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Distribution and co-expression patterns of specific cell markers of enteroendocrine cells in pig gastric epithelium

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Abstract

Although the pig is an accepted model species for human digestive physiology, no previous study of the pig gastric mucosa and gastric enteroendocrine cells has investigated the parallels between pig and human. In this study, we have investigated markers for each of the classes of gastric endocrine cells, gastrin, ghrelin, somatostatin, 5-hydroxytryptamine, histidine decarboxylase, and PYY cells in pig stomach. The lining of the proximal stomach consisted of a collar of stratified squamous epithelium surrounded by gastric cardiac glands in the fundus. This differs considerably from human that has only a narrow band of cardiac glands at its entrance, surrounded by a fundic mucosa consisting of oxyntic glands. However, the linings of the corpus and antrum are similar in pig and human. Likewise, the endocrine cell types are similar and similarly distributed in the two species. As in human, gastrin cells were almost exclusively in the antrum, ghrelin cells were most abundant in the oxyntic mucosa and PYY cells were rare. In the pig, 70% of enterochromaffin-like (ECL) cells in the antrum and 95% in the fundus contained 5-hydroxytryptamine (5-HT), higher proportions than in human. Unlike the enteroendocrine of the small intestine, most gastric enteroendocrine cells (EEC) did not contain colocalised hormones. This is similar to human and other species. We conclude that the pig stomach has substantial similarity to human, except that the pig has a protective lining at its entrance that may reflect the difference between a pig diet with hard abrasive components and the soft foods consumed by humans.

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References

  • Avau B, Carbone F, Tack J, Depoortere I (2013) Ghrelin signaling in the gut, its physiological properties, and therapeutic potential. Neurogastroenterol Motil 25:720–732

    CAS  PubMed  Google Scholar 

  • Balasuriya GK, Hill-Yardin EL, Gershon MD, Bornstein JC (2016) A sexually dimorphic effect of cholera toxin: rapid changes in colonic motility mediated via a 5-HT3 receptor-dependent pathway in female C57Bl/6 mice. J Physiol Lond 594:4325–4338

    CAS  PubMed  PubMed Central  Google Scholar 

  • Buchan AMJ, Sikora LKJ, Levy JG, McIntosh CHS, Dyck I, Brown JC (1985) An immunocytochemical investigation with monoclonal antibodies to somatostatin. Histochemistry 83:175–180

    CAS  PubMed  Google Scholar 

  • Canfield SP, Spencer JE (1983) The inhibitory effects of 5-hydroxytryptamine on gastric acid secretion by the rat isolated stomach. Br J Pharmacol 78:123–129

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chandrasoma PT (2013) Histologic definition of gastro-esophageal reflux disease. Curr Opin Gastroenterol 29:460–467

    Google Scholar 

  • Cho H-J, Kosari S, Hunne B, Callaghan B, Rivera LR, Bravo DM, Furness JB (2015) Differences in hormone localisation patterns of K and L type enteroendocrine cells in the mouse and pig small intestine and colon. Cell Tissue Res 359:693–698

    CAS  PubMed  Google Scholar 

  • Choi E, Roland JT, Barlow BJ, O’Neal R, Rich AE, Nam KT, Shi C, Goldenring JR (2014) Cell lineage distribution atlas of the human stomach reveals heterogeneous gland populations in the gastric antrum. Gut 63:1711–1720

    PubMed  PubMed Central  Google Scholar 

  • Chuang C-N, Tanner M, Lloyd KCK, Wong H, Soll AH (1993) Endogenous somatostatin inhibits histamine release from canine gastric mucosal cells in primary culture. Am J Physiol Gastrointest Liver Physiol 28:G521–G525

    Google Scholar 

  • Date Y, Kojima M, Hosoda H, Sawaguchi A, Mondal MS, Suganuma T, Matsukura S, Kangawa K, Nakazato M (2000) Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology 141:4255–4261

    CAS  PubMed  Google Scholar 

  • Diwakarla S, Fothergill LJ, Fakhry J, Callaghan B, Furness JB (2017) Heterogeneity of enterochromaffin cells within the gastrointestinal tract. Neurogastroenterol Motil 29:e13101

    Google Scholar 

  • Dornonville De La Cour C, Björkqvist M, Sandvik AK, Bakke I, Zhao C-M, Chen D, Håkanson R (2001) A-like cells in the rat stomach contain ghrelin and do not operate under gastrin control. Regul Pept 99:141–150

