Helicobacter pylori infection and hypochlorhydria in Zambian adults and children: A secondary data analysis.

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.

Gastric microbiota composition in patients with corpus atrophic gastritis.

BACKGROUND: In corpus atrophic gastritis (CAG), hypochlorhydria makes plausible the overgrowth of intragastric bacteria, whose role in gastric carcinogenesis is under debate. AIMS: To characterize the antrum/corpus composition of the gastric bacterial microbiota in CAG patients compared to controls without CAG. METHODS: A cross-sectional monocentric study on consecutive patients with known histological diagnosis of CAG undergoing gastroscopy for gastric cancer surveillance and patients without CAG undergoing gastroscopy for dyspepsia or anemia (108 biopsies from 55 patients, median age 61.5). Genomic DNA from one antral and one corpus biopsy from each case (n = 23) and control (n = 32) was extracted. Gastric microbiota was assessed by sequencing hypervariable regions of the 16SrRNA gene. RESULTS: Bacterial abundance and diversity were significantly lower in CAG cases than in controls (p < 0.001). Firmicutes were more frequent in cases, Bacteroidetes and Fusobacteria in controls (p < 0.0001). Streptococcaceae were more abundant in cases (p < 0.0001), Prevotellaceae in controls (p < 0.0001). The genus Streptococcus was positively correlated with severe OLGA/OLGIM stages linked to a higher risk of gastric cancer. CONCLUSION: Gastric bacterial microbiota in CAG showed a reduced abundance and complexity but was characterized by higher colonization of Firmicutes, in particular Streptococcus, increased in subjects with severe atrophy/metaplasia stages at higher risk of gastric cancer.

Proton pump inhibitors and dysbiosis: Current knowledge and aspects to be clarified.

Proton pump inhibitors (PPIs) are common medications within the practice of gastroenterology. These drugs, which act through the irreversible inhibition of the hydrogen/potassium pump (H+/K+-ATPase pump) in the gastric parietal cells, are used in the treatment of several acid-related disorders. PPIs are generally well tolerated but, through the long-term reduction of gastric acid secretion, can increase the risk of an imbalance in gut microbiota composition (i.e., dysbiosis). The gut microbiota is a complex ecosystem in which microbes coexist and interact with the human host. Indeed, the resident gut bacteria are needed for multiple vital functions, such as nutrient and drug metabolism, the production of energy, defense against pathogens, the modulation of the immune system and support of the integrity of the gut mucosal barrier. The bacteria are collected in communities that vary in density and composition within each segment of the gastrointestinal (GI) tract. Therefore, every change in the gut ecosystem has been connected to an increased susceptibility or exacerbation of various GI disorders. The aim of this review is to summarize the recently available data on PPI-related microbiota alterations in each segment of the GI tract and to analyze the possible involvement of PPIs in the pathogenesis of several specific GI diseases.

Comparison of the human gastric microbiota in hypochlorhydric states arising as a result of Helicobacter pylori-induced atrophic gastritis, autoimmune atrophic gastritis and proton pump inhibitor use.

Several conditions associated with reduced gastric acid secretion confer an altered risk of developing a gastric malignancy. Helicobacter pylori-induced atrophic gastritis predisposes to gastric adenocarcinoma, autoimmune atrophic gastritis is a precursor of type I gastric neuroendocrine tumours, whereas proton pump inhibitor (PPI) use does not affect stomach cancer risk. We hypothesised that each of these conditions was associated with specific alterations in the gastric microbiota and that this influenced subsequent tumour risk. 95 patients (in groups representing normal stomach, PPI treated, H. pylori gastritis, H. pylori-induced atrophic gastritis and autoimmune atrophic gastritis) were selected from a cohort of 1400. RNA extracted from gastric corpus biopsies was analysed using 16S rRNA sequencing (MiSeq). Samples from normal stomachs and patients treated with PPIs demonstrated similarly high microbial diversity. Patients with autoimmune atrophic gastritis also exhibited relatively high microbial diversity, but with samples dominated by Streptococcus. H. pylori colonisation was associated with decreased microbial diversity and reduced complexity of co-occurrence networks. H. pylori-induced atrophic gastritis resulted in lower bacterial abundances and diversity, whereas autoimmune atrophic gastritis resulted in greater bacterial abundance and equally high diversity compared to normal stomachs. Pathway analysis suggested that glucose-6-phospahte1-dehydrogenase and D-lactate dehydrogenase were over represented in H. pylori-induced atrophic gastritis versus autoimmune atrophic gastritis, and that both these groups showed increases in fumarate reductase. Autoimmune and H. pylori-induced atrophic gastritis were associated with different gastric microbial profiles. PPI treated patients showed relatively few alterations in the gastric microbiota compared to healthy subjects.

