RESUMEN
In recent years, the role of gastric and duodenal microbiota has acquired increasing importance in the homeostasis of the host, although, to date, most evidence concern the faecal microbiota. Indeed, the gastric, and duodenal microbiota are challenging to study, due to gastric acid, bile, digestive enzymes, and rapid transit time. Specifically, the gastric acid environment may influence their bacterial composition since the acid barrier protects against orally ingested microorganisms and leads to their inactivation before reaching the intestine. The aim of this study was to assess a correlation between intragastric pH and gastric as well as intestinal microbiota of patients with histologic gastric alterations. pH was measured in the gastric juice and the bacterial composition in gastric and duodenal biopsies and faecal samples, was investigated via 16s rRNA gene sequencing. The main result is the direct correlation of duodenal microbiota biodiversity, via alpha diversity measures, with intragastric pH values. In particular, patients with hypochlorhydria showed increased duodenal microbiota biodiversity, higher intragastric pH values being prevalent in patients with chronic atrophic gastritis. Lastly, the latter was also strongly associated to the presence of oral bacteria, like Rothia mucilaginosa, Streptococcus salivarius and Granulicatella adiacens, in the duodenal microbiota. In conclusions, our results suggest a low-acid gastric environment as a contributive factor for duodenal dysbiosis, potentially leading to the development of pathological conditions of the gastrointestinal tract.
Asunto(s)
Aclorhidria , Infecciones por Helicobacter , Helicobacter pylori , Aclorhidria/patología , Disbiosis/microbiología , Mucosa Gástrica/microbiología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/genética , Humanos , ARN Ribosómico 16S/genéticaRESUMEN
A 69-year-old woman with multiple neuroendocrine neoplasms (NENs) was referred to our hospital. Although she had extreme hypergastrinemia (11,675 pg/mL), no findings that indicated types I to III gastric NENs were found. Although gastric corpus atrophy was suspected on conventional white-light imaging, findings on magnifying endoscopy with narrow-band imaging indicated no severe atrophy. A biopsy from the background fundic gland mucosa revealed no atrophic changes, parietal cells with vacuolated cytoplasm and negative findings for H+K+-ATPase. Thus, this case was diagnosed as multiple NENs with parietal cell dysfunction. Neither progression nor metastasis has been confirmed during two-year follow-up.
Asunto(s)
Aclorhidria , Gastritis Atrófica , Tumores Neuroendocrinos , Neoplasias Gástricas , Aclorhidria/etiología , Aclorhidria/patología , Anciano , Atrofia/patología , Femenino , Mucosa Gástrica/patología , Gastritis Atrófica/patología , Humanos , Tumores Neuroendocrinos/complicaciones , Tumores Neuroendocrinos/diagnóstico por imagen , Tumores Neuroendocrinos/patología , Células Parietales Gástricas/metabolismo , Células Parietales Gástricas/patología , Neoplasias Gástricas/complicaciones , Neoplasias Gástricas/patologíaRESUMEN
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.
Asunto(s)
Aclorhidria/metabolismo , Infecciones por Helicobacter/metabolismo , Helicobacter pylori/patogenicidad , Estómago/química , Aclorhidria/microbiología , Aclorhidria/patología , Adulto , Anciano , Niño , Preescolar , Endoscopía , Femenino , Gastroscopía , VIH , Infecciones por VIH/epidemiología , Infecciones por VIH/metabolismo , Infecciones por VIH/virología , Infecciones por Helicobacter/epidemiología , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Helicobacter pylori/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Lactante , Masculino , Persona de Mediana Edad , Factores de Riesgo , Estómago/patología , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/virologíaRESUMEN
Parietal cells of the gastric mucosa contain a complex and extensive secretory membrane system that harbors gastric H+, K+-adenosine triphosphatase (ATPase), the enzyme primarily responsible for gastric lumen acidification. Here, we describe the characterization of mice deficient in the H+, K+-ATPase α subunit (Atp4a-/-) to determine the role of this protein in the biosynthesis of this membrane system and the biology of the gastric mucosa. Atp4a-/- mice were produced by gene targeting. Wild-type (WT) and Atp4a-/- mice, paired for age, were examined at 10, 12, 14 and 16 weeks for histopathology, and the expression of mucin 2 (MUC2), α-methylacyl-CoA racemase (AMACR), Ki-67 and p53 proteins was analyzed by immunohistochemistry. For further information, phosphoinositide 3-kinase (PI3K), phosphorylated-protein kinase B (p-AKT), mechanistic target of rapamycin (mTOR), hypoxia-inducible factor 1α (HIF-1α), lactate dehydrogenase A (LDHA) and sirtuin 6 (SIRT6) were detected by Western blotting. Compared with the WT mice, hypochlorhydric Atp4a-/- mice developed parietal cell atrophy and significant antral inflammation (lymphocyte infiltration) and intestinal metaplasia (IM) with elevated MUC2 expression. Areas of dysplasia in the Atp4a-/- mouse stomach showed increased AMACR and Ki-67 expression. Consistent with elevated antral proliferation, tissue isolated from Atp4a-/- mice showed elevated p53 expression. Next, we examined the mechanism by which the deficiency of the H+, K+-ATPase α subunit has an effect on the gastric mucosa. We found that the expression of phosphorylated-PI3K, p-AKT, phosphorylated-mTOR, HIF-1α, LDHA and SIRT6 was significantly higher in tissue from the Atp4a-/- mice compared with the WT mice (P<0.05). The H+, K+-ATPase α subunit is required for acid-secretory activity of parietal cells in vivo, the normal development and cellular homeostasis of the gastric mucosa, and attainment of the normal structure of the secretory membranes. Chronic achlorhydria and hypergastrinemia in aged Atp4a-/- mice produced progressive hyperplasia and mucolytic and IM, and activated the Warburg effect via PI3K/AKT/mTOR signaling.