    CAS  PubMed  Google Scholar 

  • Egerod KL, Engelstoft MS, Grunddal KV et al (2012) A major lineage of enteroendocrine cells coexpress CCK, secretin, GIP, GLP-1, PYY, and neurotensin but not somatostatin. Endocrinology 153:5782–5795

    CAS  PubMed  Google Scholar 

  • Eysselein VE, Maxwell V, Reedy T, Wünsch E, Walsh JH (1984) Similar acid stimulatory potencies of synthetic human big and little gastrins in man. J Clin Invest 73:1284–1290

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fakhry J, Stebbing MJ, Hunne B, Bayguinov Y, Ward SM, Sasse KC, Callaghan B, McQuade RM, Furness JB (2019) Relationships of endocrine cells to each other and to other cell types in the human gastric fundus and corpus. Cell Tissue Res 376:37–49

    CAS  PubMed  Google Scholar 

  • Feldman M, Walsh JH, Wong HC (1978) Role of gastrin heptadecapeptide in the acid secretory response to amino acids in man. J Clin Invest 61:308–313

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fothergill LJ, Furness JB (2018) Diversity of enteroendocrine cells investigated at cellular and subcellular levels: the need for a new classification scheme. Histochem Cell Biol 150:693–702

    CAS  PubMed  Google Scholar 

  • Fothergill LJ, Callaghan B, Hunne B, Bravo DM, Furness JB (2017) Costorage of enteroendocrine hormones evaluated at the cell and subcellular levels in male mice. Endocrinology 158:2113–2123

    PubMed  Google Scholar 

  • Friis-Hansen L (2002) Gastric functions in gastrin gene knock-out mice. Pharmacol Toxicol 91:363–367

    CAS  PubMed  Google Scholar 

  • Friis-Hansen L, Sundler F, Li Y, Gillespie PJ, Saunders TL, Greenson JK, Owyang C, Rehfeld JF, Samuelson LC (1998) Impaired gastric acid secretion in gastrin-deficient mice. Am J Physiol Gastrointest Liver Physiol 274:G561–G568

    CAS  Google Scholar 

  • Furness JB, Cottrell JJ, Bravo DM (2015) Comparative physiology of digestion. J Anim Sci 93:485–491

    CAS  PubMed  Google Scholar 

  • Gonzalez LM, Moeser AJ, Blikslager AT (2015) Porcine models of digestive disease: the future of large animal translational research. Transl Res 166:12–27

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gribble FM, Reimann F, Roberts GP (2018) Gastrointestinal hormones. In: Said HM (ed) Physiology of the gastrointestinal tract, 6th edn. Academic Press, pp 31–70

  • Habib AM, Richards P, Cairns LS, Rogers GJ, Bannon CAM, Parker HE, Morley TCE, Yeo GSH, Reimann F, Gribble FM (2012) Overlap of endocrine hormone expression in the mouse intestine revealed by transcriptional profiling and flow cytometry. Endocrinology 153:3054–3065

    CAS  PubMed  PubMed Central  Google Scholar 

  • Håkanson R, Böttcher G, Ekblad T, Panula P, Simonsson M, Dohlsten M, Hallberg T, Sundler F (1986) Histamine in endocrine cells in the stomach. Histochemistry 86:5–17

    PubMed  Google Scholar 

  • Holst JJ, Jørgensen PN, Rasmussen TN, Schmidt P (1992) Somatostatin restraint of gastrin secretion in pigs revealed by monoclonal antibody immunoneutralization. Am J Physiol Gastrointest Liver Physiol 263:G908–G912

    CAS  Google Scholar 

  • Hunne B, Stebbing MJ, McQuade RM, Furness JB (2019) Distributions and relationships of chemically defined enteroendocrine cells in the rat gastric mucosa. Cell Tissue Res (in press)

  • Ito H, Yokozaki H, Tokumo K, Nakajo S, Tahara E (1986) Serotonin-containing EC cells in normal human gastric mucosa and in gastritis. Virchows Archiv A 409:313–323

    CAS  Google Scholar 

  • Kasacka I, Łebkowski W, Janiuk I, Łapińska J, Lewandowska A (2012) Immunohistochemical identification and localisation of gastrin and somatostatin in endocrine cells of human pyloric gastric mucosa. Folia Morphol (Warsz) 71:39–44

