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Physiology of gastric acid secretion

Section Editor
Mark Feldman, MD, MACP, AGAF, FACG
Deputy Editor
Shilpa Grover, MD, MPH, AGAF


The regulation of acid and pepsin secretion reflects an intricate balance of chemotransmitters delivered to the gastric mucosa by several pathways that mediate both stimulatory and inhibitory mechanisms [1]. Similarly, several mechanisms contribute to the remarkable ability of normal gastroduodenal mucosa to defend itself against injury from the acid/peptic activity in gastric juice and to rapidly repair injury when it does occur. Secretory, defense, and healing mechanisms are regulated by the same type of overlapping neural, endocrine, paracrine, and autocrine control pathways.

Gastric acid facilitates the digestion of protein and the absorption of iron, calcium, vitamin B12, and is necessary for the absorption of some drugs such as ketoconazole, itraconazole, and thyroid hormone [2]. Gastric acid, by lowering pH, kills ingested microorganisms and limits bacterial growth in the stomach and prevents intestinal infections such as Clostridium difficile. In addition, gastric acid may have a role in preventing spontaneous bacterial peritonitis [3-5].


The stomach consists of three anatomical (fundus, corpus, and antrum) and two functional areas (oxyntic and pyloric glands). The oxyntic area comprises approximately 80 percent of the stomach and contains parietal cells that produce gastric acid. Also present in the oxyntic glands are neuroendocrine cells producing paracrine and hormonal agents that modify parietal cell activity. The antrum of the stomach contains pyloric glands and their main feature is the presence of gastrin secreting G cells. Somatostatin secreting D cells are present in the pyloric and oxyntic glands and modulate gastrin release [1].


The physiologic stimulation of acid secretion has classically been divided into three interrelated phases: cephalic, gastric, and intestinal [6].

The cephalic phase is activated by the thought, taste, smell, and sight of food, and swallowing. It is mediated mostly by cholinergic/vagal mechanisms.

