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Gastric secretion
Abstract
The review summarizes the past year's literature, basic science and clinical, regarding the neural, paracrine, hormonal, and intracellular regulation of gastric acid secretion.
Gastric acid facilitates the digestion of protein as well as the absorption of iron, calcium, vitamin B12, and certain medications (e.g. thyroxin). It also kills ingested microorganisms and prevents bacterial overgrowth, enteric infection, and possibly spontaneous bacterial peritonitis. Stimulants of acid secretion include histamine, gastrin, acetylcholine, and ghrelin. Inhibitors include somatostatin, nefstatin-1, interleukin-11, and calcitonin gene-related peptide. Helicobacter pylori stimulates or inhibits acid secretion depending upon the time course of infection and the area of the stomach predominantly infected. Acute infection activates calcitonin gene-related peptide sensory neurons coupled to inhibition of histamine and acid secretion. Serum chromogranin A, a marker for neuroendocrine tumors, is elevated in patients taking proton pump inhibitors.
Progress continues in our understanding of the regulation of gastric acid secretion in health and disease, as well as the function of gastric neuroendocrine cells. The recognition that gastrin is not only a secretagogue but also a trophic hormone has led to new research into the role of gastrin and its receptor (cholecystokinin-2 receptor) in carcinogenesis and the development of cholecystokinin-2 receptor antagonists.
... The key player in acid secretion is a H + /K + ATPase (the proton pump) located in the parietal cell which is responsible for the transport of hydrogen ions into the gastric lumen [1]. The H + /K + ATPase has been shown to be an α, β-heterodimeric enzyme which catalyses a one-to-one exchange of hydrogen (H + ) and potassium (K + ) ions [2,3]. ...
... The parietal cells bear receptors for three stimulators of acid secretion, acetylcholine, histamine and gastrin reflecting neural, paracrine and endocrine control, respectively ( Figure 1). Gastrin is the main mediator released from antral G-cells into peripheral blood (i.e., hormonal pathways), stimulating enterochromaffin-like (ECL) cells via gastrin/cholecystokinin 2 (CCK 2 ) receptors accelerating histamine release [1,4]. Histamine diffuses (i.e., through a paracrine pathway) to interact with H 2 -receptors on parietal cells. ...
... Gastrin/CCK 2 receptors have been well documented on ECL cells but not on parietal cells [6]. However, gastrin is believed to stimulate parietal cells directly, to some extent, but this is considered to be a less extensive mechanism [1]. The stimulatory effect of acetylcholine and gastrin is mediated by an increase in cytosolic calcium (Ca 2+ ), whereas that of histamine is mediated by the activation of adenylate cyclase and generation of cyclic adenosine monophosphate (cAMP) [2]. ...
Proton pump inhibitors (PPIs) are recommended as a first-line treatment for gastroesophageal reflux disease (GERD) and other acid related disorders. In recent years, concerns have been raised about the increasing prevalence of patients on long-term PPI therapy and inappropriate PPI use. It is well known that short-term PPI therapy is generally well tolerated and safe; however, their extensive long-term use is a major global issue. One of these long-standing concerns is PPI-induced gastrin elevation secondary to hypoacidity. Hypergastrinemia is believed to play a role in rebound hyperacidity when PPIs are discontinued resulting in induced dyspeptic symptoms that might result in the reinstitution of therapy. Gastrin exerts tropic effects in the stomach, especially on enterochromaffin-like (ECL) cells, and concerns have also been raised regarding the potential progression to dysplasia or tumor formation following long-term therapy. It is well known that a substantial number of patients on long-term PPI therapy can discontinue PPIs without recurrence of symptoms in deprescribing trials. What is unknown is how sustainable deprescribing should be undertaken in practice and how effective it is in terms of reducing long-term outcomes like adverse drug events, morbidity and mortality. Moreover, there is no clear consensus on when and how deprescribing strategies should be attempted in practice. This review sought to summarize the harms and benefits of long-term PPI therapy with special focus on gastrin elevation and its relation to deprescribing studies and future interventions that may improve PPI use.
... После этого каталитический цикл может повториться. Таким образом, в результате циклических изменений конформации Н + , К + -АТФазы и ее последовательного фосфорилирования-дефосфорилирования, приводящих к изменению сродства фермента к переносимым катионам и закрытию-открытию наружной и внутренней части канала, осуществляется последовательный перенос иона гидроксония из париетальной клетки наружу и иона калия из окружающей среды в клетку [2,3,10,20]. ...
... Н + , К + -АТФаза париетальных клеток обеспечивает секрецию клеткой Н + в обмен на К + , однако париетальные клетки секретируют не протон, а соляную кислоту, т. е. Н + и анион Сl - [6,19,20]. Это становится возможным благодаря тому, что, помимо протонной помпы, в апикальной мембране париетальных клеток имеются К + -и Сl --каналы. Концентрация ионов К + в клетке высока, кроме того, функционирующий протонный насос постоянно вносит в клетку новые ионы К + из окружающей среды [10]. ...
... Благодаря присутствию в апикальной мембране париетальных клеток Н+, К+-АТФазы, К+ и Сl-ионных каналов, из клеток в секреторные канальцы секретируются ионы Н+ и Сl-, образуя соляную кислоту, а ионы К+ перемещаются из цитозоля клетки в окружающую среду и обратно в клетке в результате метаболизма [6,19,20]. Источником протона, секретируемого париетальной клеткой, является вода, которая диссоциирует с образованием Н + и ОН -. Помимо воды, в клетке имеется большое количество буферных соединений, поэтому непродолжительная секреция Н + из париетальной клетки не приводит к защелачиванию цитозоля [10]. ...
The article provides a systematic review of modern literary data on the basics of gastric acid secretion. It describes the ionic transport systems of the parietal cell involved in the hydrochloric acid synthesis. The molecular structure of H +, K + -ATPhase (proton pump) is discussed. The article characterizes various ways of regulation of gastric acid secretion (neural, hormonal and paracrine) and intracellular signal transduction processes of a parietal cell.
... The α-CA was shown to possess a periplasmic localization, the β-CA has been found in the cytoplasm, whereas no information is available on the expression/localization of the H. pylori γ-CA. H. pylori has developed exclusive adaptive mechanisms for growing in the highly acid environment of the stomach (pH between 1 and 2) [44]. These mechanisms involve the urease and the CA enzymes, which allow the bacteria to colonize the stomach by regulating the periplasmic pH and elevating the cytoplasmic pH trough the production of NH 3 . ...
... CAs were identified in the anterior uvea of the eye and were shown to be responsible for the bicarbonate secretion. CAIs represent the most physiological treatment of glaucoma, as by inhibiting the ciliary-process enzyme -the sulphonamide susceptible isozyme CA II (TABLE 1) -the rate of bicarbonate and aqueous humour secretion is reduced, resulting in a 25-30% decrease in IOP [44][45][46][47][48][49][50][51] . ...
... Glaucoma is a chronic, degenerative eye disease, characterised by high intraocular pressure (IOP) that causes irreversible damage to the optic nerve head, resulting in the progressive loss of visual function and eventually blindness [44][45][46] . Studies on the chemistry and dynamics of aqueous humour have identified the main constituent of this secretion to be sodium bicarbonate 1,2,44-46 . ...
The possibility to develop new antibacterial agents raised much interest recently. The main classes of antibiotics clinically used nowadays act towards the inhibition of four classical targets: a) cell wall biosynthesis; b) protein biosynthesis; c) DNA and RNA biosynthesis; d) folate biosynthesis. Recently, carbonic anhydrases (CAs, EC 4.2.1.1) started to be investigated in detail in pathogenic bacteria, in the search for antibiotics with a novel mechanism of action, since it has been demonstrated that in many bacteria, CAs are essential for the life cycle of the organism and that their inhibition leads to growth impairment or growth defects of the pathogen. CAs catalyze a simple but physiologically relevant reaction in all life kingdoms, carbon dioxide hydration to bicarbonate and protons. Several classes of CA inhibitors (CAIs) are known to date: the metal complexing anions and the unsubstituted sulfonamides, which bind to the Zn(II) ion of the enzyme either by substituting the non-protein zinc ligand or add to the metal coordination sphere, generating trigonal-bipyramidal species are the classical, most frequently investigated ones. In many cases effective inhibitors were detected, some of which also inhibited the bacterial growth in vivo. However, very few of the detected inhibitors were also selective for the bacterial over the human, off target isoforms such as hCA II. Using structure-based drug design processes, we estimate that it will be possible to achieve the desired selectivity for inhibiting preferentially the bacterial but not the host CA isoforms.
... On the other hand, the density of somatostatin-immunoreactive cells was lower in all the subtypes of IBS than in the healthy controls. Gastrin is the main hormonal stimulant of acid secretion in the stomach (47)(48)(49)(50)(51); it stimulates parietal cells both directly and indirectly by releasing histamine from enterochromaffinlike cells (47,48,51,52). Somatostatin inhibits acid secretion directly by acting on parietal cells and indirectly by inhibiting histamine and gastrin secretion (47)(48)(49)(50)(51). ...
... On the other hand, the density of somatostatin-immunoreactive cells was lower in all the subtypes of IBS than in the healthy controls. Gastrin is the main hormonal stimulant of acid secretion in the stomach (47)(48)(49)(50)(51); it stimulates parietal cells both directly and indirectly by releasing histamine from enterochromaffinlike cells (47,48,51,52). Somatostatin inhibits acid secretion directly by acting on parietal cells and indirectly by inhibiting histamine and gastrin secretion (47)(48)(49)(50)(51). ...
... Gastrin is the main hormonal stimulant of acid secretion in the stomach (47)(48)(49)(50)(51); it stimulates parietal cells both directly and indirectly by releasing histamine from enterochromaffinlike cells (47,48,51,52). Somatostatin inhibits acid secretion directly by acting on parietal cells and indirectly by inhibiting histamine and gastrin secretion (47)(48)(49)(50)(51). The present findings of increased gastrin and decreased somatostatin in all IBS subtypes may cause a high level of gastric acid secretion, which may account for the high incidence of dyspepsia and gastrooesophageal reflux observed in patients with IBS (53)(54)(55)(56)(57)(58)(59)(60)(61). ...
To the best of our knowledge, stomach antral endocrine cells have not previously been investigated in patients with irritable bowel syndrome (IBS). Thus, in the present study, 76 patients with IBS were examined (designated as IBS-total). Diarrhoea was the predominant symptom in 26 of these patients (IBS-D), while in 21 patients, the predominant symptoms were both diarrhoea and constipation (IBS-M) and in 29 patients the predominant symptom was constipation (IBS-C). Forty-three healthy subjects were enrolled as the controls. Stomach antral biopsy samples obtained from all of the subjects were immunostained using the avidin-biotin-complex method for serotonin, gastrin, somatostatin and serotonin transporter (SERT). The immunopositive cell densities and immunoreactivity intensities were determined by computer-aided image analysis. The density of the serotonin-immunoreactive cells was significantly decreased in the IBS-M patients and increased in the IBS-C patients relative to the controls. The immunoreactivity intensity did not differ significantly between the controls and IBS-total. The density of the gastrin-immunoreactive cells was significantly greater in the IBS-D, IBS-M and IBS-C patients than in the controls. The immunoreactivity intensity of gastrin was significantly greater in the IBS-D patients than in the controls. The density of the somatostatin-immunoreactive cells cells was significantly lower in the IBS-total, IBS-D, IBS-M and IBS-C patients than in the controls. The immunoreactivity intensities of both somatostatin and SERT did not differ significantly between the controls and IBS-total. The increase in gastrin cell density and the decrease in somatostatin cell density in all IBS subtypes may cause high levels of gastric secretion, which may in turn contribute to the high incidence of dyspepsia and gastro-oesophageal reflux observed in patients with IBS.
... The wall of the stomach is made of four layers, namely, mucosa, submucosa, muscularis externa, and the serosa. Mucosa is the innermost layer that plays roles in secretion, digestion, and absorption [9][10][11][12] . It consists mainly of the gastric glands for secretion, and is protected by the mucosa barrier including a sticky neutralizing mucus coat from self-digestion in the corrosive acidic environments [13][14][15][16][17][18][19] . ...
... About 100 µg of protein samples were then digested using trypsin. Tryptic peptides were separated in a homemade reverse-phase C18 column in a pipette tip with nine fractions using a stepwise gradient of increasing acetonitrile (6,9,12,15,18,21,25,30, and 35%) under basic conditions (pH 10). The nine fractions were combined into six MS samples, dried in a vacuum concentrator (Thermo Scientific), and then analyzed by LC-MS/MS. ...
The human gastric mucosa is the most active layer of the stomach wall, involved in food digestion, metabolic processes and gastric carcinogenesis. Anatomically, the human stomach is divided into seven regions, but the protein basis for cellular specialization is not well understood. Here we present a global analysis of protein profiles of 82 apparently normal mucosa samples obtained from living individuals by endoscopic stomach biopsy. We identify 6,258 high-confidence proteins and estimate the ranges of protein expression in the seven stomach regions, presenting a region-resolved proteome reference map of the near normal, human stomach. Furthermore, we measure mucosa protein profiles of tumor and tumor nearby tissues (TNT) from 58 gastric cancer patients, enabling comparisons between tumor, TNT, and normal tissue. These datasets provide a rich resource for the gastrointestinal tract research community to investigate the molecular basis for region-specific functions in mucosa physiology and pathology including gastric cancer.
... In the latter, a close association between H. suis and parietal cells has been observed and these cells can show signs of degeneration or malfunction [16]. In previous studies, it has been described that malfunction of acid secretion by parietal cells is closely associated with the development of gastritis [31], indicating that the function of parietal cells might be influenced by gastritis. On the other hand, a direct effect of H. suis on the health and function of parietal cells might also be involved. ...