Hunger and microbiology: is a low gastric acid-induced bacterial overgrowth in the small intestine a contributor to malnutrition in developing countries?

Underproduction of hydrochloric acid into the stomach is frequently encountered in subjects from developing countries. We explore the hypothesis that hypochlorhydria compromises the gastric barrier and favours bacterial overgrowth in the proximal parts of the small intestine where nutrient absorption takes place. Food calories are thus deviated into bacterial metabolism. In addition to an adequate caloric supply, correcting hypochlorhydria might be needed to decrease childhood malnutrition.

Genetic Evolution of a Helicobacter pylori Acid-Sensing Histidine Kinase and Gastric Disease.

Helicobacter pylori is the strongest risk factor for gastric adenocarcinoma, which develops within a hypochlorhydric environment. We sequentially isolated H. pylori (strain J99) from a patient who developed corpus-predominant gastritis and hypochlorhydia over a 6-year interval. Archival J99 survived significantly better under acidic conditions than recent J99 strains. H. pylori arsRS encodes a 2-component system critical for stress responses; recent J99 isolates harbored 2 nonsynonymous arsS mutations, and arsS inactivation abolished acid survival. In vivo, acid-resistant archival, but not recent J99, successfully colonized high-acid-secreting rodents. Thus, genetic evolution of arsS may influence progression to hypochlorhydia and gastric cancer.

Expression of Tlr2, Defa, Muc2 genes in rat duodenal upon long-term gastric hypacidity and with multiprobiotic correction.

Expression of Tlr2, Muc2, Defa genes in rat duodenal upon long-term gastric hypacidity (hypochlorhydria) and with multiprobiotic correction was investigated. Increasing of Tlr2, Muc2, Defa expression on the background of the intensification of lipid peroxidation in rat duodenal villus and crypt epithelial cells upon gastric hypoacidity was shown. The mRNAs patterns of genes mentioned above were shown to decrease or approach to control values as well as the level of lipid peroxidation products under the treatment of hypoacidic rats with the multiprobiotic. The data obtained may indicate involvement of genes Tlr2, Muc2, Defa in development of inflammation in the duodenum due to dysbiotic changes under conditions of prolonged hypochlorhydria.

Helicobacter pylori induced gastric immunopathology is associated with distinct microbiota changes in the large intestines of long-term infected Mongolian gerbils.

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.

Helicobacter pylori-induced posttranscriptional regulation of H-K-ATPase α-subunit gene expression by miRNA.

Acute Helicobacter pylori infection of gastric epithelial cells induces CagA oncoprotein- and peptidoglycan (SLT)-dependent mobilization of NF-κB p50 homodimers that bind to H-K-ATPase α-subunit (HKα) promoter and repress HKα gene transcription. This process may facilitate gastric H. pylori colonization by induction of transient hypochlorhydria. We hypothesized that H. pylori also regulates HKα expression posttranscriptionally by miRNA interaction with HKα mRNA. In silico analysis of the HKα 3' untranslated region (UTR) identified miR-1289 as a highly conserved putative HKα-regulatory miRNA. H. pylori infection of AGS cells transfected with HKα 3' UTR-Luc reporter construct repressed luciferase activity by 70%, whereas ΔcagA or Δslt H. pylori infections partially abrogated repression. Transfection of AGS cells expressing HKα 3' UTR-Luc construct with an oligoribonucleotide mimetic of miR-1289 induced maximal repression (54%) of UTR activity within 30 min; UTR activity was unchanged by nontargeting siRNA transfection. Gastric biopsies from patients infected with cagA(+) H. pylori showed a significant increase in miR-1289 expression compared with uninfected patients or those infected with cagA(-) H. pylori. Finally, miR-1289 expression was necessary and sufficient to attenuate biopsy HKα protein expression in the absence of infection. Taken together, these data indicate that miR-1289 is upregulated by H. pylori in a CagA- and SLT-dependent manner and targets HKα 3' UTR, affecting HKα mRNA translation. The sensitivity of HKα mRNA 3' UTR to binding of miR-1289 identifies a novel regulatory mechanism of gastric acid secretion and offers new insights into mechanisms underlying transient H. pylori-induced hypochlorhydria.

The role of the gastrointestinal microbiome in Helicobacter pylori pathogenesis.

The discovery of Helicobacter pylori overturned the conventional dogma that the stomach was a sterile organ and that pH values<4 were capable of sterilizing the stomach. H. pylori are an etiological agent associated with gastritis, hypochlorhydria, duodenal ulcers, and gastric cancer. It is now appreciated that the human stomach supports a bacterial community with possibly 100s of bacterial species that influence stomach homeostasis. Other bacteria colonizing the stomach may also influence H. pylori-associated gastric pathogenesis by creating reactive oxygen and nitrogen species and modulating inflammatory responses. In this review, we summarize the available literature concerning the gastric microbiota in humans, mice, and Mongolian gerbils. We also discuss the gastric perturbations, many involving H. pylori, that facilitate the colonization by bacteria from other compartments of the gastrointestinal tract, and identify risk factors known to affect gastric homeostasis that contribute to changes in the microbiota.

H. pylori acutely inhibits gastric secretion by activating CGRP sensory neurons coupled to stimulation of somatostatin and inhibition of histamine secretion.

Acute Helicobacter 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 an 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) to 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.

Helicobacter pylori-associated hypochlorhydria in children, and development of iron deficiency.

AIMS: Acute Helicobacter pylori infection is associated with transient hypochlorhydria. In H pylori-associated atrophy, hypochlorhydria has a role in iron deficiency (ID) through changes in the physiology of iron-complex absorption. The aims were to evaluate the association between H pylori-associated hypochlorhydria and ID in children. METHODS: Symptomatic children (n=123) were prospectively enrolled. Blood, gastric juice and gastric biopsies were taken, respectively, for haematological analyses, pH assessment and H pylori determination, and duodenal biopsies for exclusion of coeliac disease. Stool samples were collected for parasitology/microbiology. Thirteen children were excluded following parasitology and duodenal histopathology, and five due to impaired blood analysis. RESULTS: Ten children were hypochlorhydric (pH>4) and 33 were H pylori positive. In H pylori-positive children with pH>4 (n=6) serum iron and transferrin saturation levels % were significantly lower (p<0.01) than H pylori-positive children with pH≤4. No differences in ferritin, or total iron binding capacity, were observed. In H pylori-negative children with pH>4, iron and transferrin saturation were not significantly different from children with pH≤4. CONCLUSIONS: Low serum iron and transferrin in childhood H pylori infection is associated with hypochlorhydria. In uninfected children, hypochlorhydria was not associated with altered serum iron parameters, indicating a combination of H pylori infection and/or inflammation, and hypochlorhydria has a role in the aetiology of ID. Although H pylori-associated hypochlorhydria is transient during acute gastritis, this alters iron homeostasis with clinical impact in developing countries with a high H pylori prevalence.

How Helicobacter pylori infection controls gastric acid secretion.

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

Role of Helicobacter pylori in refractory iron deficiency anaemia.

