Cell and Tissue Research

, Volume 376, Issue 1, pp 37–49 | Cite as

Relationships of endocrine cells to each other and to other cell types in the human gastric fundus and corpus

  • Josiane Fakhry
  • Martin J. Stebbing
  • Billie Hunne
  • Yulia Bayguinov
  • Sean M. Ward
  • Kent C. Sasse
  • Brid Callaghan
  • Rachel M. McQuade
  • John B. FurnessEmail author
Regular Article


Gastric endocrine cell hormones contribute to the control of the stomach and to signalling to the brain. In other gut regions, enteroendocrine cells (EECs) exhibit extensive patterns of colocalisation of hormones. In the current study, we characterise EECs in the human gastric fundus and corpus. We utilise immunohistochemistry to investigate EECs with antibodies to ghrelin, serotonin (5-HT), somatostatin, peptide YY (PYY), glucagon-like peptide 1, calbindin, gastrin and pancreastatin, the latter as a marker of enterochromaffin-like (ECL) cells. EECs were mainly located in regions of the gastric glands populated by parietal cells. Gastrin cells were absent and PYY cells were very rare. Except for about 25% of 5-HT cells being a subpopulation of ECL cells marked by pancreastatin, colocalisation of hormones in gastric EECs was infrequent. Ghrelin cells were distributed throughout the fundus and corpus; most were basally located in the glands, often very close to parietal cells and were closed cells i.e., not in contact with the lumen. A small proportion had long processes located close to the base of the mucosal epithelium. The 5-HT cells were of at least three types: small, round, closed cells; cells with multiple, often very long, processes; and a subgroup of ECL cells. Processes were in contact with their surrounding cells, including parietal cells. Mast cells had very weak or no 5-HT immunoreactivity. Somatostatin cells were a closed type with long processes. In conclusion, four major chemically defined EEC types occurred in the human oxyntic mucosa. Within each group were cells with distinct morphologies and relationships to other mucosal cells.


Oxyntic gland Gastrointestinal hormones Ghrelin 5-Hydroxytryptamine Somatostatin Pancreastatin 


Funding information

This work was supported by NIH (SPARC) grant ID no. OT2OD023847 (PI Terry Powley) to JBF. SMW was supported by NIH DK57236.