... In the present study, mRNA expression levels of Atp4a, part of the proton pump, showed a trend towards being higher in H. suis positive pigs, which may be somewhat surprising, since other studies have shown that H. pylori infection can inhibit acid secretion through down-regulation of the expression of H + /K + ATPase, resulting in hypochlorhydria [14,46,47]. However, yet another group of studies have described that H. pylori infection can in fact also cause hyperchlorhydria [48,49], depending on the distribution of bacteria within the stomach, the infection stage, the profile of cytokines produced by the local epithelial cells or immune cells, and the pattern of gastritis [31,50]. Therefore, the effect of H. suis infection on the dynamic changes of expression of H + /K + ATPase as well as the function of parietal cells in the pig stomach needs to be further explored in future experimental studies. ...
The stomach of pigs at slaughter age is often colonized by Helicobacter (H.) suis, which is also the most prevalent gastric non-H. pylori Helicobacter (NHPH) species in humans. It is associated with chronic gastritis, gastric ulceration and other gastric pathological changes in both hosts. Parietal cells are highly specialized, terminally differentiated epithelial cells responsible for gastric acid secretion and regulation. Dysfunction of these cells is closely associated with gastric pathology and disease. Here we describe a method for isolation and culture of viable and responsive parietal cells from slaughterhouse pigs. In addition, we investigated the interactions between H. suis and gastric parietal cells both in H. suis-infected six-month-old slaughter pigs, as well as in our in vitro parietal cell model. A close interaction of H. suis and parietal cells was observed in the fundic region of stomachs from H. suis positive pigs. The bacterium was shown to be able to directly interfere with cultured porcine parietal cells, causing a significant impairment of cell viability. Transcriptional levels of Atp4a, essential for gastric acid secretion, showed a trend towards an up-regulation in H. suis positive pigs compared to H. suis-negative pigs. In addition, sonic hedgehog, an important factor involved in gastric epithelial differentiation, gastric mucosal repair, and stomach homeostasis, was also significantly up-regulated in H. suis positive pigs. In conclusion, this study describes a successful approach for the isolation and culture of porcine gastric parietal cells. The results indicate that H. suis affects the viability and function of this cell type.
... Although the trophic properties of gastrin are well established (45,46), the intracellular and molecular mechanisms by which gastrin modulates cell growth in the gastrointestinal tract have yet to be fully elucidated. It has been reported that stimulation of CCK2R by gastrin activates several signal transduction pathways involved in cell proliferation and migration, such as the mitogen-activated protein kinase (MAPK) that includes ERK, JNK, p38 kinase, and RhoA activation (47). ...
... Previous reports on LARG showed simultaneously interaction with the RH domain (at the N-terminal domain of LARG) and DH-PH domain (51). Similarly, it has been shown that activated G␣ 13 can interact with the RH domain and the DH-PH domains of p115RhoGEF (45,46,52,53). Further investigations will examine the functional role of the interaction through the region containing the DH-PH domains, if the association of Rgnef with G␣ 13 is direct, and determine whether Rgnef mediates GTPaseactivating protein activity toward G␣ 13 . ...
The guanine-nucleotide exchange factor Rgnef (also known as ArhGEF28 or p190RhoGEF) promotes colon carcinoma cell motility and tumor progression via interaction with focal adhesion kinase (FAK). Mechanisms of Rgnef activation downstream of integrin or G protein-coupled receptors (GPCRs) remain undefined. In the absence of a recognized G-protein signaling homology (RH) domain in Rgnef, no proximal linkage to G proteins was known. Utilizing multiple methods, we have identified Rgnef as a new effector for Gα13 downstream of gastrin and the type 2 cholecystokinin receptor (CCK2R). In DLD-1 colon carcinoma cells depleted of Gα13, gastrin-induced FAK pY397 and paxillin pY31 phosphorylation were reduced. RhoA GTP binding and serum response element (SRE) promoter activity is increased by Rgnef in combination with active Gα13. Rgnef co-immunoprecipitated with activated Gα13Q226L but not Gα12Q229L. The Rgnef C-terminal (CT, 1279-1582) region was sufficient for co-immunoprecipitation and Rgnef-CT exogenous expression prevented Gα13-stimulated SRE activity. A domain at the C-terminus of the protein close to the FAK binding domain is necessary to bind to Gα13. Point mutations of Rgnef-CT residues disrupt association with active Gα13 but not Gαq. These results show that Rgnef functions as an effector of Gα13 signaling and that this linkage may mediate FAK activation in DLD-1 colon carcinoma cells.
Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
... The stomach essentially is devoted to the preparation of the bolus for the best digestion conditions in the downstream digestive tracts. Neural, hormonal, paracrine signals resulting from luminal content sensing (chemicals and nutrients, xenobiota components), are integrated in the stomach [1] to adjust the intake, passage rate and metabolism in collaboration with the intestine. ...
... Real Time RT-PCR1 Microarray 1Values normalized for hydroxymethylbilane synthase and ribosomal protein L4 gene expression.ATP4A, H+/K+ Atpase a; GAST, gastrin; GHRL, ghrelin/obestatin prepropeptide; PIGR, polymeric immunoglobulin receptor.All gene values differed for the different mucosae inside each analysis method (P,0.05). doi:10.1371/journal.pone.0111447.t006 ...
The stomach is often considered a single compartment, although morphological differences among specific areas are well known. Oxyntic mucosa (OXY) and pyloric mucosa (PYL, in other species called antral mucosa) are primarily equipped for acid secretion and gastrin production, respectively, while it is not yet clear how the remainder of genes expressed differs in these areas. Here, the differential gene expression between OXY and PYL mucosa was assessed in seven starter pigs. Total RNA expression was analyzed by whole genome Affymetrix Porcine Gene 1.1_ST array strips. Exploratory functional analysis of gene expression values was done by Gene Set Enrichment Analysis, comparing OXY and PYL. Normalized enrichment scores (NESs) were calculated for each gene (statistical significance defined when False Discovery Rate %
... Interspersed between parietal cells are neuroendocrine, enterochromaffin-like cells (EC cells) which aid in the secretion of acid by release of histamine (Soybel, 2005). These represent 30-50% of enteroendocrine cells in the oxyntic mucosa (Zhao and Chen, 2012;Chu and Schubert, 2013). Enteroendocrine cells are the largest endocrine organ (< 1% of gut epithelial cells) of the human body (Chen et al., 1999;Schubert and Peura, 2008), and regulate secretion, motility, food intake and metabolism. ...
Oral administration is the most common route of drug delivery. The absorption of a drug from the gut into the bloodstream involves disintegration of the solid dosage form, dissolution of the active pharmaceutical ingredient and its transport across the gut wall. The efficiency of these processes is determined by highly complex and dynamic interplay between the gastrointestinal tract, the dosage form and the API. The European Network on Understanding Gastrointestinal Absorption-related Processes (UNGAP)aims to improve our understanding of intestinal drug absorption by creating a multidisciplinary Network of researchers from academia and industry engaging in scientific discussions. As part of the basis for the UNGAP project, this review aims to summarize the current knowledge on anatomy and physiology of the human gastrointestinal tract with emphasis on human studies for the evaluation of the regional drug absorption and the prediction of oral dosage form performance. A range of factors and methods will be considered, including imaging methods, intraluminal sampling and, models for predicting segmental/regional absorption. In addition, in vitro and in silico methods to evaluate regional drug absorption will be discussed. This will provide the basis for further work on improving predictions for the in vivo behavior of drug products in the gastrointestinal tract.
... Cholecystokinin (CCK) and polypeptide YY (PYY) are released in response to fat and protein, and constitute important hormones in the regulation of appetite, body weight, gastrointestinal motility (17,18). Ghrelin concentrations are suppressed in response to meal intake (19), whereas basal levels are increased after weight reduction (20). ...
... Mechanical scratch ulceration is generally superficial and short-lived and superficial lamina propria covered by fibrin, mucus and scattered neutrophils (Wilcock, 2013). Secretion of hydrochloric acid that creates acidity catalyzes pepsinogen to the active proteolytic enzyme pepsin (Chu and Schubert, 2012). Hamper integrity and protective mechanism disturbance in mucosal layer initially, increase rate of reverse diffusion of gastric acid and pepsin lead to GI inflammation and haemorrhages than inflammatory components (e.g. ...
... The most important effect of PYY is regulation of appetite and body weight, but recent research suggests that PYY also has an impact on beta cell mass, thereby participating in glucose homeostasis (12). Ghrelin plays a role in body energy metabolism and its concentration is greatest in the fasting state, to be suppressed in response to meal intake (13). ...
Background
An Okinawa-based Nordic diet with moderately low carbohydrate content and high fat and protein content has been shown to improve anthropometry and metabolism in type 2 diabetes.
Objective
The objectives of this study were to measure plasma or serum levels of hormones regulating energy metabolism and metabolic control, that is, cholecystokinin (CCK), Cortisol, C-peptide, ghrelin, glucagon, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), insulin, leptin, plasminogen activator inhibitor-1 (PAI-1), polypeptide YY (PYY), resistin, and visfatin after this diet intervention, and to determine partial correlations between hormonal levels and anthropometric and metabolic responses.
Design
A total of 30 patients (17 women) with type 2 diabetes, mean age 57.5 ± 8.2 years, and body mass index (BMI) 29.9 ± 4.1 kg/m² were served the diet for 12 weeks. Fasting hormones were measured by Luminex and enzyme–linked immunosorbent assay (ELISA) before study start and after 12 and 28 weeks, along with anthropometric and metabolic parameters.
Result
The levels of CCK (P = 0.005), cortisol (P = 0.015), C-peptide (P = 0.022), glucagon (P = 0.003), GLP-1 (P = 0.013), GIP (P < 0.001), insulin (P = 0.004), leptin (P < 0.001), and PYY (P < 0.001) were lowered after dietary intervention. These reduced levels only remained for PYY at week 28 (P = 0.002), when also ghrelin (P = 0.012) and visfatin (P = 0.021) levels were reduced. Changes of glucose values correlated with changed levels of C-peptide and PYY (P < 0.001), insulin (P = 0.002), and PAI-1 (P = 0.009); changes of triglyceride values with changed levels of C-peptide, insulin, and PYY (P < 0.001) and PAI-1 (P = 0.005); changes of insulin resistance with changes of leptin levels (P = 0.003); and changes of BMI values with changed levels of C-peptide, insulin, and leptin (P < 0.001).
Conclusions
Okinawa-based Nordic diet in type 2 diabetes has significant impact on the endocrine profile, which correlates with anthropometric and metabolic improvements.
... In some patients, ongoing inflammation leads to progression of chronic gastritis to atrophic gastritis, which is characterized by a loss of glandular cells and acid producing parietal (or oxyntic) cells. Normal gastric acidity is maintained through an interplay between different enteroendocrine cells, with G-cells located in the antrum of the stomach producing the hormone gastrin which stimulates hydrochloric acid (HCL) production, and somastatin produced by D-cells reducing HCL production [40]. ...
Helicobacter Pylori is a gram negative rod shaped microaerophilic bacterium that colonizes the stomach of approximately half the world's population. Infection with c may cause chronic gastritis which via a quite well described process known as Correas cascade can progress through sequential development of atrophic gastritis, intestinal metaplasia and dysplasia to gastric cancer. H. pylori is currently the only bacterium that is classified as a class 1 carcinogen by the WHO, although the exact mechanisms by which this bacterium contributes to gastric carcinogenesis are still poorly understood. Only a minority of H. pylori-infected patients will eventually develop gastric cancer, suggesting that host factors may be important in determining the outcome of H. pylori infection. This is supported by a growing body of evidence suggesting that the host genetic background contributes to risk of H. pylori infection and gastric carcinogenesis. In particular single nucleotide polymorphisms in genes that influence bacterial handling via pattern recognition receptors appear to be involved, further strengthening the link between host risk factors, H. pylori incidence and cancer. Many of these genes influence cellular pathways leading to inflammatory signaling, inflammasome formation and autophagy. In this review we summarize known carcinogenic effects of H. pylori, and discuss recent findings that implicate host genetic pattern recognition pathways in the development of gastric cancer and their relation with H. pylori.
... Upper gastrointestinal (UGI) endoscopy enables physicians to estimate the secreting ability of gastric mucosa and gastric cancer risk based on the findings of the background gastric mucosa (Fig. 1). To measure the secreting ability of gastric mucosal cells, noninvasive serologic tests are preferred over invasive tube tests [1]. Noninvasive tests consist of the serum pepsinogen (PG) assay, calcium carbonate breath test, and hydrogen breath test, while invasive tests consist of aspiration tests (pentagas-trin and tetragastrin tests), endoscopic gastrin test, and intragastric pH measurements [2]. ...
Endoscopic findings of the background gastric mucosa are important in the Helicobacter pylori-seroprevalent population. It is strongly correlated not only with the risk of gastric cancer, but also with the excretion ability of gastric mucosa cells. In noninfected subjects, common endoscopic findings are regular arrangement of collecting venules, chronic superficial gastritis, and erosive gastritis. In cases of active H. pylori infection, nodularity on the antrum, hemorrhagic spots on the fundus, and thickened gastric folds are common endoscopic findings. The secreting ability of the gastric mucosa cells is usually intact in both noninfected and actively infected stomachs, and the intragastric condition becomes hyperacidic upon inflammation. Increased serum pepsinogen II concentration correlates well with active H. pylori infection, and also indicates an increased risk of diffuse-type gastric cancer. In chronic inactive H. pylori infection, metaplastic gastritis and atrophic gastritis extending from the antrum (closed-type chronic atrophic gastritis) toward the corpus (open-type chronic atrophic gastritis) are common endoscopic findings. The intragastric environment is hypoacidic and the risk of intestinal-type gastric cancer is increased in such conditions. Furthermore, there is a decrease in serum pepsinogen I concentration when the secreting ability of the gastric mucosa cells is damaged. Serologic and endoscopic changes that occur upon H. pylori infection are important findings for estimating the secreting ability of the gastric mucosa cells, and could be applied for the secondary prevention of gastric cancer.
... The distribution of the apelin/APJ system in the stomach indicates a potential role for apelin in gastric functions. Apelin is an angiogenic factor that is involved in the proliferation of gastric cells [4] and the regulation of gastric acid secretion [5,7,8]. Recently, centrally administered apelin-13 was shown to inhibit gastric emptying in mice [9]. ...
The objective of this study was to explore the role of apelin in the healing of gastric lesions induced by stress. Male Wistar rats were exposed to water immersion and restraint stress (WIRS) for 6 h with or without the apelin receptor antagonist F13A. The rats were killed on the 1st, 3rd, 5th or 10th day after the end of stress induction. Apelin and hypoxia-inducible factor-1α expression was increased on the 1st day after the end of stress exposure and was decreased daily thereafter. However, F13A retarded the healing of gastric lesions by preventing the improvement of mucosal blood flow, prostaglandin E2 production and vascular endothelial growth factor expression in rats exposed to WIRS. Additionally, F13A increased the gastric 4-hydroxynonenol + malondialdehyde content on the 1st and 3rd days after the end of stress induction but did not affect the change in gastric mucosal nitric oxide levels. In conclusion, apelin may be a regulatory protein involved in the healing mechanism of stress-induced gastric damage.
... It has multifunction in regulating acid secretion, cell growth, cell apoptosis, and cell division in the gastric mucosa. 5 Gastrin has also been proved to stimulate enterochromaffin-like cells to produce histamine which contributes to the healing of experimentally induced ulcers in rat stomach. 6 Although precursor forms of gastrin, such as progastrin and glycine-extended gastrin have been found to encourage cell growth, division and hyperproliferation in normal murine colon, 7-9 few report that whether gastrin has effects upon small intestinal epithelial cells as the Cholecystokinin-2 (CCK-2) receptor is lowly expressed in the tissue. ...
Intestinal ischemia-reperfusion (I/R) injury is a devastating complication when the blood supply is reflowed in ischemic organs. Gastrin has critical function in regulating acid secretion, proliferation, and differentiation in the gastric mucosa. We aimed to determine whether gastrin has an effect on intestinal I/R damage. Intestinal I/R injury was induced by 60-min occlusion of the superior mesenteric artery followed by 60-min reperfusion, and the rats were induced to be hypergastrinemic by pretreated with omeprazole or directly injected with gastrin. Some hypergastrinemic rats were injected with cholecystokinin-2 (CCK-2) receptor antagonist prior to I/R operation. After the animal surgery, the intestine was collected for histological analysis. Isolated intestinal epithelial cells or crypts were harvested for RNA and protein analysis. CCK-2 receptor expression, intestinal mucosal damage, cell apoptosis, and apoptotic protein caspase-3 activity were measured. We found that high gastrin in serum significantly reduced intestinal hemorrhage, alleviated extensive epithelial disruption, decreased disintegration of lamina propria, downregulated myeloperoxidase activity, tumor necrosis factor-α, and caspase-3 activity, and lead to low mortality in response to I/R injury. On the contrary, CCK-2 receptor antagonist L365260 could markedly impair intestinal protection by gastrin on intestinal I/R. Severe edema of mucosal villi with severe intestinal crypt injury and numerous intestinal villi disintegrated were observed again in the hypergastrinemic rats with L365260. The survival in the hypergastrinemic rats after intestinal I/R injury was shortened by L365260. Finally, gastrin could remarkably upregulated intestinal CCK-2 receptor expression. Our data suggest that gastrin by omeprazole remarkably attenuated I/R induced intestinal injury by enhancing CCK-2 receptor expression and gastrin could be a potential mitigator for intestinal I/R damage in the clinical setting.
... Ghrelin, a 28-amino acid peptide and an endogenous ligand of GHSR, was originally isolated from the rat stomach (4) and characterized, but both ghrelin and GHSR are expressed in a number of other tissues, including the hypothalamus, where the highest concentration of GHSR has been described (5). GHRH acts to induce the proliferation of somatotroph cells, as well as the synthesis and secretion of GH. ...
Ghrelin, as a brain-gut peptide, has growth hormone (GH)-releasing and appetite-inducing activities and a widespread tissue distribution. Furthermore, ghrelin is an endogenous ligand of the GH secretagogue receptor (GHSR), and both ghrelin and GHSR are expressed in the pituitary; however, the data regarding the expression of ghrelin and GHSR in pituitary adenomas are divergent and conflicting. In the present study, therefore, the expression of ghrelin and GHSR was examined in the full spectrum of human pituitary adenoma subtypes (n=34) and in normal pituitary tissue (n=3). The mRNA and protein expression levels were quantified using a competitive reverse transcription-polymerase chain reaction and western blotting and the correlation of the results with the clinical parameters was assessed. mRNA and protein expression of ghrelin and GHSR was detected in all samples with the highest mean level in GH adenomas, a moderate level in clinically non-functioning adenomas and the lowest level in adrenocorticotropin adenomas. A significant correlation between the ghrelin and GHSR mRNA expression levels was observed in the GH adenomas (n=12) (r=0.8435, P=0.0006). The ghrelin mRNA expression level in the GH adenomas correlated positively with the basic serum GH level (n=12) (r=0.6488, P=0.0225). Furthermore, the mean level of ghrelin mRNA expression was significantly higher in invasive adenomas than in noninvasive adenomas (P<0.01). Collectively, the results of the study provided evidence that ghrelin and GHSR are expressed in the various subtypes of pituitary adenoma, with specific overexpression in GH adenomas. The study suggests that the binding of ghrelin to GHSR promotes the secretion of GH and plays an important role in the development of GH adenomas via autocrine and/or paracrine effects.
... Total resection of the stomach and following esophago-duodenal anastomosis negatively change pH value of intestinal juice in duodenum and jejunum influencing digestive enzyme activity. 10,11 In long-term studies on growing pigs, it was shown that performed fundectomy was associated with impaired protein digestion, limited amino acid absorption processes, and severe osteopenia development in trabecular and cortical bone compartments of lumbar spine. 5 Apart from consequences for protein metabolism, partial or total gastrectomy impairs carbohydrate, lipid, macro-and microelement (calcium, magnesium, iron, copper, zinc, potassium, and selenium), and vitamin (vitamins B1, B9, B12, A, D, E, and K) absorption within several parts of small intestine. ...
The aim of the study was to determine one-year effects of total gastrectomy on plasma silicon and free amino acid concentrations in patients and evaluate changes of volumetric bone mineral density (vBMD) in lumbar spine. Eight patients were enrolled to the control (CTR) group. Six patients subjected to total gastrectomy (GX group) were included to the experimental group. vBMD in trabecular and cortical bone was measured in lumbar vertebrae at baseline (before surgery) and one year later using quantitative computed tomography. Plasma concentrations of silicon and free amino acids were determined at baseline and one year later using photometric method and ion-exchange chromatography. Body weights within CTR and GX groups were not different after one-year follow-up when compared to the baseline values (P > 0.05). An average annual decrease of vBMD in the trabecular bone in the gastrectomized patients reached 15.0% in lumbar spine and was significantly different in comparison to the percentage changes observed in CTR group (P = 0.02). One-year percentage change of vBMD in the cortical bone in L1 and L2 has shown significantly decreased values by 10.5 and 9.1% in the GX group when compared to the percentage change observed in the controls (P < 0.05). Plasma concentration of adipic acid was significantly higher by 101.6% one year after total gastrectomy procedure in the patients when compared to the baseline value (P = 0.01). Plasma concentration of silicon was significantly lowered by 26.7% one year after the total gastrectomy when compared to the baseline value (P = 0.009). Total gastrectomy in patients has induced severe osteoporotic changes in lumbar spine within one-year period. The observed osteoporotic changes were associated with decreased plasma concentration of silicon indicating importance of exocrine and endocrine functions of stomach for silicon homeostasis maintenance. Gastrectomy-induced bone loss was not related to decreased amino acid concentration in plasma obtained from overnight fasted patients.
© 2015 by the Society for Experimental Biology and Medicine.
... Protein digestion starts in the stomach with pepsin and continues in the duodenum with trypsin and chymotrypsin [28]. Gastric acid plays a key role in the digestion of protein by activating pepsin and denaturing the protein which can then become readily accessible by digestive proteases [29]. The changes in patterns of polypeptides observed by SDS-PAGE (Figure 1) shows the release of polypeptides and their subsequent degradation, such as the Mr 135 kDa polypeptide which increased in intensity in sample GU and then decreased through the digestive process. ...
... Gastrin is released from the G cells and stimulates parietal cells either directly or indirectly by interacting with receptors of cholecystokinin-2 (CCK-2) present in ECL cells, inducing the release of histamine [47,69]. The acetylcholine released from postganglionic neurons, stimulate the parietal cell receptors directly or indirectly via M3, M2 and M4 receptors coupled to the inhibition of secretion of somatostatin [47, 69,70]. ...
Peptic ulcer is a common disease characterized by lesions that affect the mucosa of the esophagus, stomach and/or duodenum, and may extend into the muscular layer of the mucosa. Natural products have played an important role in the process of development and discovery of new drugs, due to their wide structural diversity and present, mostly specific and selective biological activities. Among natural products the alkaloids, biologically active secondary metabolites, that can be found in plants, animals or microorganisms stand out. The alkaloids are compounds consisting of a basic nitrogen atom that may or may not be part of a heterocyclic ring. This review will describe 15 alkaloids with antiulcer activity in animal models and in vitro studies.
... Malted barley is used in the manufacture of beer, and beer consumption is known to be associated with an increase in appetite and gastric acid and pancreatic secretions. Gastric acid facilitates the digestion of complex nutrients as proteins and carbohydrates and also promotes the absorption of minerals and vitamins (Chu and Schubert, 2013). The secretogogue gastrin is one of a number of factors that increase gastric acid and pancreatic secretion. ...
N-methyltyramine (NMT) is a protoalkaloid isolated from various plant species. It is assumed that NMT is an adrenergic agonist with pharmacological properties similar to other structurally related biogenic amines. Current research studies indicate that NMT is an α-adrenoreceptor antagonist, and exhibits modest inhibitory (antagonistic) activity with respect to the breakdown of fats (lipolysis). Furthermore, NMT has been shown to enhance appetite and digestion of foods through its stimulatory effects on gastrin and pancreatic secretions. As a consequence, NMT is not an ingredient that should be used in dietary supplements designed to promote weight loss. It may result in an increase in perceived energy by promoting appetite and the digestion and absorption of nutrients while inhibiting the breakdown to fats to energy. Copyright © 2014 John Wiley & Sons, Ltd.
... In addition, one might speculate that via the neuroendocrine route, for instance, mediators (e.g. gastrin, somatostatin, cytokines, low proton concentration, among other factors) released in the stomach during H. pylori infection and induced immunopathology [32,33] exert their effect in the lower intestinal tract. Of note, patients suffering from H. pylori infection and hypochlorhydria occasionally complain about rather unspecific intestinal symptoms such as irregular bowel movements, flatulence or abdominal pain of otherwise unknown origin [34,35], which might be attributed to bacterial microbiota changes (e.g. ...
Background
Gastrointestinal (GI) inflammation in mice and men are frequently accompanied by distinct changes of the GI microbiota composition at sites of inflammation. Helicobacter (H.) pylori infection results in gastric immunopathology accompanied by colonization of stomachs with bacterial species, which are usually restricted to the lower intestine. Potential microbiota shifts distal to the inflammatory process following long-term H. pylori infection, however, have not been studied so far.
Methodology/Principal Findings
For the first time, we investigated microbiota changes along the entire GI tract of Mongolian gerbils after 14 months of infection with H. pylori B8 wildtype (WT) or its isogenic ΔcagY mutant (MUT) strain which is defective in the type IV secretion system and thus unable to modulate specific host pathways. Comprehensive cultural analyses revealed that severe gastric diseases such as atrophic pangastritis and precancerous transformations were accompanied by elevated luminal loads of E. coli and enterococci in the caecum and together with Bacteroides/Prevotella spp. in the colon of H. pylori WT, but not MUT infected gerbils as compared to naïve animals. Strikingly, molecular analyses revealed that Akkermansia, an uncultivable species involved in mucus degradation, was exclusively abundant in large intestines of H. pylori WT, but not MUT infected nor naïve gerbils.
Conclusion/Significance
Taken together, long-term infection of Mongolian gerbils with a H. pylori WT strain displaying an intact type IV secretion system leads to distinct shifts of the microbiota composition in the distal uninflamed, but not proximal inflamed GI tract. Hence, H. pylori induced immunopathogenesis of the stomach, including hypochlorhydria and hypergastrinemia, might trigger large intestinal microbiota changes whereas the exact underlying mechanisms need to be further unraveled.
Of all the organ systems in the body, the gastrointestinal tract is the most complicated in terms of numbers of the structures involved, each with different functions, and the numbers and types of signaling molecules utilized. The digestion of food and absorption of nutrients, electrolytes and waters occurs in a hostile luminal environment that contains a large and diverse microbiota. At the core of regulatory control of the digestive and defensive functions of the gastrointestinal tract is the enteric nervous system (ENS), a complex system of neurons and glia in the gut wall. In this review, we discuss (i) the intrinsic neural control of gut functions involved in digestion, and (ii) how the ENS interacts with the immune system, gut microbiota and epithelium to maintain mucosal defense and barrier function. We highlight developments that have revolutionized our understanding of the physiology and pathophysiology of enteric neural control. These include the molecular architecture of the ENS, the organization and function of enteric motor circuits, and the roles of enteric glia. We explore the transduction of luminal stimuli by enteroendocrine cells, the regulation of intestinal barrier function by enteric neurons and glia, local immune control by the ENS and the role of the gut microbiota in regulating the structure and function of the ENS. Multifunctional enteric neurons work together with enteric glial cells, macrophages, interstitial cells and enteroendocrine cells integrating an array of signals to initiate outputs that are precisely regulated in space and time to control digestion and intestinal homeostasis.
Most individual fish in wild and farmed populations can be infected with parasites. Fish intestines can harbour protozoans, myxozoans and helminths, which include several species of digeneans, cestodes, nematodes and acanthocephalans. Enteric parasites often induce inflammation of the intestine; the pathogen provokes changes in the host physiology, which will be genetically selected for if they benefit the parasite. The host response to intestinal parasites involves neural, endocrine and immune systems and interaction among these systems is coordinated by hormones, chemokines, cytokines and neurotransmitters including peptides. Intestinal fish parasites have effects on the components of the enteric nervous and endocrine systems; mechanical/chemical changes impair the activity of these systems, including gut motility and digestion. Investigations on the role of the neuroendocrine system in response to fish intestinal parasites are very few. This paper provides immunohistochemical and ultrastructural data on effects of parasites on the enteric nervous system and the enteric endocrine system in several fish–parasite systems. Emphasis is on the occurrence of 21 molecules including cholecystokinin-8, neuropeptide Y, enkephalins, galanin, vasoactive intestinal peptide and serotonin in infected tissues.
This chapter provides a description of the gastric environment. Gastric fluids consist of numerous components either secreted by the stomach (gastric acid, enzymes, electrolytes, mucus), swallowed/ingested (saliva, food, liquids), or refluxed from the duodenum in the stomach. Gastric content volume can be described as the resultant volume in the stomach of ingested material, swallowed saliva, gastric secretions, and the emptying of gastric content in the small intestine, whereas total gastric volume also takes into account parts of the stomach void of liquid or solid material. Gastric acidity is crucial for several of the stomach's functions. In fed state, buffer capacity of gastric content is expected to initially be similar to that of the ingested meal, given the typically high meal‐to‐gastric fluid ratio. The chapter also presents the composition of the small intestinal contents under fasting and fed conditions and the luminal environment in the proximal colon.
Background
Hypochlorhydria (gastric pH >4) increases susceptibility to diarrhoea, iron deficiency, and gastric cancer. We sought to clarify the prevalence of this condition and its predisposing factors in Zambia by pooling data from previous studies conducted in hospital and community settings.
Methods
Gastric pH was measured in participants from five separate studies by collecting gastric aspirate from fasted adults and children under 3 years of age undergoing gastroscopy. Gastric pH was correlated with serological testing for Human Immunodeficiency Virus (HIV) and Helicobacter pylori ( H . pylori ) infections.
Results
We studied 597 individuals (487 adults and 110 children). Hypochlorhydria was present in 53% of adults and 31% of children. HIV infection was detected in 41% of adults and 11% of children. H . pylori serology was available for 366 individuals: 93% of adults and 6% of children were seropositive. In univariate analysis, hypochlorhydria was significantly associated with HIV seropositivity (OR 1.7; 95% CI 1.2–2.4; p = 0.004) and H . pylori antibody seropositivity (OR 4.9; 95% CI 2.8–8.6; p<0.0001), and with advancing age in HIV negative individuals (p = 0.0001). In multivariable analysis, only H . pylori was associated with hypochlorhydria (OR 4.0; 95% CI 2.2–7.2; p<0.0001) while excluding possible exposure to proton pump inhibitors.
Conclusions
Hypochlorhydria is common in our population, with H . pylori being the dominant factor. Only young HIV seronegative individuals had a low prevalence of hypochlorhydria. This may have implications for the risk of other health conditions including gastric cancer.
Abstract Background Scarce is knowledge on the process regulating the development of acid secretion, orexigenic signaling, and chemosensing in the stomach of young pigs. Changes of early microbial encounters by suckling pigs can interact with the gut maturation, by the induction of different molecular signaling. Our goal was to assess if the age of offspring and the maternal environment, influenced by sow antibiotic treatment peripartum, could affect gastric morphology and the expression of genes involved in the control of hydrochloric secretion, feed intake, taste, and inflammation in offspring stomach. Methods 84 pigs from sows fed a diet with amoxicillin (on –d10 to +d21 from farrowing, ANT) or without (CON) were sacrificed at d14, d21, d28 (weaning) or d42. Samples of oxyntic (OXY), pyloric (PY) and cardiac mucosae close to OXY were collected and parietal and enteroendocrine cells (EECs) were counted. Relative gene expression of a set of 11 key genes (ATP4A, SSTR2, GAST, GHRL, MBOAT4, PCSK1, GNAT1, TAS1R1, TAS1R3, IL8 and TNF) was assessed by qRT-PCR. In addition, 40 offspring obtained from the same ANT and CON sows were offered a normal or a fat-enriched diet for 4 weeks between 140 and 169 d of age, and then OXY and PY were sampled. Results The number of parietal and EECs increased with age (P
The stomach has complex neuromuscular and secretory functions that initiate the digestive process. Gastric acid secretion is controlled by a series of substances, including gastrin, histamine, and acetylcholine, with a number of inhibitors, including somatostatin, cholecystokinin, and secretin.
On the basis of trophic behavior, fish are classified as herbivores, carnivores, omnivores, or detritivores. Epithelial mucous cells secrete mucin types specific to diet and digestive function. Mucus secretion is regulated mainly by molecular modulators produced by epithelial endocrine cells in response to luminal or tissue stimuli. These modulators are involved in control of food intake and digestive functions. Immunohistochemical and immunofluorescence studies were conducted on 10 adult northern pike (Esox lucius Linnaeus, 1758) from Lake Piediluco (Central Italy) to quantify distribution of sub-types of mucous and endocrine cells in alimentary mucosal epithelium. Neutral mucins predominated in the esophagus, and mixed and acidic mucins predominated in stomach and intestine. The gastric epithelium contained endocrine cells secreting somatostatin, tyrosine hydroxylase, and substance P. Mucous cells secreting neutral mucins increased in number from proximal to distal intestine, with endocrine cells containing substance P in the proximal intestine and those containing Leu-enkephalin throughout the intestine. Lectin histochemistry of gut sections revealed an abundance of N-acetyl-glucosamine and N-acetyl-galactosamine as carbohydrate residues on the mucin chain. The quantity and content of endocrine and mucous cells in the alimentary canal of E. lucius showed a direct relationship with its diet.
Fiber is an inadequately understood and insufficiently consumed nutrient. This review examines the possible causal relation between fiber-induced microbiome changes and the anti-inflammatory activity of fiber. To demonstrate the dominant role of fermentable plant fiber in shaping the intestinal microbiome, animal and human fiber-feeding studies are reviewed. Using culture-, PCR-, and sequencing-based microbial analyses, a higher prevalence of Bifidobacterium and Lactobacillus genera was observed from the feeding of different types of fermentable fiber. This finding was reported in studies performed on several host species including human. Health conditions and medications that are linked to intestinal microbial alterations likely also change the nutrient environment of the large intestine. The unique gene clusters of Bifidobacterium and Lactobacillus that enable the catabolism of plant glycans and the ability of Bifidobacterium and Lactobacillus to reduce the colonization of proteobacteria probably contribute to their prevalence in a fiber-rich intestinal environment. The fiber-induced microbiome changes could contribute to the anti-inflammatory activity of fiber. Although most studies did not measure fecal microbial density or total daily fecal microbial output (colon microbial load), limited evidence suggests that the increase in intestinal commensal microbial load plays an important role in the anti-inflammatory activity of fiber. Various probiotic supplements, including Bifidobacterium and Lactobacillus, showed anti-inflammatory activity only in the presence of fiber, which promoted microbial growth as indicated by increasing plasma short-chain fatty acids. Probiotics alone or pure fiber administered under sterile conditions showed no anti-inflammatory activity. The potential mechanisms that could mediate the anti-inflammatory effect of common microbial metabolites are reviewed, but more in vivo trials are needed. Future studies including simultaneous microbial composition and load measurements are also important.
Langdurige maagzuurremming met ppi’s kan zorgen voor een tekort aan vitamines en mineralen. Bijwerkingencentrum Lareb ontving onder meer meldingen van hypomagnesiëmie, ijzerdeficiëntie en tekort aan vitamine B12. Bijbehorende klachten treden in de regel sluipend op, wat het lastig maakt ze als bijwerking te herkennen.
Before being absorbed in the small intestine and/or colon, orally administered drugs inevitably need to pass through the stomach. Hence, it seems reasonable that the residence of a dosage form in the gastric environment, however brief it may be, may influence drug disposition further down the gastrointestinal tract and may potentially impact systemic exposure to a drug of interest. However, research efforts in the past mainly focused on drug disposition at the level of the intestine, i.e. the main site of absorption, hereby disregarding or oversimplifying the stomach's contribution to gastrointestinal drug disposition. In the first part of this review, the complexity of the stomach with regard to anatomy, physiology and gastric fluid composition is emphasized. Between-population differences in gastric functioning and physicochemical characteristics of gastric fluids are discussed. The second part of this review focuses on several of the processes to which a dosage form can be exposed during its passage through the stomach and the implications for gastrointestinal drug behaviour and systemic drug disposition. Finally, the influence of real-life dosing conditions on drug disposition is discussed in the context of the stomach.
Memora nodosa is popularly known as "caroba" and widely found in the Cerrado regions of Brazil. In traditional medicine, the leaves and stems are used for the healing of external ulcer and the roots for abdominal pain. This study investigated the effect of ethanolic roots extract of Memora nodosa (EMN) on the gastric mucosa of mice. In the indomethacin induced gastric ulcer model, the treatments of the animals with EMN at doses of 100, 300 and 1000 mg/kg, p.o., markedly reduced the index of lesions. In the gastric ulcer models induced by ethanol and cold restraint-stress the previous treatment with EMN at dose of 300 mg/kg showed 69% and 43% of protection, respectively. Seven days after food-restriction, the animals treated with EMN (300 mg/kg p.o.) showed reduction in the index of lesion by 65% as compared to control group. The intraduodenal administration of EMN (300 mg/kg) did not alter the gastric acid secretion parameters. The treatment with EMN (300 mg/kg p.o.) did not alter glutathione levels (GSH), but showed an increase of adhered gastric mucus as compared to the control group with lesion. These results showed that EMN has gastroprotective activity probably due with an increase of adhered gastric mucus.
Background:
To investigate the regularity and the influence factors of nasogastric decompression volume after esophagectomy, and explore whether the volume of nasogastric decompression can be employed as a predictor for postoperative complications of esophageal carcinoma.
Methods:
Consecutive 247 patients with esophageal cancer who underwent esophagectomy were retrospectively evaluated. The volume of postoperative nasogastric decompression was recorded and the regularity based on it was described. The single and multiple factors regression analysis were used to find out relative factors of the nasogastric decompression volume among the patients without postoperative complication. Gender, age, height, weight, tobacco or alcohol exposure, location of the tumor, histological type, pathological staging, operation time, surgical procedures, anastomotic position and gastric conduit reconstruction were considered as the independent variable. Then, verify the former regression models using the data of patients with postoperative complications.
Results:
In trend analysis, the curve estimation revealed a quadratic trend in the relationship between nasogastric decompression volume and postoperative days (R(2) =0.890, P=0.004). The volume of postoperative nasogastric decompression was described by daily drainage (mL) =82.215 + 69.620 × days - 6.604 × days(2). The results of multiple linear stepwise regression analysis showed that gastric conduit reconstruction (β=0.410, P=0.000), smoking (β=-0.231, P=0.000), age (β=-0.193, P=0.001) and histological type of the tumor (β=-0.169, P=0.006) were significantly related to the volume of nasogastric decompression. The average drainage in 5 days after surgery =262.287 + 132.873 × X1 - 72.160 × X2 - 27.904 × X3 - 36.368 × X4 (X1, gastric conduit reconstruction; X2, smoking; X3, histological type; X4, age). The nasogastric decompression of the patients with delayed gastric emptying, and lung infection statistically differ from their predictive values respectively according to the former equation (P<0.01), but the data of anastomotic leakage cases had no significance difference (P=0.344).
Conclusions:
It is found that the volume of postoperative nasogastric decompression presents a quadratic trend based on the days after esophagectomy. Gastric conduit reconstruction, smoking history, age and histological type were independent factors affecting on the volume of postoperative nasogastric decompression. Also, the volume of nasogastric decompression has validity and application value for predicting postoperative complications.
In recent years, much attention has been paid to the role of hormones and biogenic amines, contained in the gastric mucosa, in the regulation of gastric secretion. At the same time, monoamines ratio plays a significant role in changing the activity of gastric juice and impaired regulatory mechanisms of the stomach. These disorders are caused by various reasons, resulting in insufficient secretory function of the stomach. Unfortunately, there are not enough data on the significance of these factors in polyps' formation. This led us to conduct a comprehensive study of gastrointestinal hormones and biogenic amines in patients with gastric polyps of different locations, sizes and shapes. We believe that our study will come closer to understanding the mechanisms of polyps' formation and its cancerous transformation.
Our hypothesis was that carbohydrate, fat, and protein content of meals affect satiety, glucose homeostasis, and hormone secretion. The objectives of this crossover trial were to examine satiety, glycemic-insulinemic response, and plasma peptide levels in response to two different recommended diabetes diets with equivalent energy content. One traditional reference breakfast and one test breakfast, with lower carbohydrate and higher fat and protein content, were randomly administered to healthy volunteers (8 men, 12 women). Blood samples were collected, and satiety was scored on a visual analog scale (VAS) before and 3 h following meals. Plasma glucose was measured, and levels of C-peptide, ghrelin, glucagon, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), insulin, plasminogen activator inhibitor-1 (PAI-1), and adipokines were analyzed by Luminex. Greater satiety, VAS total and delta area under the curve (tAUC and dAUC) (P < .001), and lower glucose postprandial peak (max) and change from baseline (dmax) (P < .001), was observed following test meal compared with reference meal. Postprandial increments of C-peptide, insulin, and GIP were suppressed after test meal compared with reference meal [tAUC (P = .03, .006, and .004), dAUC (P = .006, .003, and .02), max (P = .01, .007, and .002), and dmax (P = .004, .008, and .007), respectively]. Concentrations of other peptides were similar between meals. A lower carbohydrate and higher fat and protein content provides greater satiety and attenuation of C-peptide, glucose, insulin, and GIP responses compared with the reference breakfast but does not affect adipokines, ghrelin, glucagon, GLP-1, and PAI-1.
Keywords:
adipokines, blood glucose, diet, gastrointestinal hormones, humans, satiety
Our stomach produces about 2L/day of gastric acid secretion/juice. Its high H+ ions (pH=1–2) kill most of the ingested germs; it catalyzes the conversion of inactive pepsinogen to pepsin. The presence of acid/pepsin begins the digestion of dietary protein. However, pancreatic proteases can hydrolyze all ingested protein in the absence of pepsin. An important component of gastric juice is intrinsic factor (IF), which binds vitamin B12 in the duodenum, allowing it to be eventually absorbed in the distal ileum (see B12 absorption of Chap. 9); it is the only indispensable substance of gastric juice. Its deficiency, following gastric surgery or in pernicious anemia, must take injections of B12 or oral B12 with IF. The surface epithelia cells of stomach secrete mucus and bicarbonate that protect the mucosa from acid/pepsin erosion.
Background/aims:
To evaluate the occurrence of gastroesophageal reflux and possible mechanisms in Helicobacter pylori infection.
Materials and methods:
Symptoms of H. pylori-infected children, their total gastroesophageal reflux episodes, acid exposure percentage, gastrin, ghrelin, and motilin levels were evaluated before and after H. pylori eradication.
Results:
Forty-two H. pylori-infected children were eligible for this study. Acid exposure % and total reflux episodes before and after H. pylori eradication were 10.2%±14.8% vs. 7.71%±5.0% and 94.7%±102.1% vs. 64.6%±55.0%, respectively (p=0.28, p=0.082). There was an insignificant change in the serum gastrin (93.4±153.8 pmol/L vs. 1.28±149.4 pmol/L, p=0.67), ghrelin (7.69±197.5 pg/mL vs. 8.36±299.5 pg/mL, p=0.274), and motilin (75.1±81.2 pg/mL vs. 97.2±80.5 pg/mL, p=0.206) levels after eradication. Gastrin and ghrelin levels were negatively correlated after H. pylori eradication (r=-0.38, p=0.031). There was no association between gastroesophageal reflux episodes and gastrin, ghrelin, and motilin levels (r=0.25 and p=0.11; r= 0.24 and p=0.13; r=-0.23 and p=0.14, respectively).
Conclusion:
H. pylori infection is neither protective nor harmful in the gastroesophageal reflux. Neither ghrelin nor motilin levels was associated with gastroesophageal reflux. None of gastrin, ghrelin, and motilin levels was affected by H. pylori infection. There is an inverse association between gastrin and ghrelin levels after H. pylori eradication.
Toll-like receptor 4 is a part of the innate immune system and recognizes Helicobacter pylori lipopolysaccharide. The goal of this study was to analyze the role of Toll-like receptor 4 polymorphisms +896 (rs4986790) and +1196 (rs4986791) in the pathogenesis of Helicobacter pylori related gastroduodenal diseases in relation to gastric secretion and inflammation. Toll-like receptor 4 polymorphisms, serum gastrin-17 and pepsinogen I and II concentrations were determined, and gastroscopies with histopathological analyses were performed to 216 dyspeptic patients. As genotype controls, 179 controls and 61 gastric cancer patients were studied. In our study, the Toll-like receptor 4 +896 and +1196 polymorphisms were in total linkage disequilibrium. The homozygous wild types displayed higher gastrin-17 serum concentrations than the mutants (p = 0.001) and this effect was independent of Helicobacter pylori. The homozygous wild types also displayed an increased risk for peptic ulcers (OR: 4.390). Toll-like receptor 4 genotypes did not show any association with Helicobacter pylori positivity or the features of gastric inflammation. Toll-like receptor 4 expression was seen in gastrin and somatostatin expressing cells of antral mucosa by immunohistochemistry. Our results suggest a role for Toll-like receptor 4 in gastric acid regulation and that the Toll-like receptor 4 +896 and +1196 wild type homozygozity increases peptic ulcer risk via gastrin secretion.
A new γ-class carbonic anhydrase (CA, EC 4.2.1.1) was cloned, purified and characterized from the Antarctic bacterium Pseudoalteromonas haloplanktis, PhaCAγ. The enzyme has a medium-low catalytic activity for the physiologic reaction of CO2 hydration to bicarbonate and protons, with a kcat of 1.4×10(5)s(-1) and a kcat/Km of 1.9×10(6)M(-1)s(-1). An anion inhibition study of PhaCAγ with inorganic anions and small molecule inhibitors is also reported. Many anions present in sea water, such as chloride, fluoride, sulfate, iodide, but also others such as azide, perchlorate and tetrafluoroborate did not inhibit this enzyme. Pseudohalides such as cyanate, thiocyanate, cyanide, selenocyanide, and also bicarbonate, nitrate, nitrite and many complex inorganic anions showed inhibition in the millimolar range (KI in the range of 1.7-9.3mM). The best PhaCAγ inhibitors detected in this study were diethyldithiocarbamate (KI of 0.96mM) as well as sulfamide, sulfamate, phenylboronic acid and phenylarsonic acid (KI in the range of 82-91μM). Since γ-CAs are poorly understood at this moment, being present in carboxysomes and thus involved in photosynthesis, this study may be relevant for a better understanding of these processes in Antarctic bacteria/cyanobacteria.
Copyright © 2015 Elsevier Ltd. All rights reserved.
The Celtis iguanaea (Jacq.) Sargent (Cannabaceae) is one of the native species of the Cerrado region of Brazil widely used in folk medicine to treat dyspepsia. The objective of the present study was to evaluate the gastroprotective effect of the Celtis iguanaea (Jacq.) Sargent (HE) hexane leaf extract in the lesion and gastric secretion models.Antiulcerogenic activity of the Celtis iguanaea (HE) hexane leaf extract was observed with the experimental models, such as indomethacin and pyloric ligation-induced gastric ulcers. In order to evaluate the antisecretory activity of this extract, isolated Rana catesbeiana mucosa and pyloric ligation in mice were used. The HE treatment reduced the lesion index of indomethacin and pyloric ligation-induced ulcer. This extract also reduced the gastric acid secretion and total acidity (increasing the gastric pH) in mice. The secretion of H+ was reduced in the basal values (15.58 ± 1.99 μEq H+/g/15 min) when isolated Rana catesbeiana mucosa was incubated with HE. Intraduodenal administration of HE reduced the gastric secretion produced by bethanecol or histamine. The antiulcerogenic and antisecretory efficacy of HE in this study suggest anticholinergic and antihistaminergic mechanism or interruption of intracellular events that are linked to acid secretion.
Helicobacter pylori (Hp) infection is known to alter levels of pepsinogens (PG) and is correlated with several disease states, including gastric and cardiovascular diseases. This study sought to assess whether Hp infection is associated with hypertension as well as to identify the value of assessing the PG I/PG II ratio in patients with hypertension. The study included 396 individuals with hypertension who were assessed for infection with Hp by colloidal gold assay. Participants' weight, height, blood pressure, and serum lipids were measured, and participants were examined for the presence of renal or ocular damage. H. pylori infection status or PG I/PG II ratio were compared against other variables (e.g., body mass index, serum cholesterol, diastolic blood pressure) by t-test or ⇨(2) test, and Pearson's correlation analysis was used to identify associations. Consistent with other studies, the PG I/PG II ratio of patients with Hp infection was significantly lower than that of patients without Hp infection (P < 0.001). The serum total cholesterol and triglycerides of patients with Hp infection were significantly higher than those of patients without Hp infection (P < 0.001), and the PG I/PG II ratio was negatively correlated with total cholesterol (r=-0.61) and triglycerides (r=-0.56) levels. However, there was no significant difference in hypertension severity by Hp infection status or PG I/PG II ratio. Interestingly, the PG I/PG II ratio was significantly lower in patients with hypertensive nephropathy or hypertensive retinopathy than in patients without these symptoms (P < 0.05). The areas under the receiver-operating characteristic curve were 0.77 and 0.83 in the diagnosis of nephropathy and retinopathy, respectively. These findings indicate that the PG I/PG II ratio is lower in individuals with hypertensive nephropathy and hypertensive retinopathy. Thus, the detection of the PG I/PG II ratio may be valuable for diagnostic screening for hypertensive organ damage.
To evaluate the efficacy and safety of the Xiaoyao pill for treatment of functional dyspepsia (FD) associated with perimenopausal depression.
This was a double-blind, randomized, controlled trial including 180 patients with FD accompanied by depression that were divided into two groups of 90. Patients in the treatment group received oral administration of the Xiaoyao pill for soothing the liver and activating the spleen, and patients in the control group received a placebo. This trial included an 8-wk therapy period with a follow-up period of 6 mo. The total efficacy and degree of depression, as assessed by the Hamilton Rating Scale for Depression (HRSD), were evaluated. Plasma levels of motilin and gastrin were measured and a gastric emptying test was conducted in each participant.
The Xiaoyao pill had a good therapeutic effect and improved the symptoms in patients with perimenopausal FD as assessed by the HRSD score, motilin and gastrin levels, and rate of gastric emptying. The total effective rate of the Xiaoyao pill in the treatment group was significantly superior to that of the placebo in the control group. In the control group, the initial HRSD score was 12.12 ± 2.29 and decreased to 7.14 ± 1.67 after therapy (P < 0.01). In the treatment group, the initial HRSD score was 11.44 ± 2.15, which significantly decreased to 6.20 ± 2.08 after therapy (P < 0.01). Moreover, the HRSD score in the treatment group was significantly lower than in control group after 8 wk (P < 0.01). Motilin and gastrin levels in both groups were significantly increased after the 8-wk therapy (P < 0.05). The gastric emptying rate was also improved in both groups after therapy (P < 0.05), and the improvement was significantly better in the treatment group compared to the controls (P < 0.05). These results confirm the therapeutic effects of the Xiaoyao pill in perimenopausal FD patients and indicate that it is worthy of clinical promotion.
The Xiaoyao pill is effective and safe for the treatment of perimenopausal women with FD associated with depression.
The stomach has distinct functions in relation to the ingestion and handling of solids and liquids. These functions include storage of the food before it is gradually emptied into the duodenum, mechanical crushing of larger food particles to increase the surface area, secretion of an acidic enzyme rich gastric juice and mixing the ingested food with the gastric juice. In addition, the stomach ‘senses’ the composition of the gastric content and this information is passed via the vagal nerve to the lateral hypothalamus and the limbic system, most likely as palatability signals that influence eating behaviour. Other sensory qualities related to the stimulation of gastric tension receptors are satiety and fullness. Receptors that respond to macronutrient content or gastric wall tension influence appetite and meal related hormone responses.
The stomach produces acid, which may play an important role in the regulation of bone homeostasis. The aim of this study was to reveal signalling pathways in gastric mucosa that involve the acid secretion and possibly the bone metabolism in CCK1 and/or CCK2 receptor knockout (KO) mice. Gastric acid secretion was impaired and the ECL cell signaling pathway was inhibited in CCK2 receptor KO mice but not in CCK1 receptor KO mice. However, in CCK1 + 2 receptor double KO mice the acid secretion in response to pylorus ligation-induced vagal stimulation as well as the ECL cell pathway were partially normalized, which was associated with an up-regulated pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor (PAC1). Basal part of gastric mucosa expressed parathyroid hormone-like hormone (PTHLH) in a subpopulation of likely ECL cells (and possibly other cells) and vitamin D3 1α hydroxylase probably in trefoil peptides2-immunoreactive cells. In conclusion, mice lacking CCK receptors exhibited a functional shift from the gastrin-CCK pathways to the neuronal pathway in control of the ECL cells and eventually the acid secretion. Taken the present data together with previous findings, we suggest a possible link between gastric PTHLH and vitamin D might the regulation of bone metabolism.
Background/objectives:
The gastric endocrine cells in patients with irritable bowel syndrome (IBS) tend to normalize following dietary guidance. The aim of the present study was to identify the gastric endocrine cell types that are changed following such dietary guidance.
Subjects/methods:
Fourteen IBS patients and 14 healthy subjects were included in the study. Patients received three sessions of individual dietary management guidance. Gastroscopy was performed on both the controls and the patients at baseline and then again for the patients at 3-9 months after dietary guidance. Biopsy samples from the corpus and antrum were immunostained for all gastric endocrine cell types. Endocrine cells were quantified by computerized image analysis.
Results:
The densities of the ghrelin cells for the controls and IBS patients before and after dietary guidance were 149.6 ± 36.2 (mean ± s.e.m.; 95% confidence interval (CI) 71.3-227.8), 114.5 ± 32.7 and 161.8 ± 37.8 cells/mm(2), respectively. The densities of the gastrin cells in these groups were 155.8 ± 21.0 (95% CI 110.3-201.2), 159.4 ± 24.3 and 211.6 ± 28.0 cells/mm(2), respectively; the corresponding densities of serotonin cells in the corpus were 18.2 ± 3.9 (95% CI 9.8-26.6), 10.6 ± 3.4 and 14 ± 2.0 cells/mm(2) and in the antrum were 44.6 ± 12.2 (95% CI 18.1-71.1), 1.7 ± 0.5 and 14.7 ± 6.3 cells/mm(2). The densities of the somatostatin cells in the corpus were 40.0 ± 7.7 (95% CI 23.5-56.5), 23.0 ± 3.0 and 37.3 ± 4.2 cells/mm(2), respectively, and in the antrum were 138.9 ± 22.0 (95% CI 91.4-186.3), 95.6 ± 15.9 and 86.0 ± 16.9 cells/mm(2), respectively.