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Literature review current through: Nov 2017. | This topic last updated: Sep 06, 2016.
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  1. Schubert ML, Peura DA. Control of gastric acid secretion in health and disease. Gastroenterology 2008; 134:1842.
  2. Irving SA, Vadiveloo T, Leese GP. Drugs that interact with levothyroxine: an observational study from the Thyroid Epidemiology, Audit and Research Study (TEARS). Clin Endocrinol (Oxf) 2015; 82:136.
  3. Kwon JH, Koh SJ, Kim W, et al. Mortality associated with proton pump inhibitors in cirrhotic patients with spontaneous bacterial peritonitis. J Gastroenterol Hepatol 2014; 29:775.
  4. Hegarty JP, Sangster W, Harris LR 3rd, Stewart DB. Proton pump inhibitors induce changes in colonocyte gene expression that may affect Clostridium difficile infection. Surgery 2014; 156:972.
  5. Buendgens L, Bruensing J, Matthes M, et al. Administration of proton pump inhibitors in critically ill medical patients is associated with increased risk of developing Clostridium difficile-associated diarrhea. J Crit Care 2014; 29:696.e11.
  6. Lloyd KCK, Debas HT. Peripheral regulation of gastric acid secretion. In: Physiology of the Gastrointestinal Tract, Johnson LR, Christensen J, Jackson MJ, et al (Eds), Raven Press, New York 1994.
  7. Soll AH, Berglindh T. Receptors regulating acid secretory function. In: Physiology of the Gastrointestinal Tract, 3rd ed, Johnson LR, Alpers DH, Christensen J, et al (Eds), Raven Press, New York 1994. p.1139.
  8. Feldman M. Gastrin secretion: Normal and abnormal. In: Gastrointestinal Disease, Feldman M, Scharschmidt BF, Sleisenger MH (Eds), WB Saunders, 1997. p.587.
  9. Yao X, Forte JG. Cell biology of acid secretion by the parietal cell. Annu Rev Physiol 2003; 65:103.
  10. Hersey SJ, Sachs G. Gastric acid secretion. Physiol Rev 1995; 75:155.
  11. Roepke TK, Anantharam A, Kirchhoff P, et al. The KCNE2 potassium channel ancillary subunit is essential for gastric acid secretion. J Biol Chem 2006; 281:23740.
  12. Geibel JP. Role of potassium in acid secretion. World J Gastroenterol 2005; 11:5259.
  13. Heitzmann D, Warth R. No potassium, no acid: K+ channels and gastric acid secretion. Physiology (Bethesda) 2007; 22:335.
  14. Courtois-Coutry N, Roush D, Rajendran V, et al. A tyrosine-based signal targets H/K-ATPase to a regulated compartment and is required for the cessation of gastric acid secretion. Cell 1997; 90:501.
  15. Sandvik AK, Waldum HL. Aspects of the regulation of gastric histamine release. Scand J Gastroenterol Suppl 1991; 180:108.
  16. Kidd M, Modlin IM, Tang LH. Gastrin and the enterochromaffin-like cell: an acid update. Dig Surg 1998; 15:209.
  17. Chen D, Monstein HJ, Nylander AG, et al. Acute responses of rat stomach enterochromaffinlike cells to gastrin: secretory activation and adaptation. Gastroenterology 1994; 107:18.
  18. Waldum HL, Hauso Ø, Fossmark R. The regulation of gastric acid secretion - clinical perspectives. Acta Physiol (Oxf) 2014; 210:239.
  19. Soll AH, Amirian DA, Thomas LP, et al. Gastrin receptors on isolated canine parietal cells. J Clin Invest 1984; 73:1434.
  20. Bitziou E, Patel BA. Simultaneous detection of gastric acid and histamine release to unravel the regulation of acid secretion from the guinea pig stomach. Am J Physiol Gastrointest Liver Physiol 2012; 303:G396.
  21. Kopin AS, Lee YM, McBride EW, et al. Expression cloning and characterization of the canine parietal cell gastrin receptor. Proc Natl Acad Sci U S A 1992; 89:3605.
  22. Langhans N, Rindi G, Chiu M, et al. Abnormal gastric histology and decreased acid production in cholecystokinin-B/gastrin receptor-deficient mice. Gastroenterology 1997; 112:280.
  23. Samuelson LC, Hinkle KL. Insights into the regulation of gastric acid secretion through analysis of genetically engineered mice. Annu Rev Physiol 2003; 65:383.