  1. Adrian TE, Ferri G-L, Bacarese-Hamilton AJ, Fuessl HS, Polak JM, Bloom SR (1985) Human distribution and release of a putative’ new gut hormone, peptide YY. Gastroenterology 89:1070–1077CrossRefGoogle Scholar
  2. Andersson J, Mei Q, Sundler F (1998) Immunohistochemical markers for enterochromaffin-like (ECL) cells of the rat stomach. Biomed Res 19:227–236CrossRefGoogle Scholar
  3. Andrews PLR, Davis CJ, Bingham S, Davidson HI, Hawthorn J, Maskell L (1990) The abdominal visceral innervation and the emetic reflex: pathways, pharmacology, and plasticity. Can J Physiol Pharmacol 68:325–345CrossRefGoogle Scholar
  4. Andrews PLR, Naylor RJ, Joss RA (1998) Neuropharmacology of emesis and its relevance to anti-emetic therapy. Support Care Cancer 6:197–203CrossRefGoogle Scholar
  5. Bansal PP, Ardell AJ (1972) Average nearest neighbour distances between uniformly distributed finite particle. Metallography 5:97–111CrossRefGoogle Scholar
  6. Bellono NW, Bayrer JR, Leitch DB, Castro J, Zhang C, O’Donnell TA, Brierley SM, Ingraham HA, Julius D (2017) Enterochromaffin cells are gut chemosensors that couple to sensory neural pathways. Cell 170:1–14CrossRefGoogle Scholar
  7. Bordi C, D’Adda T, Azzoni C, Ferraro G (2000) Classification of gastric endocrine cells at the light and electron microscopical levels. Microsc Res Tech 48:258–271CrossRefGoogle Scholar
  8. Böttcher G, Ekblad E, Ekman R, Håkanson R, Sundler F (1993) Peptide YY: a neuropeptide in the gut. Immunocytochemical and immunochemical evidence. Neuroscience 55:281–290CrossRefGoogle Scholar
  9. Buchan AMJ, Sikora LKJ, Levy JG, McIntosh CHS, Dyck I, Brown JC (1985) An immunocytochemical investigation with monoclonal antibodies to somatostatin. Histochemistry 83:175–180CrossRefGoogle Scholar
  10. Canfield SP, Spencer JE (1983) The inhibitory effects of 5-hydroxytryptamine on gastric acid secretion by the rat isolated stomach. Brit J Pharmacol 78:123–129CrossRefGoogle Scholar
  11. Chen D, Zhao C-M, Andersson K, Meister B, Panula P, Håkanson R (1998) ECL cell morphology. Yale J Biol Med 71:217–231Google Scholar
  12. Cho H-J, Callaghan B, Bron R, Bravo DM, Furness JB (2014) Identification of enteroendocrine cells that express TRPA1 channels in the mouse intestine. Cell Tissue Res 356:77–82CrossRefGoogle Scholar
  13. 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 359:693–698CrossRefGoogle Scholar
  14. 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 63:1711–1720CrossRefGoogle Scholar
  15. Chuang C-N, Tanner M, Lloyd KC, Wong H, Soll AH (1993) Endogenous somatostatin inhibits histamine release from canine gastric mucosal cells in primary culture. Am J Physiol GI Liver 265:G521–G525CrossRefGoogle Scholar
  16. 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 141:4255–4261CrossRefGoogle Scholar
  17. Diwakarla S, Fothergill LJ, Fakhry J, Callaghan B, Furness JB (2017) Heterogeneity of enterochromaffin cells within the gastrointestinal tract. Neurogastroenterol Motil 29:e13101CrossRefGoogle Scholar
  18. 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 99:141–150CrossRefGoogle Scholar
  19. Dornonville de la Cour C, Lindström E, Norlén P, Håkanson R (2004) Ghrelin stimulates gastric emptying but is without effect on acid secretion and gastric endocrine cells. Regul Pept 120:23–32CrossRefGoogle Scholar
  20. 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 153:5782–5795CrossRefGoogle Scholar
  21. Egerod KL, Engelstoft MS, Lund ML, Grunddal KV, Zhao M, Barir-Jensen D, Nygaard EB, Petersen N, Holst JJ, Schwartz TW (2015) Transcriptional and functional characterization of the G protein-coupled receptor repertoire of gastric somatostatin cells. Endocrinology 156:3909–3923CrossRefGoogle Scholar
  22. Engelstoft MS, Park W-M, Sakata I et al (2013) Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells. Mol Metab 2:376–392CrossRefGoogle Scholar
  23. 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 (in press)Google Scholar
  24. 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 158:2113–2123CrossRefGoogle Scholar
  25. Friis-Hansen L, Wierup N, Rehfeld JF, Sundler F (2005) Reduced ghrelin, islet amyloid polypeptide, and peptide YY expression in the stomach of gastrin-cholecystokinin knockout mice. Endocrinology 146:4464–4471CrossRefGoogle Scholar