Asunto(s)
Aclorhidria/enzimología , Proliferación Celular , Transformación Celular Neoplásica/metabolismo , ATPasa Intercambiadora de Hidrógeno-Potásio/deficiencia , Células Parietales Gástricas/enzimología , Lesiones Precancerosas/enzimología , Neoplasias Gástricas/enzimología , Aclorhidria/genética , Aclorhidria/patología , Animales , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Enfermedad Crónica , Metabolismo Energético , ATPasa Intercambiadora de Hidrógeno-Potásio/genética , Metaplasia , Ratones Endogámicos C57BL , Ratones Noqueados , Mucina 2/metabolismo , Células Parietales Gástricas/patología , Fosfatidilinositol 3-Quinasa/metabolismo , Lesiones Precancerosas/genética , Lesiones Precancerosas/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Serina-Treonina Quinasas TOR/metabolismo , Factores de TiempoRESUMEN
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.
Asunto(s)
Aclorhidria/microbiología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/patogenicidad , Intestino Grueso/microbiología , Microbiota/inmunología , Estómago/microbiología , Aclorhidria/complicaciones , Aclorhidria/inmunología , Aclorhidria/patología , Animales , Sistemas de Secreción Bacterianos/inmunología , Bacteroides/inmunología , Bacteroides/patogenicidad , Chlamydiaceae/inmunología , Chlamydiaceae/patogenicidad , Escherichia coli/inmunología , Escherichia coli/patogenicidad , Femenino , Gerbillinae , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/patología , Helicobacter pylori/inmunología , Inmunidad Innata , Intestino Grueso/inmunología , Intestino Grueso/patología , Prevotella/inmunología , Prevotella/patogenicidad , Estómago/inmunología , Estómago/patologíaRESUMEN
Free-radical processes upon long-term omeprazole-induced gastric hypochlorhydria in the rat liver were researched. Intensification of oxidative processes in the liver tissue upon gastric hypoacid state was established: overproduction of superoxide anion, hydrogen peroxide, the quantitative changes of lipid functional groups, increased level of lipid peroxidation products, and augmentation of xanthine oxidase activity. The expression of Tgfb1 gene increased, while the expression of Hgf gene was not detected upon long-term suppression of gastric acid secretion of hydrochloric acid by omeprazole that indicated possible development of liver fibrosis. Abovementioned parameters were only partially restored to control values in the case of simultaneous administration of multiprobiotic "Symbiter acidophilic" concentrated with omeprazole, thus indicating the ability of this preparation to counteract the development of oxidative damages in liver tissues upon long-term gastric hypoacidic conditions.
Asunto(s)
Aclorhidria/prevención & control , Factor de Crecimiento de Hepatocito/metabolismo , Hígado/efectos de los fármacos , Probióticos/farmacología , Factor de Crecimiento Transformador beta1/metabolismo , Aclorhidria/inducido químicamente , Aclorhidria/metabolismo , Aclorhidria/patología , Animales , Animales no Consanguíneos , Antioxidantes/metabolismo , Regulación de la Expresión Génica , Factor de Crecimiento de Hepatocito/genética , Peroxidación de Lípido , Hígado/metabolismo , Masculino , Omeprazol , Estrés Oxidativo , