Gastric Secretion Abstracts 1


Clinical Tests of Gastric Secretion: History, methodology and interpretation
            (Baron, 1978) Download
The plan of this book is based on my inaugural Quadrennial Review72 at the World Congress of Gastroenterology in Copenhagen in 1970 on The Clinical Use of Gastric Function Tests. The regulation of human gastric secretion is briefly discussed, after which the conduct of gastric secretion tests is described in detail, with chapters on the measurement of basal and stimulated secretion with maximal and vagal stimuli, and on gastrin, pepsin and tubeless tests. The second part of the book assesses the clinical usefulness of measurements of gastric secretion in different diseases- anaemia and gastritis, gastric ulcer and carcinoma, duodenal ulcer and its complications, and X-ray negative dyspep- sia. The final section considers the value of secretion tests in patients after the various gastrectomies and vagotomies. An appendix by Mr R. F. McCloy provides precise instructions for the basal-insulin-pentagastrin intravenous infusion test.

Complexity of gastric acid secretion revealed by targeted gene disruption in mice.
            (Chen and Zhao, 2010) Download
Physiology of gastric acid secretion is one of the earliest subjects in medical research and education. Gastric acid secretion has been sometimes inadequately expressed as pH value rather than amount of gastric H(+) secreted per unit time. Gastric acid secretion is regulated by endocrine, paracrine and neurocrine signals via at least three messenger pathways: gastrin-histamine, CCK-somatostatin, and neural network. These pathways have been largely validated and further characterized by phenotyping a series of knockout mouse models. The complexity of gastric acid secretion is illustrated by both expected and unexpected phenotypes of altered acid secretion. For examples, in comparison with wild-type mice, gastrin and CCK double knockout and SSTR(2) knockout mice displayed a shift in the regulation of ECL cells from somatostatin-SSTR(2) pathway to galanin-Gal1 receptor pathway; a shift in the regulation of parietal cells from gastrin-histamine pathway to vagal pathway; and a shift in the CCK(2) receptors on parietal cells from functional silence to activation. The biological function of glycine-extended gastrin in synergizing gastrin-17 has been revealed in gastrin knockout mice. The roles of gastric acid secretion in tumorigenesis and ulceration have not been fully understood. Transgenic hypergastrinemic INS-GAS mice developed a spontaneous gastric cancer, which was associated with an impaired acid secretion. Gastrin knockout mice were still able to produce acid in response to vagal stimulation, especially after H. pylori infection. Taken together, phenotyping of a series of genetically engineered mouse models reveals a high degree of complexity of gastric acid secretion in both physiological and pathophysiological conditions.

Gastric secretion.
            (Chu and Schubert, 2012) Download
PURPOSE OF REVIEW:  This review summarizes the past year's literature regarding the regulation of gastric exocrine and endocrine secretion, both basic science and clinical. RECENT FINDINGS:  Gastric acid secretion facilitates the digestion of protein as well as the absorption of iron, calcium, vitamin B12, and certain medications as well as prevents bacterial overgrowth, enteric infection, and possibly community-acquired pneumonia, spontaneous bacterial peritonitis, and IgE-mediated food allergy. It is regulated by neural (e.g., pituitary adenylate cyclase-activating peptide), hormonal (e.g., gastrin, ghrelin, and apelin), and paracrine (e.g., histamine) pathways as well as by chemical (e.g., amino acids) and bacterial stimuli (e.g., Helicobacter pylori). Novel peptides, which may possess physiologic function, have been identified in gastric mucosal neuroendocrine cells including parathyroid hormone-like hormone in histamine-secreting enterochromaffin-like cells and hepcidin in acid-secreting parietal cells. The secretion of hydrochloric acid by parietal cells involves translocation of the proton pump, HK-ATPase, to the apical membrane along with activation of apical chloride and potassium channels. Serum markers include chromogranin A for neuroendocrine tumors, pepsinogen I for gastric atrophy, and pepsinogen II for H. pylori infection. SUMMARY:  We continue to make progress in our understanding of the regulation of gastric acid secretion in health and disease.

Gastric acid secretion: changes during a century.
            (Di Mario and Goni, 2014) Download
The advances in knowledge of gastric physiology within the past century have been the most exciting and important in this area of interest for many decades. The aim of this presentation consists of a comprehensive review of the extensive recent literature on this topic in order to highlight milestones in the field of gastric physiology, in particular in gastric acid secretion, gastric pathophysiology, acid-related diseases and use of acid regulatory drugs. Moreover, in the 21st century there have been many epidemiologic changes as well as a decrease of Helicobacter pylori infection and gastric cancer together with an increase of gastroesophageal reflux disease and the related increase of pomp proton inhibitor wide use.


Review article: methods of measuring gastric acid secretion.
            (Ghosh et al., 2011) Download
BACKGROUND:  Gastric acid has an important pathophysiological role in human beings. Numerous methods have been evaluated over the years in an attempt to measure gastric acid and stomach acidity, to study the role of gastric acid in gastrointestinal diseases in humans and to evaluate the effects of acid suppressing drugs. AIM:  To review methods that have been used to measure gastric acid and gastric acidity. METHODS:  Searches of the electronic databases PUBMED, MEDLINE and EMBASE, were performed with articles restricted to English language and human subjects. References were also identified from the bibliographies of selected articles. RESULTS:  Methods for measuring gastric acid include both invasive and non-invasive techniques. Invasive tests include the conventional gastric acid aspiration tests, gastric pH measurement techniques and endoscopic methods. Non-invasive methods use urinary analysis, breath analysis, serum pepsinogens assay, scintigraphic techniques, impedence tomography and alkaline tide for measurement of gastric acid. CONCLUSIONS:  Several methods of measuring gastric acid exist. Invasive tube tests are uncomfortable and time consuming, whereas most of the non-invasive methods are at best semiquantitative and useful in detecting low or absent acid secretion. Further attempts to explore new methods for measuring gastric acid are therefore warranted.

Gastric acidity in older adults.
            (Hurwitz et al., 1997) Download
CONTEXT:  Early studies suggested that gastric acidity declines as people age. However, sequelae of achlorhydria are uncommon in older people, making this conventional wisdom unlikely. OBJECTIVE:  To ascertain the prevalence of basal gastric acidity and atrophic gastritis (indicated by serum pepsinogen ratio) in older adults. DESIGN:  Cross-sectional study in a volunteer sample. SETTING:  Retirement communities in suburbs of Kansas City, Mo. SUBJECTS:  A total of 248 white male and female volunteers aged 65 years or older living independently. MAIN OUTCOME MEASURES:  Presence of basal unstimulated gastric acid was evaluated noninvasively by having subjects swallow quininium resin. Gastric acid with a pH lower than 3.5 releases quinine, which is then absorbed and excreted into urine. Atrophic gastritis was defined as a ratio of serum pepsinogen I/pepsinogen II of less than 2.9. RESULTS:  Basal unstimulated gastric content was acidic (pH <3.5) in 208 (84%) of 248 elderly subjects. On retesting 66 subjects (35 normals and 31 hyposecretors), 28 (80%) of 35 had pH less than 3.5 both times, and 22 (71%) of 31 had pH of 3.5 or higher twice; in the remaining 16 subjects, low vs high gastric pH changed between tests. Weighted population prevalence estimates in this sample were 67% for consistent acid secretion, 22% for intermittent secretion, and 11% for consistent gastric pH higher than 3.5. Whereas 14 (67%) of 21 consistent hyposecretors had serum pepsinogen ratios of less than 2.9, indicating atrophic gastritis, only 2 (5%) of 44 consistent or intermittent secretors of acid had ratios in this range (P<.001). CONCLUSIONS:  In contrast to what is commonly stated, nearly 90% of elderly people in this study were able to acidify gastric contents, even in the basal, unstimulated state. Of those who were consistent hyposecretors of acid, most had serum markers of atrophic gastritis.

Fasting hypochlorhydria with gram positive gastric flora is highly prevalent in healthy old people.
            (Husebye et al., 1992) Download
Fifteen healthy old people mean age 84 years (range 80-91 years), were examined to assess the effect of advanced age on the microecology of the upper gastrointestinal tract. Twelve of 15 (80%) were hypochlorhydric with pH 6.6 (0.3) (mean (SEM) and a mean bacterial count of 10(8) colony forming units (CFU) per ml (range 10(5)-10(10)) in fasting gastric aspirate. Normochlorhydric subjects had low counts (< or = 10(1) CFU/ml). The microbial flora was dominated by viridans streptococci, coagulase negative staphylococci, and Haemophilus sp. Only one subject harboured significant concentrations of Gram negative bacilli with Escherichia coli (10(4-5) CFU/ml) and Klebsiella (10(4-5)). Strict anaerobes were not found. The total concentration of short chain fatty acids in gastric aspirate was 10.6 (2.9) mmol/l (mean (SEM). Absence of significant, intraluminal fermentation of xylose to CO2 was shown by the 14C-d Xylose breath test, and ambulatory manometry showed preserved fasting motility pattern of the small intestine. Serum immunoglobulins were normal. Advanced age is accompanied by fasting hypochlorhydria and colonisation with mainly Gram positive flora in the upper gut. Other factors than old age and fasting hypochlorhydria are required for colonisation with Gram negative bacilli.

Update on the mechanisms of gastric acid secretion.
            (Kopic and Geibel, 2010) Download
Acid-related disorders represent a major healthcare concern. In recent years, our understanding of the physiologic processes underlying gastric acid secretion has improved notably. The identity of several apical ion transport proteins, which are necessary for acid secretion to take place, has been resolved. The recent developments have uncovered potential therapeutic targets for the treatment of acid-related disorders. This brief review provides an update on the mechanisms of gastric acid secretion, with a particular focus on apical ion transport.


Gastric secretion.
            (Schubert, 2001) Download
The influence of central and peripheral stimuli on gastric acid secretion is mediated via activation of histaminergic, gastrinergic, and cholinergic pathways coupled to intracellular second-messenger systems that determine the trafficking and activity of H+ K+-ATPase, the proton pump of the parietal cell. Histamine, released from enterochromaffin-like cells stimulates the parietal cell directly via H-2 receptors coupled to generation of cAMP. Gastrin, acting via cholecystokinin-2 receptors on enterochromaffin-like cells coupled to an increase in intracellular calcium, stimulates the parietal cell indirectly by activating histidine decarboxylase, releasing histamine, and inducing enterochromaffin-like cell hypertrophy and hyperplasia. Acetylcholine, released from gastric postganglionic intramural neurons, stimulates the parietal cell directly via M-3 receptors coupled to intracellular calcium release and calcium entry. The second-messenger systems activated in the parietal cell converge on H+ K+-ATPase that catalyzes the exchange of luminal K+ for cytoplasmic H+ and is responsible for gastric luminal acidification. The main inhibitor of acid secretion is somatostatin which, acting via sst2 receptors, exerts a tonic inhibitory influence on parietal, enterochromaffin-like, and gastrin cells. Acute infection with Helicobacter pylori results in hypochlorhydria, whereas chronic infection may be associated with either hypo- or hyperchlorhydria. Although prostaglandins are thought to play a physiologic role in the regulation of acid secretion and maintenance of gastric mucosal integrity, the precise roles of cyclooxygenase-1 and cyclooxygenase-2 in these processes still eludes us.

Control of gastric acid secretion in health and disease.
            (Schubert and Peura, 2008) Download
Recent milestones in the understanding of gastric acid secretion and treatment of acid-peptic disorders include the (1) discovery of histamine H(2)-receptors and development of histamine H(2)-receptor antagonists, (2) identification of H(+)K(+)-ATPase as the parietal cell proton pump and development of proton pump inhibitors, and (3) identification of Helicobacter pylori as the major cause of duodenal ulcer and development of effective eradication regimens. This review emphasizes the importance and relevance of gastric acid secretion and its regulation in health and disease. We review the physiology and pathophysiology of acid secretion as well as evidence regarding its inhibition in the management of acid-related clinical conditions.


Gastric secretion.
            (Schubert, 2014) Download
PURPOSE OF REVIEW:  This review summarizes the past year's literature regarding the neural, paracrine, hormonal, and intracellular regulation of gastric acid secretion. RECENT FINDINGS:  Gastric acid facilitates the digestion of protein as well as the absorption of iron, calcium, vitamin B12, and certain medications. High gastric acidity, in combination with pepsin and lipase, kills ingested microorganisms and may play a role in preventing bacterial overgrowth, enteric infection, and possibly spontaneous bacterial peritonitis, community-acquired pneumonia, and infection with Mycobacterium tuberculosis. Stimulants of acid secretion include histamine, gastrin, acetylcholine, and ghrelin. Inhibitors include somatostatin, gastric inhibitory polypeptide, calcitonin gene-related peptide, and adrenomedullin. Helicobacter pylori stimulates or inhibits depending upon the time course of infection and the area of the stomach predominantly infected. Proteins implicated in H-K-ATPase membrane trafficking include myosin IIB, F-actin, ezrin, and Rab GTPases. SUMMARY:  Our understanding of the regulation of gastric acid secretion continues to advance. Such knowledge is crucial for the management of acid-peptic disorders and the development of novel medications, such as cholecystokinin-2 receptor antagonists.

How Helicobacter pylori infection controls gastric acid secretion.
            (Smolka and Backert, 2012) Download
Infection of the human stomach mucosa by Helicobacter pylori induces strong inflammatory responses and a transitory hypochlorhydria which can progress in ~2 % of patients to atrophic gastritis, dysplasia, or gastric adenocarcinoma. H. pylori infection of gastric biopsies or cultured gastric epithelial cells in vitro represses the activity of endogenous or transfected promoter of the alpha-subunit (HKα) of gastric H,K-adenosine triphosphatase (H,K-ATPase), the parietal cell enzyme mediating acid secretion. Some mechanistic details of H. pylori-mediated repression of HKα and ensuing hypochlorhydria have been recently elucidated. H. pylori strains expressing a type IV secretion system (T4SS) encoded by the cag pathogenicity island are known to upregulate the transcription factor nuclear factor (NF)-κB. The NF-κB-binding regions in the HKα promoter were identified and shown to repress its transcriptional activity. Interaction studies have indicated that although active phosphorylated NF-κB p65 is present in infected cells, an NF-κB p50/p65 heterodimeric complex fails to bind to the HKα promoter. Point mutations at -159 and -161 bp in the HKα promoter NF-κB binding sequence prevent the binding of NF-κB p50 and prevent H. pylori repression of point-mutated HKα promoter activity. The T4SS factors CagL, CagE, CagM, and possibly CagA and the lytic transglycosylase Slt, are mechanistically involved in NF-κB activation and repression of HKα transcription. CagL, a T4SS pilus component, binds to the integrin α(5)β(1) to mediate translocation of virulence factors into the host cell and initiate signaling. During acute H. pylori infection, CagL dissociates ADAM 17 (a disintegrin and a metalloprotease 17) from the integrin α(5)β(1) complex and stimulates ADAM17-dependent release of heparin-binding epidermal growth factor (HB-EGF), EGF receptor (EGFR) stimulation, ERK1/2 kinase activation, and NF-κB-mediated repression of HKα. These studies suggest that H. pylori inhibits HKα gene expression by an integrin α(5)β(1) → ADAM17 → HB-EGF → EGFR → ERK1/2 → NF-κB pathway mediating NF-κB p50 homodimer binding to the HKα promoter. Here we review the molecular basis and recent progress of this novel pathogen-dependent mechanism of H,K-ATPase inhibition, which contributes significantly to our current understanding of H. pylori pathophysiology.

The role of protein digestibility and antacids on food allergy outcomes.
            (Untersmayr and Jensen-Jarolim, 2008) Download
Digestion assays with simulated gastric fluid have been introduced for characterization of food proteins to imitate the effect of stomach proteolysis on dietary compounds in vitro. By using these tests, dietary proteins can be categorized as digestion-resistant class 1 (true allergens triggering direct oral sensitization) or as labile class 2 allergens (nonsensitizing elicitors). Thus the results of these digestion assays mirror situations of intact gastric proteolysis. Alterations in the gastric milieu are frequently experienced during a lifetime either physiologically in the very young and the elderly or as a result of gastrointestinal pathologies. Additionally, acid-suppression medications are frequently used for treatment of dyspeptic disorders. By increasing the gastric pH, they interfere substantially with the digestive function of the stomach, leading to persistence of labile food protein during gastric transit. Indeed, both murine and human studies reveal that antiulcer medication increases the risk of food allergy induction. Gastric digestion substantially decreases the potential of food proteins to bind IgE, which increases the threshold dose of allergens required to elicit symptoms in patients with food allergy. Thus antiulcer agents impeding gastric protein digestion have a major effect on the sensitization and effector phase of food allergy.

Acid suppression therapy and allergic reactions.
            (Untersmayr, 2015a) Download
The development of pharmaceutical agents such as sucralfate, histamine 2 (H2) receptor blockers and proton pump inhibitors (PPIs) reducing gastric acidity has been a mile stone for treatment of dyspeptic disorders. However, due to current prescription habits resulting in overuse of these potent drugs as well as over-the-counter (OTC) availability associated with self-medication, substantial health concern is related to the mechanisms of drug action as well as known side effects influencing gastrointestinal physiology. More than a decade ago the first study appeared reporting an association between anti-ulcer drug intake and food allergy development. Ever since this first report several experimental as well as human studies verified this correlation, demonstrating that acid suppressive drugs not only influence the sensitization capacity of orally ingested proteins, but also represent a risk factor for food allergy patients. Additionally, gastric acid suppression was reported to increase the risk for development of drug hypersensitivity reactions. These consequences of anti-ulcer drug intake might on the one hand be associated with direct influence of these drugs on immune responses. On the other hand reduction of gastric acidity leads to impaired gastrointestinal protein degradation. Nevertheless, also disruption of the gastrointestinal barrier function, changes in microbiome or lack of tolerogenic peptic digests might contribute to the connection between anti-ulcer drug intake and allergic reaction. Therefore, these drugs should only be prescribed based on a precise gastroenterological diagnosis taking into consideration allergological mechanisms to ensure patients' safety.

The influence of gastric digestion on the development of food allergy.
            (Untersmayr, 2015b) Download
Food allergy represents an increasing health concern worldwide. To identify mechanisms and risk factors associated with food allergy development major research efforts are ongoing. For a long time only food allergens that are resistant to gastric enzymes were accepted to harbor sensitizing capacity via the oral route. However, over the past years several studies reported that even important food allergens can be readily degraded by digestive enzymes. Interestingly, a number of in vitro experiments confirmed that impairment of physiological gastric digestion by elevating gastric pH levels was associated with protein resistance. Additionally, pharmacological gastric acid suppression was found to be a risk factor for food allergy induction. In contrast, protein modifications resulting in increased susceptibility to digestive enzymes were reported to decrease the sensitization capacity via the oral route. The here reviewed data highlight the important gate keeping function of physiological gastric digestion in food allergy.

Ghrelin and gastric acid secretion.
            (Yakabi et al., 2008) Download
Ghrelin, a novel growth hormone-releasing peptide, was originally isolated from rat and human stomach. Ghrelin has been known to increase the secretion of growth hormone (GH), food intake, and body weight gain when administered peripherally or centrally. Ghrelin is also known to stimulate the gastric motility and the secretion of gastric acid. In the previous studies, the action of ghrelin on acid secretion was shown to be as strong as that of histamine and gastrin in in-vivo experiment. In the studies, the mechanism for the action of ghrelin was also investigated. It was shown that vagotomy completely inhibited the action of ghrelin on the secretion of gastric acid suggesting that vagal nerve is involved in the mechanism for the action of ghrelin on acid secretion. As famotidine did not inhibit ghrelin-induced acid secretion in the study by Masuda et al, they concluded that histamine was not involved in the action of ghrelin on acid secretion. However, we have shown that famotidine completely inhibited ghrelin-induced acid secretion and histidine decarboxylase (HDC) mRNA was increased in gastric mucosa by ghrelin injection which is inhibited by vagotomy Our results indicate that histamine is involved in the action of ghrelin on acid secretion. Furthermore synergistic action of gastrin and ghrelin on gastric acid secretion was shown. Although gastrin has important roles in postprandial secretion of gastric acid, ghrelin may be related to acid secretion during fasting period or at night. However, further studies are needed to elucidate the physiological role of ghrelin in acid secretion.