  24. Lindström E, Chen D, Norlén P, et al. Control of gastric acid secretion:the gastrin-ECL cell-parietal cell axis. Comp Biochem Physiol A Mol Integr Physiol 2001; 128:505.
  25. Koh TJ, Goldenring JR, Ito S, et al. Gastrin deficiency results in altered gastric differentiation and decreased colonic proliferation in mice. Gastroenterology 1997; 113:1015.
  26. Soll AH, Amirian DA, Park J, et al. Cholecystokinin potently releases somatostatin from canine fundic mucosal cells in short-term culture. Am J Physiol 1985; 248:G569.
  27. Schmidt WE, Schmitz F. Cellular localization of cholecystokinin receptors as the molecular basis of the periperal regulation of acid secretion. Pharmacol Toxicol 2002; 91:351.
  28. Chen D, Friis-Hansen L, Håkanson R, Zhao CM. Genetic dissection of the signaling pathways that control gastric acid secretion. Inflammopharmacology 2005; 13:201.
  29. Schubert ML, Makhlouf GM. Gastrin secretion induced by distention is mediated by gastric cholinergic and vasoactive intestinal peptide neurons in rats. Gastroenterology 1993; 104:834.
  30. Schubert ML, Makhlouf GM. Neural, hormonal, and paracrine regulation of gastrin and acid secretion. Yale J Biol Med 1992; 65:553.
  31. Sugano K, Park J, Soll AH, Yamada T. Stimulation of gastrin release by bombesin and canine gastrin-releasing peptides. Studies with isolated canine G cells in primary culture. J Clin Invest 1987; 79:935.
  32. Campos RV, Buchan AM, Meloche RM, et al. Gastrin secretion from human antral G cells in culture. Gastroenterology 1990; 99:36.
  33. Seensalu R, Avedian D, Barbuti R, et al. Bombesin-induced gastrin release from canine G cells is stimulated by Ca2+ but not by protein kinase C, and is enhanced by disruption of rho/cytoskeletal pathways. J Clin Invest 1997; 100:1037.
  34. Lindström E, Björkqvist M, Boketoft A, et al. Neurohormonal regulation of histamine and pancreastatin secretion from isolated rat stomach ECL cells. Regul Pept 1997; 71:73.
  35. Zeng N, Athmann C, Kang T, et al. PACAP type I receptor activation regulates ECL cells and gastric acid secretion. J Clin Invest 1999; 104:1383.
  36. Kinoshita Y, Nakata H, Kishi K, et al. Comparison of the signal transduction pathways activated by gastrin in enterochromaffin-like and parietal cells. Gastroenterology 1998; 115:93.
  37. Soll AH, Toomey M, Culp D, et al. Modulation of histamine release from canine fundic mucosal mast cells. Am J Physiol 1988; 254:G40.
  38. Chuang CN, Tanner M, Chen MC, et al. Gastrin induction of histamine release from primary cultures of canine oxyntic mucosal cells. Am J Physiol 1992; 263:G460.
  39. Black JW, Duncan WA, Durant CJ, et al. Definition and antagonism of histamine H 2 -receptors. Nature 1972; 236:385.
  40. Vuyyuru L, Schubert ML. Histamine, acting via H3 receptors, inhibits somatostatin and stimulates acid secretion in isolated mouse stomach. Gastroenterology 1997; 113:1545.
  41. Yakabi K, Kawashima J, Kato S. Ghrelin and gastric acid secretion. World J Gastroenterol 2008; 14:6334.
  42. Saffouri B, DuVal JW, Arimura A, Makhlouf GM. Effects of vasoactive intestinal peptide and secretin on gastrin and somatostatin secretion in the perfused rat stomach. Gastroenterology 1984; 86:839.
  43. Shulkes A, Read M. Regulation of somatostatin secretion by gastrin- and acid-dependent mechanisms. Endocrinology 1991; 129:2329.
  44. Martinez V, Curi AP, Torkian B, et al. High basal gastric acid secretion in somatostatin receptor subtype 2 knockout mice. Gastroenterology 1998; 114:1125.
  45. Yamaji N, Yokoo Y, Iwashita T, et al. Structural determination of two active compounds that bind to the muscarinic M3 receptor in beer. Alcohol Clin Exp Res 2007; 31:S9.
  46. Schubert ML. The effect of vasoactive intestinal polypeptide on gastric acid secretion is predominantly mediated by somatostatin. Gastroenterology 1991; 100:1195.
  47. Schubert ML. Gastric secretion. Curr Opin Gastroenterol 2005; 21:636.
  48. Choquet A, Magous R, Bali JP. Gastric mucosal endogenous prostanoids are involved in the cellular regulation of acid secretion from isolated parietal cells. J Pharmacol Exp Ther 1993; 266:1306.