  26. Furness JB, Costa M, Gibbins IL, Llewellyn Smith IJ, Oliver JR (1985) Neurochemically similar myenteric and submucous neurons directly traced to the mucosa of the small intestine. Cell Tissue Res 241:155–163CrossRefGoogle Scholar
  27. Furness JB, Padbury RTA, Baimbridge KG, Skinner JM, Lawson DEM (1989) Calbindin immunoreactivity is a characteristic of enterochromaffin- like cells ECL cells of the human stomach. Histochemistry 92:449–451CrossRefGoogle Scholar
  28. Gong Z, Yoshimura M, Aizawa S, Kurotani R, Zigman JM, Sakai T, Sakata I (2013) G-protein coupled receptor 120 (GPR120) signaling regulates ghrelin secretion in vivo and in vitro. Am J Physiol Endocrinol MetabGoogle Scholar
  29. Grunddal KV, Ratner CF, Svendsen B et al (2015) Neurotensin is co-expressed, co-released and acts together with GLP-1 and PYY in enteroendocrine control of metabolism. Endocrinology 157:176–194CrossRefGoogle Scholar
  30. Gustafsson BI, Bakke I, Hauso O, Kidd M, Modlin IM, Fossmark R, Brenna E, Waldum HL (2011) Parietal cell activation by arborization of ECL cell cytoplasmic projections is likely the mechanism for histamine induced secretion of hydrochloric acid. Scand J Gastroenterol 46:531–537CrossRefGoogle Scholar
  31. 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 153:3054–3065CrossRefGoogle Scholar
  32. Håkanson R, Sundler F (1991) Session 4: Histamine-producing cells in the stomach and their role in the regulation of acid secretion. Scand J Gastroenterol 26:88–94CrossRefGoogle Scholar
  33. Håkanson R, Ding X-Q, Norlén P, Chen D (1995) Circulating pancreastatin is a marker for the enterochromaffin-like cells of the rat stomach. Gastroenterology 108:1445–1452CrossRefGoogle Scholar
  34. Hauso Ø, Gustafsson BI, Waldum HL (2007) Long slender cytoplasmic extensions: a common feature of neuroendocrine cells? J Neuroendocrinol 19:739–742CrossRefGoogle Scholar
  35. Helander HF, Fändriks L (2012) The enteroendocrine “letter cells”—time for a new nomenclature? Scand J Gastroenterol 47:3–12CrossRefGoogle Scholar
  36. Kojima M, Kangawa K (2005) Ghrelin: structure and function. Physiol Rev 85:495–522CrossRefGoogle Scholar
  37. Kovacs TO, Lloyd KC, Lawson DC (1997) Inhibition of sham feeding-stimulated acid secretion in dogs by immunoneutralization of gastrin. Am. J. Physiol GI Liver 273:G399–G403CrossRefGoogle Scholar
  38. Kushnir-Sukhov NM, Brown JM, Wu Y, Kirshenbaum A, Metcalfe DD (2007) Human mast cells are capable of serotonin synthesis and release. J Allergy Clin Immunol 119:498–499CrossRefGoogle Scholar
  39. Kusumoto Y, Grube D, Sato AG, Kaneda K, Nakamae E (1988) Cytology and arrangement of enterochromaffin (EC) cells in the human stomach. Arch Histol Cytol 51:271–276CrossRefGoogle Scholar
  40. Lagunoff D, Benditt EP (1959) 5-Hydroxytryptophan decarboxylase activity in rat mast cells. Am J Phys 196:993–997CrossRefGoogle Scholar
  41. Larsson LI, Goltermann N, De Magistris L, Rehfeld JF, Schwarz TW (1979) Somatostatin cell processess as pathways for paracrine secretion. Science 205:1393–1395CrossRefGoogle Scholar
  42. 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 1 Endoc Metab 271:E669–E677CrossRefGoogle Scholar
  43. Li HJ, Johnston B, Aiello D, Caffrey DR, Giel-Moloney M, Rindi G, Leiter AB (2014) Distinct cellular origins for serotonin-expressing and enterochromaffin-like cells in the gastric corpus. Gastroenterology 146:754–764CrossRefGoogle Scholar
  44. Lippl F, Kircher F, Erdmann J, Allescher H-D, Schusdziarra V (2004) Effect of GIP, GLP-1, insulin and gastrin on ghrelin release in the isolated rat stomach. Regul Pept 119:93–98CrossRefGoogle Scholar
  45. Lönroth H, Håkanson R, Lundell L, Sundler F (1990) Histamine containing endocrine cells in the human stomach. Gut 31:383–388CrossRefGoogle Scholar
  46. Martin AM, Young RL, Leong L, Rogers GB, Spencer NJ, Jessup CF, Keating DJ (2017) The diverse metabolic roles of peripheral serotonin. Endocrinology 158:1049–1063CrossRefGoogle Scholar
  47. Martins P, Fakhry J, Chaves de Oliveira E, Hunne B, Fothergill LJ, Ringuet M, d’Ávila Reis D, Rehfeld JF, Callaghan B, Furness JB (2017) Analysis of enteroendocrine cell populations in the human colon. Cell Tissue Res 367:361–368CrossRefGoogle Scholar
  48. 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 GI Liver 297:G974–G980CrossRefGoogle Scholar