    CAS  Google Scholar 

  • Kim A, Park W-Y, Shin N, Lee HJ, Kim YK, Lee SJ, Hwang C-S, Park DY, Kim GH, Lee BE, Jo H-J (2015) Cardiac mucosa at the gastroesophageal junction: an Eastern perspective. World J Gastroenterol 21:9126–9133

    PubMed  PubMed Central  Google Scholar 

  • Kojima M, Kangawa K (2010) Ghrelin: more than endogenous growth hormone secretagogue. Ann N Y Acad Sci 1200:140–148

    CAS  PubMed  Google Scholar 

  • Kovacs TO, Lloyd KC, Lawson DC (1997) Inhibition of sham feeding-stimulated acid secretion in dogs by immunoneutralization of gastrin. Am J Physiol Gastrointest Liver Physiol 273:G399–G403

    CAS  Google Scholar 

  • Larsson LI, Goltermann N, De Magistris L, Rehfeld JF, Schwarz TW (1979) Somatostatin cell processes as pathways for paracrine secretion. Science 205:1393–1395

    CAS  PubMed  Google Scholar 

  • Lenglinger J, See SF, Beller L, Cosentini E, Asari R, Wrba F, Riegler M, Schoppmann SF (2012) The cardia: esophageal or gastric? Critical reviewing the anatomy and histopathology of the esophagogastric junction. Acta Chir Iugosl 59:15–26

    PubMed  Google Scholar 

  • Lents CA, Brown-Brandl TM, Rohrer GA, Oliver WT, Freking BA (2016) Plasma concentrations of acyl-ghrelin are associated with average daily gain and feeding behavior in grow-finish pigs. Domest Anim Endocrinol 55:107–113

    CAS  PubMed  Google Scholar 

  • LePard KJ, Chi J, Mohammed JR, Gidener S, Stephens RL Jr (1996) Gastric antisecretory effect of serotonin: quantitation of release and site of action. Am J Physiol Endocrinol Metab 271:E669–E677

    CAS  Google Scholar 

  • Levin F, Edholm T, Schmidt PT, Grybäck P, Jacobsson H, Degerblad M, Höybye C, Holst JJ, Rehfeld JF, Hellström PM, Näslund E (2006) Ghrelin stimulates gastric emptying and hunger in normal-weight humans. J Clin Endocrinol Metab 91:3296–3302

    CAS  PubMed  Google Scholar 

  • Li Y-Y (2003) Mechanisms for regulation of gastrin and somatostatin release from isolated rat stomach during gastric distention. World J Gastroenterol 9:129–133

    CAS  PubMed  PubMed Central  Google Scholar 

  • Martin AM, Young RL, Leong L, Rogers GB, Spencer NJ, Jessup CF, Keating DJ (2017) The diverse metabolic roles of peripheral serotonin. Endocrinology 158:1049–1063

    CAS  PubMed  Google Scholar 

  • Mawe GM, Hoffman JM (2013) Serotonin signalling in the gut—functions, dysfunctions and therapeutic targets. Nat Rev Gastroenterol Hepatol 10:473–486

    CAS  PubMed  PubMed Central  Google Scholar 

  • Meulengracht E (1935) The glands of the stomach in relation to pernicious anaemia; with special reference to the glands in the pyloric region. Proc R Soc Med 28:841–870

    PubMed  PubMed Central  Google Scholar 

  • Mizutani M, Atsuchi K, Asakawa A, Matsuda N, Fujimura M, Inui A, Kato I, Fujimiya M (2009) Localization of acyl ghrelin- and des-acyl ghrelin-immunoreactive cells in the rat stomach and their responses to intragastric pH. Am J Physiol Gastrointest Liver Physiol 297:G974–G980

    CAS  PubMed  Google Scholar 

  • Payne SC, Furness JB, Stebbing MJ (2018) Bioelectric neuromodulation for gastrointestinal disorders: effectiveness and mechanisms. Nat Rev Gastroenterol Hepatol 16:89–105

    Google Scholar 

  • Rehfeld JF, Friis-Hansen L, Goetze JP, Hansen TVO (2007) The biology of cholecystokinin and gastrin peptides. Curr Top Med Chem 7:1154–1165

    CAS  PubMed  Google Scholar 

  • Reynaud Y, Fakhry J, Fothergill L, Callaghan B, Ringuet MT, Hunne B, Bravo DM, Furness JB (2016) The chemical coding of 5-hydroxytryptamine containing enteroendocrine cells in the mouse gastrointestinal tract. Cell Tissue Res 364:489–497