  49. Lindström E, Håkanson R. Prostaglandins inhibit secretion of histamine and pancreastatin from isolated rat stomach ECL cells. Br J Pharmacol 1998; 124:1307.
  50. Schepp W, Chan CB, Giraud AS, et al. Effects of prostaglandins on gastrin release from canine antral mucosal cells in primary culture. Am J Physiol 1994; 266:G194.
  51. Chen MC, Sanders MJ, Amirian DA, et al. Prostaglandin E2 production by dispersed canine fundic mucosal cells. Contribution of macrophages and endothelial cells as major sources. J Clin Invest 1989; 84:1536.
  52. Guglietta A, Lesch CA, Romano M, et al. Effect of transforming growth factor-alpha on gastric acid secretion in rats and monkeys. Dig Dis Sci 1994; 39:177.
  53. Goldenring JR, Tsunoda Y, Stoch SA, et al. Transforming growth factor-alpha (TGF alpha) inhibition of parietal cell secretion: structural requirements for activity. Regul Pept 1993; 43:37.
  54. Yang H. Central and peripheral regulation of gastric acid secretion by peptide YY. Peptides 2002; 23:349.
  55. Samloff IM. Peptic ulcer: the many proteinases of aggression. Gastroenterology 1989; 96:586.
  56. Allen A, Pearson JP, Blackburn A, et al. Pepsins and the mucus barrier in peptic ulcer disease. Scand J Gastroenterol Suppl 1988; 146:50.
  57. Samloff IM. Pepsins, peptic activity, and peptic inhibitors. J Clin Gastroenterol 1981; 3:91.
  58. Hersey SJ. Pepsin secretion. In: Physiology of the Gastrointestinal Tract, Johnson LR, Christensen J, Jackson MJ, et al (Eds), Raven Press, 1994. p.1227.
  59. Sandvik AK, Brenna E, Waldum HL. Review article: the pharmacological inhibition of gastric acid secretion--tolerance and rebound. Aliment Pharmacol Ther 1997; 11:1013.
  60. Wilder-Smith CH, Ernst T, Gennoni M, et al. Tolerance to oral H2-receptor antagonists. Dig Dis Sci 1990; 35:976.
  61. Prichard PJ, Jones DB, Yeomans ND, et al. The effectiveness of ranitidine in reducing gastric acid-secretion decreases with continued therapy. Br J Clin Pharmacol 1986; 22:663.
  62. Fullarton GM, McLauchlan G, Macdonald A, et al. Rebound nocturnal hypersecretion after four weeks treatment with an H2 receptor antagonist. Gut 1989; 30:449.
  63. Prewett EJ, Hudson M, Nwokolo CU, et al. Nocturnal intragastric acidity during and after a period of dosing with either ranitidine or omeprazole. Gastroenterology 1991; 100:873.
  64. el-Omar E, Banerjee S, Wirz A, et al. Marked rebound acid hypersecretion after treatment with ranitidine. Am J Gastroenterol 1996; 91:355.
  65. Gillen D, Wirz AA, Ardill JE, McColl KE. Rebound hypersecretion after omeprazole and its relation to on-treatment acid suppression and Helicobacter pylori status. Gastroenterology 1999; 116:239.
  66. Waldum HL, Arnestad JS, Brenna E, et al. Marked increase in gastric acid secretory capacity after omeprazole treatment. Gut 1996; 39:649.
  67. Reimer C, Søndergaard B, Hilsted L, Bytzer P. Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy. Gastroenterology 2009; 137:80.
  68. Lødrup AB, Reimer C, Bytzer P. Systematic review: symptoms of rebound acid hypersecretion following proton pump inhibitor treatment. Scand J Gastroenterol 2013; 48:515.
  69. Kohn A, Annibale B, Prantera C, et al. Reversible sustained increase of gastrin and gastric acid secretion in a subgroup of duodenal ulcer patients on long-term treatment with H2 antagonists. J Clin Gastroenterol 1991; 13:284.
  70. Gledhill T, Buck M, Hunt RH. Effect of no treatment, cimetidine 1 g/day, cimetidine 2 g/day and cimetidine combined with atropine on nocturnal gastric secretion in cimetidine non-responders. Gut 1984; 25:1211.
  71. El-Omar EM, Oien K, El-Nujumi A, et al. Helicobacter pylori infection and chronic gastric acid hyposecretion. Gastroenterology 1997; 113:15.
  72. Feldman M, Cryer B, Lee E. Effects of Helicobacter pylori gastritis on gastric secretion in healthy human beings. Am J Physiol 1998; 274:G1011.