  49. Norlén P, Curry WJ, Chen D, Zhao C-M, Johnston CF, Håkanson R (1997) Expression of the chromogranin A-derived peptides pancreastatin and WE14 in rat stomach ECL cells. Regul Pept 70:121–133CrossRefGoogle Scholar
  50. Norlén P, Curry WJ, Björkqvist M, Maule A, Cunningham RT, Hogg RB, Harriott P, Johnston CF, Hutton JC, Håkanson R (2001) Cell-specific processing of chromogranin A in endocrine cells of the rat stomach. J Histochem Cytochem 49:9–18CrossRefGoogle Scholar
  51. Overduin J, Frayo RS, Grill HJ, Kaplan JM, Cummings DE (2005) Role of the duodenum and macronutrient type in ghrelin regulation. Endocrinology 146:845–850CrossRefGoogle Scholar
  52. Parratt JR, West GB (1957) 5-hydroxytryptamine and tissue mast cells. J Physiol 137:169–178CrossRefGoogle Scholar
  53. Pustovit RV, Callaghan B, Ringuet MT, Kerr NF, Hunne B, Smyth IM, Pietra C, Furness JB (2017) Evidence that central pathways that mediate defecation utilize ghrelin receptors but do not require endogenous ghrelin. Physiol Rep 5:e13385CrossRefGoogle Scholar
  54. 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 364:489–497CrossRefGoogle Scholar
  55. 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 117:511–519CrossRefGoogle Scholar
  56. Schubert ML, Edwards NF, Makhlouf GM (1988) Regulation of gastric somatostatin secretion in the mouse by luminal acidity: a local feedback mechanism. Gastroenterology 94:317–322CrossRefGoogle Scholar
  57. Smolka A, Weinstein WM (1986) Immunoassay of pig and human gastric proton pump. Gastroenteroloby 90:532–539CrossRefGoogle Scholar
  58. Steensels S, Vancleef L, Depoortere I (2016) The sweetener-sensing mechanisms of the ghrelin cell. Nutrients 8:795CrossRefGoogle Scholar
  59. Stengel A, Goebel M, Wang L, Taché Y (2010) Ghrelin, des-acyl ghrelin and nesfatin-1 in gastric X/A-like cells: role as regulators of food intake and body weight. Peptides 31:357–369CrossRefGoogle Scholar
  60. Stengel A, Hofmann T, Goebel-Stengel M, Lembke V, Ahnis A, Elbelt U, Lambrecht NWG, Ordemann J, Klapp BF, Kobelt P (2013) Ghrelin and NUCB2/nesfatin-1 are expressed in the same gastric cell and differentially correlated with body mass index in obese subjects. Histochem Cell Biol 139:909–918CrossRefGoogle Scholar
  61. 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 155:3339–3351CrossRefGoogle Scholar
  62. Veedfald S, Plamboeck A, Hartmann B, Vilsbøll T, Knop FK, Deacon CF, Svendsen LB, Holst JJ (2018) Ghrelin secretion in humans—a role for the vagus nerve? Neurogastroenterol Motil 30:e13295CrossRefGoogle Scholar
  63. Vostrikov VM, Artyukhova OA, Kholmova MA, Samorodov AV, Uranova NA (2015) Spatial organization of oligodendrocytes and pyramidal neurons in the anterior limbic cortex in health and schizophrenia. Neurosci Behav Physiol 45:579–582CrossRefGoogle Scholar
  64. 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 109:1566–1574CrossRefGoogle Scholar
  65. 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 GI Liver 273:G106–G111CrossRefGoogle Scholar
  66. Williams DL, Cummings DE, Grill HJ, Kaplan JM (2003) Meal-related ghrelin suppression requires postgastric feedback. Endocrinology 144:2765–2767CrossRefGoogle Scholar
  67. Yakabi K, Ro S, Onouhi T, Tanaka T, Ohno S, Miura S, Johno Y, Takayama K (2006) Histamine mediates the stimulatory action of ghrelin on acid secretion in rat stomach. Dig Dis Sci 51:1313–1321CrossRefGoogle Scholar
  68. Yu P-L, Fujimura M, Hayashi N, Nakamura T, Fujimiya M (2001) Mechanisms in regulating the release of serotonin from the perfused rat stomach. Am J Physiol GI Liver 280:G1099–G1105CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Josiane Fakhry
    • 1
  • Martin J. Stebbing
    • 1
    • 2
  • Billie Hunne
    • 1
  • Yulia Bayguinov
    • 3
  • Sean M. Ward
    • 3
  • Kent C. Sasse
    • 4
    • 5
  • Brid Callaghan
    • 1
  • Rachel M. McQuade
    • 1
    • 2
  • John B. Furness
    • 1
    • 2
    Email author
  1. 1.Department of Anatomy and NeuroscienceUniversity of MelbourneParkvilleAustralia
  2. 2.Florey Institute of Neuroscience and Mental HealthParkvilleAustralia
  3. 3.Department of Physiology and Cell Biology, Reno School of MedicineUniversity of NevadaRenoUSA
  4. 4.School of Medicine, Universiity of NevadaRenoUSA
  5. 5.Renown Regional Medical CenterRenoUSA

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