Conclusions:
The densities of all of the gastric endocrine cell types changed towards the healthy control values in the IBS patients following a change in food intake.
AimsWe have observed glandular downgrowth in some gastric neuroendocrine tumors (NETs), in which nonneoplastic appearing gastric glands are admixed with submucosal neuroendocrine nests, that could potentially be confused with composite tumors.Methods and ResultsWe reviewed 68 gastric NETs with at least submucosal invasion, and evaluated associations between glandular downgrowth, clinical parameters (age, gender, NET setting) and tumor characteristics (size, depth of invasion, grade). Controls included 45 duodenal NETs. Glandular downgrowth was present in 28 (41%) gastric NETs but only 2 (4.4%) duodenal NETs (P < 0.0001). It was not related to age, gender, hypergastrinemia (downgrowth present in 43% of NETs arising in autoimmune gastritis, 41% of Zollinger-Ellison syndrome, 36% of sporadic NETs), tumor size, depth of invasion, or grade. Glandular downgrowth was confined to the submucosa even though 12 (18%) gastric NETs invaded muscularis propria. Submucosal gastric glands (pyloric type in 79%, intestinal in 50%, fundic in 29%) showed metaplastic changes similar to overlying mucosa, were usually mitotically inactive (64% of cases lacked mitotic figures), were geographically restricted to the NET, and never metastasized.Conclusions
Our findings support the frequent occurrence and nonneoplastic nature of glandular downgrowth in gastric NETs, which should not be mistaken for composite tumors.This article is protected by copyright. All rights reserved.
Histamine is a potent biogenic amine that mediates numerous physiological processes throughout the body, including digestion, sleep, and immunity. It is synthesized by gastric enterochromaffin-like cells, a specific set of hypothalamic neurons, as well as a subset of white blood cells, including mast cells. Much remains to be learned about these varied histamine-producing cell populations. Here, we report the validation of a transgenic mouse line in which Cre recombinase expression has been targeted to cells expressing histidine decarboxylase (HDC), which catalyzes the rate-limiting step in the synthesis of histamine. This was achieved by crossing the HDC-Cre mouse line with Rosa26-tdTomato reporter mice, thus resulting in the expression of the fluorescent Tomato (Tmt) signal in cells containing Cre recombinase activity. As expected, the Tmt signal co-localized with HDC-immunoreactivity within the gastric mucosa and gastric submucosa and also within the tuberomamillary nucleus of the brain. HDC expression within Tmt-positive gastric cells was further confirmed by quantitative PCR analysis of mRNA isolated from highly purified populations of Tmt-positive cells obtained by fluorescent activated cell sorting (FACS). HDC expression within these FACS-separated cells was found to coincide with other markers of both ECL cells and mast cells. Gastrin expression was co-localized with HDC expression in a subset of histaminergic gastric mucosal cells. We suggest that these transgenic mice will facilitate future studies aimed at investigating the function of histamine-producing cells.
AimTo administer repeated oral doses of netazepide to healthy subjects for the first time, to assess safety, tolerability, pharmacokinetics and effect on 24h gastric pH and plasma gastrin. Method
We did two randomized, double-blind, parallel group studies. The first compared netazepide 25 and 100mg 12hourly, omeprazole 20mg once daily and placebo for 7 days. On day 7 only, we measured pH and assayed plasma gastrin. The second study compared netazepide 5, 10 and 25mg and placebo once daily for 14 days. We measured pH on days 1, 7 and 14 and assayed plasma gastrin on days 1 and 14. We compared treatments by time gastric pH 4 during 0-4, 4-9, 9-13 and 13-24h after the morning dose, and by plasma gastrin. P < 0.05 was significant. ResultsNetazepide was well tolerated. On day 7 of the first study, netazepide increased pH significantly only during 9-13h after the 100mg dose, whereas omeprazole raised pH significantly during all periods. Both netazepide and omeprazole increased plasma gastrin significantly. Netazepide had linear pharmacokinetics. In the second study, netazepide caused dose-dependent, sustained increases in pH on day 1, but as in the first study, netazepide had little effect on pH on days 7 and 14. Again, netazepide increased plasma gastrin significantly. Conclusion
Although repeated doses of netazepide led to tolerance to its effect on pH, the accompanying increase in plasma gastrin is consistent with continued inhibition of acid secretion, via gastrin receptor antagonism and gene up-regulation.
The peptide hormone gastrin is an important factor for the maintenance and homeostasis of the gastric mucosa. We show that gastrin stimulates proliferation in a dose-dependent manner in the human gastric adenocarcinoma cell line AGS-G(R). Furthermore, we demonstrate that the MAPK scaffold protein MEK partner 1 (MP1) is important for gastrin-induced phosphorylation of ERK1 and ERK2 and that MP1 promotes gastrin-induced proliferation of AGS-G(R) cells. Our results suggest a role of MP1 in gastrin-induced cellular responses involved in proliferation and homeostasis of the gastric mucosa.
Gastrin is the main hormone responsible for the stimulation of gastric acid secretion; in addition, gastrin and its derivatives exert proliferative and antiapoptotic effects on several cell types. Gastrin synthesis and secretion are increased in certain situations, for example, when proton pump inhibitors are used. The impact of sustained hypergastrinemia is currently being investigated. In vitro experiments and animal models have shown that prolonged hypergastrinemia may be related with higher cancer rates; although, this relationship is less clear in human beings. Higher gastrin levels have been shown to cause hyperplasia of several cell types; yet, the risk for developing cancer seems to be the same in normo- and hypergastrinemic patients. Some tumors also produce their own gastrin, which can act in an autocrine manner promoting tumor growth. Certain cancers are extremely dependent on gastrin to proliferate. Initial research focused only on the effects of amidated gastrins, but there has been an interest in intermediates of gastrin in the last few decades. These intermediates aren't biologically inactive; in fact, they may exert greater effects on proliferation and apoptosis than the completely processed forms. In certain gastrin overproduction states, they are the most abundant gastrin peptides secreted. The purpose of this review is to examine the gastrin biosynthesis process and to summarize the results from different studies evaluating the production, levels, and effects of the main forms of gastrin in different overexpression states and their possible relationship with Barrett's and colorectal carcinogenesis.
Gastric acid secretion by the H(+)/K(+) ATPase at the apical surface of activated parietal cells requires luminal K(+) provided by the KCNQ1/KCNE2 K(+) channel. However, little is known about the trafficking and relative spatial distribution of KCNQ1 and H(+)/K(+) ATPase in resting and activated parietal cells and the capacity of KCNQ1 to control acid secretion. Here we show that inhibition of KCNQ1 activity quickly curtailed gastric acid secretion in vivo even when the H(+)/K(+) ATPase is permanently anchored in the apical membrane, demonstrating a key role of the K(+) channel in controlling acid secretion. 3D imaging analysis of isolated mouse gastric units revealed that the majority of KCNQ1 resides in an intracytoplasmic, Rab11-positive, compartment in resting parietal cells, distinct from H(+)/K(+) ATPase-enriched tubulovesicles. Upon activation, there was a significant redistribution of H(+)/K(+) ATPase and KCNQ1 from intracytoplasmic compartments to the apical secretory canaliculi. Significantly, high FRET was detected between H(+)/K(+) ATPase and KCNQ1 in activated but not resting parietal cells. These findings demonstrate that H(+)/K(+) ATPase and KCNQ1 reside in independent intracytoplasmic membrane compartments, or membrane domains, and upon activation of parietal cells both membrane proteins are transported, possibly via Rab11-positive recycling endosomes, to apical membranes where the two molecules are closely physically opposed. In addition, these studies indicate that acid secretion is regulated by independent trafficking of KCNQ1 and H(+)/K(+) ATPase.
The H+,K+-ATPase pumps protons or hydronium ions and is responsible for the acidification of the gastric fluid. It is made up of an a-catalytic- and a b-glycosylated subunit. The relation between cation translocation and the organization of the protein in the membrane are not well understood. We describe here how pure and functionally active pig gastric H+,K+-ATPase with an apparent Stokes radius of 6.3 nm can be obtained after solubilization with the non-ionic detergent C12E8, followed by exchange of C12E8 with Tween 20 on a Superose 6 column. Mass spectroscopy indicates the b-subunit bears an excess mass of 9 Da attributable to glycosylation. From chemical analysis, there are 0.25 g phospholipids and around 0.024 g cholesterol bound per g protein. Analytical ultracentrifugation shows one main complex, sedimenting at s20w = 7.2 +/- 0.1 S, together with minor amounts of irreversibly aggregated material. From these data a buoyant molecular mass is calculated, corresponding to an H+,K+-ATPase a,b-protomer of 147.3 kDa. Complementary sedimentation velocity with deuterated water gives a picture of an a,b-protomer with 0.9-1.4 g/g bound detergent and lipids and a reasonable frictional ratio of 1.5 corresponding to Rs= 7.1 nm. An a2,b2 dimer is rejected by the data. Light scattering coupled to gel filtration confirms the monomeric state of solubilized H+,K+-ATPase. Thus, a,b H+,K+-ATPase is active at least in detergent, and may plausibly function as a monomer, as has been established for other P-type ATPases, Ca2+-ATPase and Na+,K+-ATPase.
To compare ghrelin levels in plasma and gastric mucosa before and after Helicobacter pylori (H. pylori) treatment in children with H. pylori-associated functional dyspepsia.
Children with H. pylori-associated functional dyspepsia were enrolled in this study. H. pylori infection was confirmed by positive bacterial culture results. All of the children received triple H. pylori eradication therapy (a 2 wk course of omeprazole, amoxicillin, and clarithromycin). The children were divided into two groups based on the success of the H. pylori treatment: group 1 (eradicated) - patients who had a negative 13C-urea breath test 2 mo after the end of therapy; and group 2 (non-eradicated) - patients who had a positive 13C-urea breath test. Plasma ghrelin, gastric ghrelin mRNA, and the body mass index were evaluated in both groups before and after the H. pylori treatment. The plasma ghrelin levels were measured by a radioimmunoassay. The expression of gastric ghrelin mRNA was determined by real-time reverse transcription polymerase chain reaction.
A total of 50 children with H. pylori-associated functional dyspepsia were treated with triple H. pylori eradication therapy. The mean age of the children was 5.52 ± 0.83 years, and there were 28 males and 22 females. Among the 50 H. pylori-positive children, 30 successfully achieved eradication, and 20 did not. The mean plasma ghrelin levels of group 1 were 22.17 ± 1.73 ng/L and 26.59 ± 2.05 ng/L before and after the treatment, respectively, which was a significant increase (P = 0.001). However, the mean plasma ghrelin level of group 2 before and after the H. pylori treatment was 21.34 ± 2.40 ng/L and 22.24 ± 2.10 ng/L (P = 0.785). The plasma ghrelin levels increased substantially after treatment in group 1 but showed only minor changes in group 2. Similarly, the gastric ghrelin mRNA expression in group 1 before treatment was 2.84 ± 0.08. After treatment, the level was 3.11 ± 0.65, which was significantly different (P = 0.023). The gastric ghrelin mRNA expression in group 2 did not change significantly during the treatment (2.82 ± 0.44 vs 2.79 ± 0.31, P = 0.875). The plasma ghrelin and gastric ghrelin mRNA levels in group 1 increased substantially after the treatment but did not do so in group 2. In addition, the body mass index the two groups did not differ significantly 2 mo before and after the H. pylori treatment.
H. pylori eradication increases the plasma and tissue ghrelin levels in children with H. pylori-associated functional dyspepsia.
The incidence of duodenal ulcer, especially H.pylori-negative duodenal ulcer, strongly increases with age. In humans, telomere length shortening is considered to be one critical factor in cellular senescens and organ survival. In this study, we compared basal and stimulated gastric acid and duodenal HCO(3)- secretory rates in aged late generation (G3) telomerase-deficient (mTERC-/-) mice, which are characterized by severe telomere dysfunction due to the inability to elongate telomeres during cell division. We found that basal and forskolin-stimulated HCO(3)- secretion and short circuit current (I(sc)) in isolated duodenal mucosa of G3 mTERC-/- mice were markedly reduced, compared with age-matched wild-type mice. In contrast, basal and forskolin-stimulated acid secretory rates in isolated G3 mTERC-/- gastric mucosa were not significantly altered. Correspondingly, duodenal mucosa of G3 mTERC-/- mice showed slimming and shortening of villi, whereas gastric mucosal histology was not significantly altered. But the ratios of CFTR and Slc26a6 mRNA expression in relation to cytokeratin 18 were not altered in duodenal mucosa. The further knockout of p21, which is a downstream effector of telomere shortening-induced senescence, rescued villus atrophy of duodenal mucosa, and basal and forskolin-stimulated duodenal HCO(3)- secretion and I(sc) in mTERC-/- p21-/- double knockout mice were not different from wild-type controls. In conclusion, genetic ablation of telomerase resulted in p21-dependent duodenal mucosal atrophy and reduced duodenal HCO(3)- secretory capacity, while gastric morphology and acid secretory function were preserved. This suggests that telomere shortening during aging may result in an imbalance between aggressive and protective secretions against duodenal mucosa and thus predispose to ulcer formation.
