarrhea in vivo. J Clin Invest. 2005;115:2702–2715.PubMedPubMedCentral

43.

Delgado M, Pozo D, Martinez C, et al. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit endotoxin-induced TNF-alpha production by macrophages: in vitro and in vivo studies. J Immunol. 1999;162:2358–2367.PubMed

44.

Marier JF, Mouksassi MS, Gosselin NH, Beliveau M, Cyran J, Wallens J. Population pharmacokinetics of teduglutide following repeated subcutaneous administrations in healthy participants and in patients with short bowel syndrome and Crohn’s disease. J Clin Pharmacol. 2010;50:36–49.PubMed

45.

Hansen L, Hare KJ, Hartmann B, et al. Metabolism of glucagon-like peptide-2 in pigs: role of dipeptidyl peptidase IV. Regul Pept. 2007;138:126–132.PubMed

46.

Hollander D, Kaunitz JD. The “Leaky Gut”: tight junctions but loose associations? Dig Dis Sci. 2019. https://doi.org/10.1007/s10620-019-05777-2. (in press).CrossRef

Title: GLP-2 Acutely Prevents Endotoxin-Related Increased Intestinal Paracellular Permeability in Rats
Authors: Koji Maruta
Takeshi Takajo
Yasutada Akiba
Hyder Said
Emi Irie
Ikuo Kato
Atsukazu Kuwahara
Jonathan D. Kaunitz
Publication date: 01-09-2020
Publisher: Springer US
Published in: Digestive Diseases and Sciences / Issue 9/2020
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI: https://doi.org/10.1007/s10620-020-06097-6

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Abstract

Background

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