The role of Helicobacter pylori infection in the development of iron deficiency anaemia has been the focus of attention over the past decade. However, confirmation of a relationship has not confirmed the pathophysiological mechanisms involved in the phenomenon. The aim of the present work is to study the levels of fasting gastric acidity (free and total) as well as the level of tumour necrosis factor-alpha (TNF alpha) in male refractory iron deficiency anaemia patients seropositive for H. pylori infection versus those who are seronegative. Thirty adult patients with iron deficiency anaemia and gastroduodenitis were subdivided into two groups of matched age and haemoglobin value. Group 1 was H. pylori-seropositive for infection and these patients did not receive prior treatment for eradication of H. pylori infection. Group 2 comprised patients seronegative for H. pylori infection (control group). Patients with active bleeding or previous medical problems were excluded from the study. All patients and controls were subjected to the following at presentation: history taking and thorough clinical examination, complete blood picture, reticulocytes (%), assessment of serum iron, total iron binding capacity, serum ferritin, IgG anti-Helicobacter antibody and TNF alpha, stool for occult blood and measurement of gastric acidity (total and free). Upper endoscopy was performed and multiple biopsies were taken and tested for expression of cytotoxin-associated gene A (cagA) by the polymerase chain reaction (PCR). Results showed significantly higher values of free and total gastric acidity as well as TNF alpha levels in Group 1 compared to controls (Group 2). Among those in Group 1, higher TNF alpha levels were seen in seven H. pylori cagA-positive patients than in eight cagA-negative patients. Haemoglobin values were inversely correlated with TNF alpha levels. Thus, elevated serum TNF alpha in the H. pylori-seropositive group may be one of the underlying pathophysiological mechanism for iron deficiency anaemia observed in these patients.

Helicobacter pylori cag-Pathogenicity island-dependent early immunological response triggers later precancerous gastric changes in Mongolian gerbils.

Infection with Helicobacter pylori, carrying a functional cag type IV secretion system (cag-T4SS) to inject the Cytotoxin associated antigen (CagA) into gastric cells, is associated with an increased risk for severe gastric diseases in humans. Here we studied the pathomechanism of H. pylori and the role of the cag-pathogenicity island (cag-PAI) for the induction of gastric ulcer and precancerous conditions over time (2-64 weeks) using the Mongolian gerbil model. Animals were challenged with H. pylori B128 (WT), or an isogenic B128DeltacagY mutant-strain that produces CagA, but is unable to translocate it into gastric cells. H. pylori colonization density was quantified in antrum and corpus mucosa separately. Paraffin sections were graded for inflammation and histological changes verified by immunohistochemistry. Physiological and inflammatory markers were quantitated by RIA and RT-PCR, respectively. An early cag-T4SS-dependent inflammation of the corpus mucosa (4-8 weeks) occurred only in WT-infected animals, resulting in a severe active and chronic gastritis with a significant increase of proinflammatory cytokines, mucous gland metaplasia, and atrophy of the parietal cells. At late time points only WT-infected animals developed hypochlorhydria and hypergastrinemia in parallel to gastric ulcers, gastritis cystica profunda, and focal dysplasia. The early cag-PAI-dependent immunological response triggers later physiological and histopathological alterations towards gastric malignancies.

Helicobacter pylori VacA disrupts apical membrane-cytoskeletal interactions in gastric parietal cells.

Helicobacter pylori persistently colonize the human stomach and have been linked to atrophic gastritis and gastric carcinoma. Although it is well known that H. pylori infection can result in hypochlorhydria, the molecular mechanisms underlying this phenomenon remain poorly understood. Here we show that VacA permeabilizes the apical membrane of gastric parietal cells and induces hypochlorhydria. The functional consequences of VacA infection on parietal cell physiology were studied using freshly isolated rabbit gastric glands and cultured parietal cells. Secretory activity of parietal cells was judged by an aminopyrine uptake assay and confocal microscopic examination. VacA permeabilization induces an influx of extracellular calcium, followed by activation of calpain and subsequent proteolysis of ezrin at Met(469)-Thr(470), which results in the liberation of ezrin from the apical membrane of the parietal cells. VacA treatment inhibits acid secretion by preventing the recruitment of H,K-ATPase-containing tubulovesicles to the apical membrane of gastric parietal cells. Electron microscopic examination revealed that VacA treatment disrupts the radial arrangement of actin filaments in apical microvilli due to the loss of ezrin integrity in parietal cells. Significantly, expression of calpain-resistant ezrin restored the functional activity of parietal cells in the presence of VacA. Proteolysis of ezrin in VacA-infected parietal cells is a novel mechanism underlying H. pylori-induced inhibition of acid secretion. Our results indicate that VacA disrupts the apical membrane-cytoskeletal interactions in gastric parietal cells and thereby causes hypochlorhydria.

A functional polymorphism of toll-like receptor 4 gene increases risk of gastric carcinoma and its precursors.

BACKGROUND AND AIMS: TLR4 is a cell-surface signaling receptor involved in the recognition and host response to Helicobacter pylori. The TLR4+896A>G polymorphism linked with impaired reactivity to bacterial lipopolysaccharide may play a role in gastric carcinogenesis. METHODS: We assessed associations with premalignant gastric changes in 149 relatives of gastric cancer patients, including 45 with hypochlorhydria and gastric atrophy. We also genotyped 2 independent Caucasian population-based case-control studies of upper gastrointestinal tract cancer, initially in 312 noncardia gastric carcinoma cases and 419 controls and then in 184 noncardia gastric carcinomas, 123 cardia carcinomas, 159 esophageal cancers, and 211 frequency-matched controls. Odds ratios were computed from logistic models and adjusted for potential confounding factors. RESULTS: TLR4+896G carriers had an 11-fold (95% confidence interval [CI], 2.5-48) increased odds ratio (OR) for hypochlorhydria; the polymorphism was unassociated with gastric acid output in the absence of H pylori infection. Carriers also had significantly more severe gastric atrophy and inflammation. Seventeen percent of gastric carcinoma patients in the initial study and 15% of the noncardia gastric carcinoma patients in the replication study had 1 or 2 TLR4 variant alleles vs 8% of both control populations (combined OR = 2.3; 95% CI = 1.6-3.4). In contrast, prevalence of TLR4+896G was not significantly increased in esophageal squamous cell (2%, OR = 0.2) or adenocarcinoma (9%, OR = 1.4) or gastric cardia carcinoma (11%, OR = 1.4). CONCLUSIONS: Our data suggest that the TLR4+896A>G polymorphism is a risk factor for noncardia gastric carcinoma and its precursors. The findings underscore the role of the host innate immune response in outcome of H pylori infection.

Lessons from the gastrin knockout mice.

The gastrointestinal hormone, gastrin, was discovered a century ago as the second hormone in history. Subsequently, gastrin peptides have been identified and the genes encoding the hormone as well as its receptor have been cloned in several mammalian species including the mouse. This has facilitated the development of gastrin and gastrin receptor deficient mice as models for genetic dissection of the role of gastrins in maintaining gastric homeostasis and control of acid secretion. The gastrin knockout mice are achlorhydric due to inactivation of the ECL and parietal cells. Moreover, this achlorhydria is associated with the development of intestinal metaplasia and bacterial overgrowth, which ultimately lead to development of gastric tumors. Outside the stomach, gastrin deficiency alters pancreatic islet physiology and is associated with a moderate fasting hypoglycemia in the fasting state. But lack of gastrin does not impair islet regeneration. The association between progastrin, progastrin-derived processing intermediates and colorectal carcinogenesis has also been examined through genetic or chemical cancer induction in several mouse models, although the clinical relevance of these studies still remains to be proven. While others have focused on models of increased gastrin production, the present review will describe the lessons learned from the gastrin deficient mice. These mice help understand how dysregulation of gastrin secretion may be implicated in human disease.

Achlorhydria is associated with gastric microbial overgrowth and development of cancer: lessons learned from the gastrin knockout mouse.

Gastrin and gastrin receptor-deficient mice have been used for genetic dissection of the role of gastrins in maintaining gastric homeostasis and control of acid secretion. The gastrin knockout mice are achlorhydric due to inactivation of the ECL and parietal cells. Moreover, this achlorhydria is associated with intestinal metaplasia and bacterial overgrowth, which ultimately leads to the development of gastric tumours. The association between progastrin, progastrin-derived processing intermediates and colorectal carcinogenesis has also been examined through genetic or chemical cancer induction in several mouse models, although the clinical relevance of these studies remains unproven. While others have focused on models of increased gastrin production, the present review describes the lessons learned from gastrin-deficient mice. Study of these mice helps our understanding of how dysregulation of gastrin secretion may be implicated in human disease.