Proton-pump inhibitors (PPIs) remain the leading evidence-based therapy for upper gastrointestinal disorders, including gastroesophageal reflux disease, dyspepsia, and peptic ulcer disease. The effectiveness of PPIs has led to overutilization in multiple treatment arenas, exposing patients to an increasing number of potential risks. The overutilization of PPIs in ambulatory care settings is often a result of failure to re-evaluate the need for continuation of therapy, or insufficient use of on-demand and step-down therapy. PPI overutilization in the inpatient setting is often a result of inappropriate stress ulcer prophylaxis (SUP) in nonintensive care unit patients, and failure to discontinue SUP prior to hospital discharge. Potential consequences of prolonged PPI therapy include hypergastrinemia, enterochromaffin-like cell hyperplasia, and parietal cell hypertrophy, leading to rebound acid hypersecretion. PPIs have been linked via retrospective studies to increased risk of enteric infections including Clostridium difficile-associated diarrhea, community-acquired pneumonia, bone fracture, nutritional deficiencies, and interference with metabolism of antiplatelet agents. Reducing inappropriate prescribing of PPIs in the inpatient and outpatient settings can minimize potential for adverse events, and foster controllable cost expenditure.
Context:
Chromogranin A (CgA) is used as a generic tumor marker for neuroendocrine tumors. Proton pump inhibitors (PPI) are known to increase CgA, but it is not clear to what extent, and there is little information on how long PPI need to be discontinued before the effect of PPI has disappeared. Furthermore, is it not known whether this PPI effect is dependent on the CgA assay used.
Objective:
The aim of the study was to determine the effect of 7-d treatment with a PPI and its discontinuation on CgA in serum and plasma comparing four CgA assays.
Design and participants:
Seventeen healthy subjects took lansoprazole 30 mg at bedtime for 7 d, and blood samples for CgA were obtained at baseline, d 7 of PPI use, and 1, 2, 4, and 7 d after discontinuation of the PPI. In all samples, CgA was measured using the following assays: Alpco (serum and plasma), Cis-Bio (serum and plasma), DAKO, and Cis-Bio radioisotope assay.
Results:
When using the same assay, CgA was higher in plasma than in serum. Treatment with a PPI for 1 wk resulted in a significant (about 2.5-fold) increase in CgA with significant interindividual variation. After discontinuation of PPI, serum CgA gradually declined, with a half-life of 4-5 d.
Conclusion:
Short-term PPI use results in a significant increase of CgA in serum and plasma, an effect that is largely independent of the assay used. PPI need to be discontinued for 2 wk to fully eliminate their effect on CgA. This effect of PPI needs to be considered when interpreting results of CgA measurements.
Lentiviral vectors (LVs) are powerful tools for transgene expression in vivo and in vitro. However, the construction of LVs is of low efficiency, due to the large sizes and lack of proper clone sites. Therefore, it is critical to develop efficient strategies for cloning LVs. Here, we reported a combinatorial strategy to efficiently construct LVs using EGFP, hPlk2 wild type (WT) and mutant genes as inserts. Firstly, site-directed mutagenesis (SDM) was performed to create BamH I site for the inserts; secondly, pWPI LV was dephosphorylated after BamH I digestion; finally, the amounts and ratios of the insert and vector DNA were optimized to increase monomeric ligation. Our results showed that the total percentage of positive clones was approximately 48%±7.6%. Using this method, almost all the vectors could be constructed through two or three minipreps. Therefore, our study provided an efficient method for constructing large-size vectors.
Gastric acid secretion is regulated by three primary components that activate the parietal cell: histamine, gastrin, and acetylcholine (ACh). Although much is known about these regulatory components individually, little is known on the interplay of these multiple activators and the degree of regulation they pose on the gastric acid secretion mechanism. We utilized a novel dual-sensing approach, where an iridium oxide sensor was used to monitor pH and a boron-doped diamond electrode was used for the detection of histamine from in vitro guinea pig stomach mucosal sections. Under basal conditions, gastrin was shown to be the main regulatory component of the total acid secretion and directly activated the parietal cell rather than by mediating gastric acid secretion through the release of histamine from the enterochromaffin-like cell, although both pathways were active. Under stimulated conditions with ACh, the gastrin and histamine components of the total acid secretion were not altered compared with levels observed under basal conditions, suggestive that ACh had no direct effect on the enterochromaffin-like cell and G cell. These data identify a new unique approach to investigate the regulation pathways active during acid secretion and the degree that they are utilized to drive total gastric acid secretion. The findings of this study will enhance our understanding on how these signaling mechanisms vary under pathophysiology or therapeutic management.
Gastrin and its precursors have been shown to promote mitogenesis and angiogenesis in gastrointestinal tumors. Hypoxia stimulates tumor growth, but its effect on gastrin gene regulation has not been examined in detail. Here we have investigated the effect of hypoxia on the transcription of the gastrin gene in human gastric cancer (AGS) cells. Gastrin mRNA was measured by real-time PCR, gastrin peptides were measured by RIA, and gastrin promoter activity was measured by dual-luciferase reporter assay. Exposure to a low oxygen concentration (1%) increased gastrin mRNA concentrations in wild-type AGS cells (AGS) and in AGS cells overexpressing the gastrin receptor (AGS-cholecystokinin receptor 2) by 2.1 ± 0.4- and 4.1 ± 0.3-fold (P < 0.05), respectively. The hypoxia mimetic, cobalt chloride (300 μM), increased gastrin promoter activity in AGS cells by 2.4 ± 0.3-fold (P < 0.05), and in AGS-cholecystokinin receptor 2 cells by 4.0 ± 0.3-fold (P < 0.05), respectively. The observations that either deletion from the gastrin promoter of the putative binding sites for the transcription factor hypoxia-inducible factor 1 (HIF-1) or knockdown of either the HIF-1α or HIF-1β subunit did not affect gastrin promoter inducibility under hypoxia indicated that the hypoxic activation of the gastrin gene is likely HIF independent. Mutational analysis of previously identified Sp1 regulatory elements in the gastrin promoter also failed to abrogate the induction of promoter activity by hypoxia. The observations that hypoxia up-regulates the gastrin gene in AGS cells by HIF-independent mechanisms, and that this effect is enhanced by the presence of gastrin receptors, provide potential targets for gastrointestinal cancer therapy.
While protein is regarded as the most satiating macronutrient, many studies have employed test meals that had very high and unsustainable protein contents. Furthermore, the comparative responses between lean and obese subjects and the relationships between energy intake suppression and gut hormone release remain unclear. We evaluated the acute effects of meals with modest variations in 1) fat, protein, and carbohydrate content and 2) protein load on gastrointestinal hormones, appetite, and subsequent energy intake in lean and obese subjects. Sixteen lean and sixteen obese men were studied on four occasions. Following a standardized breakfast, they received for lunch: 1) high-fat (HF), 2) high-protein (HP), 3) high-carbohydrate/low-protein (HC/LP), or 4) adequate-protein (AP) isocaloric test meals. Hunger, fullness, and gut hormones were measured throughout, and at t = 180 min energy intake at a buffet meal was quantified. In lean subjects, hunger was less and fullness greater following HF, HP, and AP compared with HC/LP meals, and energy intake was less following HF and HP compared with HC meals (P < 0.05). In the obese subjects, hunger was less following HP compared with HF, HC/LP, and AP meals, and energy intake was less following HP and AP compared with HF and HC meals (P < 0.05). There were no major differences in hormone responses to the meals among subject groups, but the CCK and ghrelin responses to HP and AP were sustained in both groups. In conclusion, HP meals suppress energy intake in lean and obese subjects, an effect potentially mediated by CCK and ghrelin, while obese individuals appear to be less sensitive to the satiating effects of fat.
Background:
Since reports on endocrine cells and their kinetics in the corpus of the human stomach are limited, the aim of this study was to examine the appearance, localization, density, and the relationship among the endocrine cell types in the corpus of the human stomach during prenatal and early postnatal development.
Methods:
We examined chromogranin A, somatostatin, ghrelin, glucagon, and serotonin expression by immunohistochemistry in 2 embryos, 38 fetuses, and 3 infants in the corpus of human stomach.
Results:
Chromogranin A secreting endocrine cells were identified in the corpus at week 10 of gestation. Somatostatin cells were present from the 10th week, ghrelin and serotonin cells from the 11th week, and glucagon cells from the 12th week of gestation. Endocrine cells were present individually or clustered within the glandular base and body during the first trimester, and were present separately within the basal and central parts of glands during the second and third trimesters. Somatostatin cells were the most common type of cells (~46 %) during the first trimester, while ghrelin cells were the most numerous during the second trimester (~34 %), and in infants (~28 %). The percentage of glucagon cells was significant only during the first trimester of pregnancy (5.5 %), and the percentage of serotonin cells was only significant just before birth (4.8 %).
Conclusions:
These results show, for the first time, that the largest number of endocrine cells are present in the corpus during the first trimester of prenatal development. Also, these results suggest that secretory products of endocrine cells play a role in the regulation of homeostasis, growth, and differentiation, and in human stomach function.
Whereas electrogenic partial reactions of the Na,K-ATPase have been studied in depth, much less is known about the influence of the membrane potential on the electroneutrally operating gastric H,K-ATPase. In this work, we investigated site-specifically fluorescence-labeled H,K-ATPase expressed in Xenopus oocytes by voltage clamp fluorometry to monitor the voltage-dependent distribution between E(1)P and E(2)P states and measured Rb(+) uptake under various ionic and pH conditions. The steady-state E(1)P/E(2)P distribution, as indicated by the voltage-dependent fluorescence amplitudes and the Rb(+) uptake activity were highly sensitive to small changes in intracellular pH, whereas even large extracellular pH changes affected neither the E(1)P/E(2)P distribution nor transport activity. Notably, intracellular acidification by approximately 0.5 pH units shifted V(0.5), the voltage, at which the E(1)P/E(2)P ratio is 50∶50, by -100 mV. This was paralleled by an approximately two-fold acceleration of the forward rate constant of the E(1)P→E(2)P transition and a similar increase in the rate of steady-state cation transport. The temperature dependence of Rb(+) uptake yielded an activation energy of ∼90 kJ/mol, suggesting that ion transport is rate-limited by a major conformational transition. The pronounced sensitivity towards intracellular pH suggests that proton uptake from the cytoplasmic side controls the level of phosphoenzyme entering the E(1)P→E(2)P conformational transition, thus limiting ion transport of the gastric H,K-ATPase. These findings highlight the significance of cellular mechanisms contributing to increased proton availability in the cytoplasm of gastric parietal cells. Furthermore, we show that extracellular Na(+) profoundly alters the voltage-dependent E(1)P/E(2)P distribution indicating that Na(+) ions can act as surrogates for protons regarding the E(2)P→E(1)P transition. The complexity of the intra- and extracellular cation effects can be rationalized by a kinetic model suggesting that cations reach the binding sites through a rather high-field intra- and a rather low-field extracellular access channel, with fractional electrical distances of ∼0.5 and ∼0.2, respectively.
The peptide hormone ghrelin is released from a distinct group of gastrointestinal cells in response to caloric restriction, whereas its levels fall after eating. The mechanisms by which ghrelin secretion is regulated remain largely unknown. Here, we have used primary cultures of mouse gastric mucosal cells to investigate ghrelin secretion, with an emphasis on the role of glucose. Ghrelin secretion from these cells upon exposure to different d-glucose concentrations, the glucose antimetabolite 2-deoxy-d-glucose, and other potential secretagogues was assessed. The expression profile of proteins involved in glucose transport, metabolism, and utilization within highly enriched pools of mouse ghrelin cells and within cultured ghrelinoma cells was also determined. Ghrelin release negatively correlated with d-glucose concentration. Insulin blocked ghrelin release, but only in a low d-glucose environment. 2-Deoxy-d-glucose prevented the inhibitory effect of high d-glucose exposure on ghrelin release. mRNAs encoding several facilitative glucose transporters, hexokinases, the ATP-sensitive potassium channel subunit Kir6.2, and sulfonylurea type 1 receptor were expressed highly within ghrelin cells, although neither tolbutamide nor diazoxide exerted direct effects on ghrelin secretion. These findings suggest that direct exposure of ghrelin cells to low ambient d-glucose stimulates ghrelin release, whereas high d-glucose and glucose metabolism within ghrelin cells block ghrelin release. Also, low d-glucose sensitizes ghrelin cells to insulin. Various glucose transporters, channels, and enzymes that mediate glucose responsiveness in other cell types may contribute to the ghrelin cell machinery involved in regulating ghrelin secretion under these different glucose environments, although their exact roles in ghrelin release remain uncertain.
Chromogranin A (CgA) is a member of the granins, a family of acidic proteins found in abundance in (neuro)endocrine cells (e.g., in chromaffin cells) and in some tumors. Like other granins, CgA has a granulogenic role in secretory granule biogenesis and is stored in these organelles. CgA is partially processed differentially in various cell types to yield biologically active peptides, such as vasostatin, pancreastatin, catestatin, and serpinins. In this review, we describe the roles of CgA and several of its derived peptides. CgA, which is elevated in the blood of cancer patients, inhibits angiogenesis and exerts protective effects on the endothelial barrier function in tumors, thus affecting response to chemotherapy. Recent studies indicate that the serpinins promote cell survival and myocardial contractility and relaxation. Other peptides such as pancreastatin were found to have significant effects on inhibition of glucose-stimulated insulin secretion and glucose up-take, induction of glycogenolysis in hepatocytes, and inhibition of lipogenesis. In contrast, catestatin has opposite effects to that of pancreastatin in glucose metabolism and lipogenesis. Catestatin appears to also play a significant role in cardiac function, blood pressure regulation, and mutations in the catestatin domain of the CgA gene are associated with hypertension in humans.