    CAS  PubMed  Google Scholar 

  • Rindi G, Necchi V, Savio A, Torsello A, Zoli M, Locatelli V, Raimondo F, Cocchi D, Solcia E (2002) Characterisation of gastric ghrelin cells in man and other mammals: studies in adult and fetal tissues. Histochem Cell Biol 117:511–519

    CAS  PubMed  Google Scholar 

  • Roura E, Koopmans S-J, Lallès J-P, Le Huerou-Luron I, de Jager N, Schuurman T, Val-Laillet D (2016) Critical review evaluating the pig as a model for human nutritional physiology. Nutr Res Rev 29:60–90

    CAS  PubMed  Google Scholar 

  • Salfen BE, Carroll JA, Keisler DH, Strauch TA (2004) Effects of exogenous ghrelin on feed intake, weight gain, behavior, and endocrine responses in weanling pigs. J Anim Sci 82:1957–1966

    CAS  PubMed  Google Scholar 

  • Sandvik AK, Dimaline R, Mårvik R, Brenna E, Waldum HL (1994) Gastrin regulates histidine decarboxylase activity and mRNA abundance in rat oxyntic mucosa. Am J Physiol Gastrointest Liver Physiol 267:G254–G258

    CAS  Google Scholar 

  • Schubert ML, Peura DA (2008) Control of gastric acid secretion in health and disease. Gastroenterology 134:1842–1860

    CAS  PubMed  Google Scholar 

  • Schubert ML, Edwards NF, Makhlouf GM (1988) Regulation of gastric somatostatin secretion in the mouse by luminal acidity: a local feedback mechanism. Gastroenterology 94:317–322

    CAS  PubMed  Google Scholar 

  • Smolka AJ, Larsen KA, Hammond CE (2000) Location of a cytoplasmic epitope for monoclonal antibody HK 12.18 on H,K-ATPase α subunit. Biochem Biophys Res Commun 273:942–947

    CAS  PubMed  Google Scholar 

  • Soll AH, Walsh JH (1979) Regulation of gastric acid secretion. Annu Rev Physiol 41:35–53

    CAS  PubMed  Google Scholar 

  • Sykaras AG, Demenis C, Cheng L, Pisitkun T, Mclaughlin JT, Fenton RA, Smith CP (2014) Duodenal CCK cells from male mice express multiple hormones including ghrelin. Endocrinology 155:3339–3351

    PubMed  Google Scholar 

  • Szelenyi I, Herold H, Göthert M (1994) Emesis induced in domestic pigs: a new experimental tool for detection of antiemetic drugs and for evaluation of emetogenic potential of new anticancer agents. J Pharmacol Toxicol Methods 32:109–116

    CAS  PubMed  Google Scholar 

  • Vitari F, Di Giancamillo A, Deponti D, Carollo V, Domeneghini C (2012) Distribution of ghrelin-producing cells in the gastrointestinal tract of pigs at different ages. Vet Res Commun 36:71–80

    PubMed  Google Scholar 

  • Vuyyuru L, Schubert ML, Harrington L, Arimura A, Makhlouf GM (1995) Dual inhibitory pathways link antral somatostatin and histamine secretion in human, dog, and rat stomach. Gastroenterology 109:1566–1574

    CAS  PubMed  Google Scholar 

  • Vuyyuru L, Harrington L, Arimura A, Schubert ML (1997) Reciprocal inhibitory paracrine pathways link histamine and somatostatin secretion in the fundus of the stomach. Am J Physiol Gastrointest Liver Physiol 273:G106–G111

    CAS  Google Scholar 

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Acknowledgements

We thank Maree Cox and Jeremy Cottrell for assistance in tissue harvesting and Melinda Goga and Iain Burchill for assistance with preparation for histology. Confocal imaging was performed at the Biological Optical Microscopy Platform, University of Melbourne.

Funding

This work was financially supported by NIH (SPARC) grant ID # OT2OD023847 (PI Terry Powley) to JBF.

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Correspondence to John B. Furness.

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Procedures were approved by the University of Melbourne Animal Ethics Committee (ethics approval number 1714291). All applicable National and Institutional guidelines for the care and use of animals were followed.

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Fothergill, L.J., Galiazzo, G., Hunne, B. et al. Distribution and co-expression patterns of specific cell markers of enteroendocrine cells in pig gastric epithelium. Cell Tissue Res 378, 457–469 (2019). https://doi.org/10.1007/s00441-019-03065-z

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