The effect of Aloe vera A. Berger (Liliaceae) on gastric acid secretion and acute gastric mucosal injury in rats.
            (Yusuf et al., 2004) Download
The effect of varying doses of ethanol extract of Aloe vera (Liliaceae) on acute gastric mucosal lesions induced by 0.6 M HCl and acid output was studied in the pylorus ligated and lumen perfuse rats, respectively. Acid secretion was determined by titration of the collected gastric juice to pH 7.0. Intraperitoneal injection of Aloe vera, dose dependently inhibited gastric acid secretion. The plant was more active as a gastroprotective agent at lower concentration against mucosal injury induced by 0.6 M HCl. In conclusion, Aloe vera is endowed with gastric acid anti-secretory activity and could protect the gastric mucosa at low concentrations against injurious agents.



Chen, D and CM Zhao (2010), ‘Complexity of gastric acid secretion revealed by targeted gene disruption in mice.’, Curr Pharm Des, 16 (10), 1235-40. PubMed: 20166994
Baron, JH (1978), Clinical Tests of Gastric Secretion: History, methodology and interpretation, (London: The Macmillan Press Ltd).
Chu, S and ML Schubert (2012), ‘Gastric secretion.’, Curr Opin Gastroenterol, 28 (6), 587-93. PubMed: 22954692
Di Mario, F and E Goni (2014), ‘Gastric acid secretion: changes during a century.’, Best Pract Res Clin Gastroenterol, 28 (6), 953-65. PubMed: 25439063
Ghosh, T, et al. (2011), ‘Review article: methods of measuring gastric acid secretion.’, Aliment Pharmacol Ther, 33 (7), 768-81. PubMed: 21261669
Hurwitz, A, et al. (1997), ‘Gastric acidity in older adults.’, JAMA, 278 (8), 659-62. PubMed: 9272898
Husebye, E, et al. (1992), ‘Fasting hypochlorhydria with gram positive gastric flora is highly prevalent in healthy old people.’, Gut, 33 (10), 1331-37. PubMed: 1446855
Kopic, S and JP Geibel (2010), ‘Update on the mechanisms of gastric acid secretion.’, Curr Gastroenterol Rep, 12 (6), 458-64. PubMed: 20821079
Schubert, ML (2001), ‘Gastric secretion.’, Curr Opin Gastroenterol, 17 (6), 481-88. PubMed: 17031207
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Schubert, ML (2014), ‘Gastric secretion.’, Curr Opin Gastroenterol, 30 (6), 578-82. PubMed: 25211241
Smolka, AJ and S Backert (2012), ‘How Helicobacter pylori infection controls gastric acid secretion.’, J Gastroenterol, 47 (6), 609-18. PubMed: 22565637
Untersmayr, E and E Jensen-Jarolim (2008), ‘The role of protein digestibility and antacids on food allergy outcomes.’, J Allergy Clin Immunol, 121 (6), 1301-8; quiz 1309. PubMed: 18539189
Untersmayr, E (2015a), ‘Acid suppression therapy and allergic reactions.’, Allergo J Int, 24 (8), 303-11. PubMed: 28603686
——— (2015b), ‘The influence of gastric digestion on the development of food allergy.’, Rev Fr Allergol (2009), 55 (7), 444-47. PubMed: 28616101
Yakabi, K, J Kawashima, and S Kato (2008), ‘Ghrelin and gastric acid secretion.’, World J Gastroenterol, 14 (41), 6334-38. PubMed: 19009648
Yusuf, S, A Agunu, and M Diana (2004), ‘The effect of Aloe vera A. Berger (Liliaceae) on gastric acid secretion and acute gastric mucosal injury in rats.’, J Ethnopharmacol, 93 (1), 33-37. PubMed: 15182901