Acute myeloid leukemia (AML) cells home to the endosteal region of the bone marrow. They interact with bone marrow stromal components including extracellular matrix proteins, glycosaminoglycans, and stromal cells, by which they derive proliferative and growth inhibitory signals. Furthermore, adhesion to marrow stroma confers chemotherapy drug resistance and thereby promotes leukemia survival. A subpopulation of the leukemic blasts, known as leukemia stem cells, that are capable of propagating the leukemia, remain sheltered in the bone marrow microenvironment, exhibit resistance to chemotherapy, and serve as the origin of relapse after a variable period of remission. Detachment of these cells from the bone marrow in combination with chemotherapy may improve the outcome of therapy for AML.
Calcitonin gene-related peptide (CGRP) is a neuropeptide with multiple neuroendocrine roles, including vasodilation, migraine, and pain. The receptor for CGRP is a G protein-coupled receptor (GPCR) that requires three proteins for function. CGRP binds to a heterodimer composed of the GPCR calcitonin-like receptor (CLR) and receptor activity-modifying protein (RAMP1), a single transmembrane protein required for pharmacological specificity and trafficking of the CLR/RAMP1 complex to the cell surface. In addition, the CLR/RAMP1 complex requires a third protein named CGRP-receptor component protein (RCP) for signaling. Previous studies have demonstrated that depletion of RCP from cells inhibits CLR signaling, and in vivo studies have demonstrated that expression of RCP correlates with CLR signaling and CGRP efficacy. It is not known whether RCP interacts directly with CLR to exert its effect. The current studies identified a direct interaction between RCP and an intracellular domain of CLR using yeast two-hybrid analysis and coimmunoprecipitation. When this interacting domain of CLR was expressed as a soluble fusion protein, it coimmunoprecipitated with RCP and inhibited signaling from endogenous CLR. Expression of this dominant-negative domain of CLR did not significantly inhibit trafficking of CLR to the cell surface, and thus RCP may not have a chaperone function for CLR. Instead, RCP may regulate CLR signaling in the cell membrane, and direct interaction between RCP and CLR is required for CLR activation. To date, RCP has been found to interact only with CLR and represents a novel neuroendocrine regulatory step in GPCR signaling.
Atrophic gastritis (AG) results most often from Helicobacter pylori (H. pylori) infection. AG is the most important single risk condition for gastric cancer that often leads to an acid-free or hypochlorhydric stomach. In the present paper, we suggest a rationale for noninvasive screening of AG with stomach-specific biomarkers.
The paper summarizes a set of data on application of the biomarkers and describes how the test results could be interpreted in practice.
In AG of the gastric corpus and fundus, the plasma levels of pepsinogen I and/or the pepsinogen I/pepsinogen II ratio are always low. The fasting level of gastrin-17 is high in AG limited to the corpus and fundus, but low or non-elevated if the AG occurs in both antrum and corpus. A low fasting level of G-17 is a sign of antral AG or indicates high intragastric acidity. Differentiation between antral AG and high intragastric acidity can be done by assaying the plasma G-17 before and after protein stimulation, or before and after administration of the proton pump inhibitors (PPI). Amidated G-17 will rise if the antral mucosa is normal in structure. H. pylori antibodies are a reliable indicator of helicobacter infection, even in patients with AG and hypochlorhydria.
Stomach-specific biomarkers provide information about the stomach health and about the function of stomach mucosa and are a noninvasive tool for diagnosis and screening of AG and acid-free stomach.
IL-is important in gastric damage, mucosal repair and gastric cancer progression. We analysed IL-11 expression in H.pylori infected mouse stomach, the site of gastric IL-11 expression in mice and humans, and the effect of exogenous IL-11 on gastric mucosal homeostasis.
IL-11 protein was localised in mouse and human stomach. The impact of chronic, exogenous IL-11 on normal mouse stomach was examined histologically and transcriptionally by microarray, confirmed by mRNA and protein analysis. Functional impact of IL-11 on gastric acid secretion was determined.
In mice infected with H.pylori, IL-11 was increased in fundic mucosa with temporal expression similar to IL-1b. IL-11 protein was localised predominantly to parietal cells in mouse and human stomach. Application of exogenous IL-11 to resulted in fundic parietal and chief cell loss, hyperplasia, mucous cell metaplasia and inflammation. Coincident with cellular changes were an increased gastric pH, altered parietal cell ultrastructure and altered gene expression, particularly genes involved in immune response and ion transport which could result in compromised acid secretion. We confirmed that a single dose of IL-11 effectively ablated the gastric response to histamine.
IL-11 is a parietal cell cytokine that blocks gastric acid secretion, likely via reducing expression of parietal cell ion transport genes, CCKb and histamine H2 receptors. IL-11 expression is increased in H. pylori infected mouse stomach and treatment of wild type mice with IL-11 induced changes in the gastric fundic mucosa reminiscent of chronic atrophic gastritis, a precursor to gastric cancer.
The vacuolar-type H-ATPase (V-ATPase) plays an important role in the active acidification of intracellular organelles. In certain specialized cells, such as the renal intercalated cell, apical V-ATPase can also function as a proton secretion pathway. In the parietal cells of the stomach, it has been thought that acid secretion is controlled solely via the H,K-ATPase. However, recent observations suggest that functional V-ATPase is necessary for acid secretion to take place. This study aimed to investigate and characterize the role of V-ATPase in parietal cell proton transport. Individual rat gastric glands were incubated with the pH-sensitive dye (BCECF) to monitor changes in intracellular pH in real time. Parietal cell V-ATPase activity was measured by quantifying the rate of intracellular alkalinization (ΔpH/minute) following an acid load, while excluding the contribution of non-V-ATPase proton transport mechanisms through pharmacological inhibition or ion substitution. Expression of V-ATPase was confirmed by immunohistochemistry. We observed concanamycin A-sensitive V-ATPase activity in rat parietal cells following intracellular acidification and H,K-ATPase inhibition. Furthermore, V-ATPase-mediated proton transport could be abolished by inhibiting trafficking mechanisms with paclitaxel and by stimulating H,K-ATPase with acid secretagogues. Our results propose that parietal cells contain a functional V-ATPase that can be mobilized using a microtubule network. V-ATPase may function as an auxiliary acid secretion or proton-buffering pathway in parietal cells, which is inactive during H,K-ATPase activity. Our findings may have important implications for patients experiencing acid breakthrough under proton pump inhibitor therapy.
Background
Sustained acid inhibition with PPI stimulates gastrin secretion, exerting a proliferative drive on enterochromaffin-like cells (ECL cells) of the oxyntic mucosa. It may also accelerate development of gastric gland atrophy in Helicobacter pylori-infected individuals. AimsTo evaluate gastric exocrine and endocrine cell changes in GERD patients randomised to laparoscopic antireflux surgery (LARS, n = 288) or long-term (5 years) esomeprazole (ESO) treatment (n = 266). Methods
Antral and corpus biopsies were taken at endoscopy and serum gastrin and chromogranin A levels were assayed, at baseline and after 1, 3 and 5 years’ therapy. ResultsBiopsies were available at each time point for 158 LARS patients and 180 ESO patients. In H. pylori-infected subjects, antral mucosal inflammation and activity improved significantly (P < 0.001) and stabilised after 3 years on esomeprazole while no change in inflammation was observed after LARS. Oxyntic mucosal inflammation and activity remained stable on esomeprazole but decreased slightly over time after LARS. Neither intestinal metaplasia nor atrophy developed in the oxyntic mucosa. ECL cell density increased significantly after ESO (P < 0.001), corresponding with an increase in circulating gastrin and chromogranin A. After LARS, there was a significant decrease in ECL cell density (P < 0.05), accompanied by a marginal decrease in gastrin and chromogranin. Conclusions
Antral gastritis improved in H. pylori-infected GERD patients after 5 years on esomeprazole, with little change in laparoscopic antireflux surgery patients, who acted as a control. Despite a continued proliferative drive on enterochromaffin-like cells during esomeprazole treatment, no dysplastic or neoplastic lesions were found and no safety concerns were raised. NCT 00251927.
Background:
Scant data exist on the normal range of serum gastrin in infants. In phase I and III trials of rabeprazole in gastroesophageal reflux disease, we studied serum gastrin levels in infants 1 to 11 months old, and assessed normal ranges and the effect of acid-suppressive drugs.
Methods:
Overall, 349 treatment-naïve or treatment-experienced (previously exposed to proton pump inhibitors and/or H2-receptor antagonists) infants with gastroesophageal reflux disease were screened for baseline serum gastrin. Repeat gastrin was monitored at early termination or end of study, allowing assessment of 1 to 8 week daily rabeprazole (5- or 10-mg) treatment on gastrin levels.
Results:
Median (5%-95% range) baseline gastrin was 118 ng/L (39-315) in the treatment-naïve group (n = 251), driven mostly by high levels (121.5 [48-326] ng/L) in the 1- to <4-month-old subgroup. Treatment-experienced infants (n = 98) had elevated baseline gastrin levels (152 [48-487] ng/L; P = 0.0011) with no clear difference between previously proton pump inhibitor-exposed and H2-receptor antagonist-exposed groups. At the end of study, mean (standard deviation) levels were unchanged from baseline in infants withdrawn from rabeprazole to placebo (124 [94] ng/L), but elevated from baseline in those continuing treatment with 5-mg (245 [151] ng/L) and 10-mg (332 [222] ng/L) rabeprazole during the study.
Conclusions:
Gastrin levels in treatment-naïve infants were elevated through 8 months of age. Between 8 and 12 months of age, they declined so that the median level was within the upper limit of the normal adult range (<100 ng/L). Previous exposure to acid-suppressive medications and short-term exposure to rabeprazole significantly increased gastrin levels in infants younger than 1 year.
The classifications of neuroendocrine proliferations that lead from enterochromaffin-like cell hyperplasia to neuroendocrine tumors in the stomach are complicated and relatively inaccessible to nonspecialists. Consequently, these lesions tend to remain widely underdiagnosed until they progress to easily recognizable neuroendocrine tumors. This review provides simple, yet rigorous guidelines on how to recognize, classify, and diagnose the neuroendocrine proliferations found in the stomach, emphasizing the most common background in which they arise, atrophic gastritis. After a succinct outline of the types and distribution of the neuroendocrine cells in the normal gastric mucosa we discuss the most common situations in which the pathologist needs to think about gastric neuroendocrine cells. In general practice gastric biopsy specimens are often numerically and topographically inadequate for the evaluation of atrophic gastritis; therefore, we have included an algorithm to address specifically the steps that should be taken when confronted with suboptimal sampling. Finally, we illustrate the suggested diagnostic process with 4 cases that are fairly representative of the type of situations encountered in everyday practice. The pathologist who follows our simple steps will be better aware of this neglected area of gastric pathology and will learn to suspect, recognize, and accurately diagnose the most common abnormalities of the neuroendocrine system in the stomach.
Background & aims:
Rabs are monomeric guanosine triphosphatases that regulate membrane trafficking and acid secretion in gastric parietal cells. Using a proteomics approach, we identified a new Rab, Rab27b, in tubulovesicle membranes and determined its role in parietal cell activation.
Methods:
We used mass spectrometry (MS) to identify Rab27b in purified tubulovesicular membrane fractions and used immunoblot and immunofluorescence analyses to study its expression. Wild-type, constitutively active (Rab27bQ78L), and dominant negative (Rab27bN133I) forms of Rab27b were tagged with yellow fluorescent protein (YFP) and expressed in parietal cells using adenoviral constructs to study localization and function. Localization was visualized by fluorescence microscopy in resting and stimulated cells. Acid secretion in primary cell cultures was measured by aminopyrine accumulation.
Results:
A tandem MS peptide mass fingerprint was matched to 7 peptides of Rab27b. Rab27b localized to tubulovesicle membranes, based on immunoblot and immunocytochemical analyses. Endogenous Rab27b, YFP/wild-type Rab27b, Rab27bQ78L, and Rab27bN133I all distributed throughout the cytoplasm of resting parietal cells. After stimulation, wild-type Rab27b and YFP-Rab27bQ78L translocated to the apical membrane, but YFPR-ab27bN133I did not. Expression of wild-type YFP-Rab27b or YFP-Rab27bQ78L did not affect acid secretion, whereas expression of Rab27bN133I almost completely inhibited acid secretion.
Conclusions:
Rab27b is associated with tubulovesicle membranes in the parietal cell and Rab27b may play a role in stimulation-associated membrane recruitment and gastric acid secretion.
Acute H. pylori infection produces hypochlorhydria. The decrease in acid facilitates survival of the bacterium and its colonization of the stomach. The present study was designed to identify the pathways in oxyntic mucosa by which acute H. pylori infection inhibits acid secretion. In rat fundic sheets in Ussing chamber, perfusion of the luminal surface with H. pylori in spent broth (10(3)-10(8) cfu/ml) or spent broth alone (1:10(5) - 1:10(0) final dilution) caused a concentration-dependent increase in somatostatin (SST; maximal: 200±20% and 194±9% above basal; P<0.001) and decrease in histamine secretion (maximal: 45±5% and 48±2% below basal; P<0.001); the latter was abolished by SST antibody, implying that changes in histamine secretion reflected changes in SST secretion. Both responses were abolished by the axonal blocker tetrodotoxin (TTX), the sensory neurotoxin capsaicin, or the CGRP antagonist CGRP8-37, implying that the reciprocal changes in SST and histamine secretion were due to release of CGRP from sensory neurons. In isolated rabbit oxyntic glands, H. pylori inhibited basal and histamine-stimulated acid secretion in a concentration-dependent manner; the responses were not affected by TTX or SST antibody, implying that H. pylori can directly inhibit parietal cell function. In conclusion, acute administration of H. pylori is capable of inhibiting acid secretion directly as well as indirectly by activating intramural CGRP sensory neurons coupled to stimulation of SST and inhibition of histamine secretion. Activation of neural pathways provides one explanation as to how initial patchy colonization of the superficial gastric mucosa by H. pylori can acutely inhibit acid secretion.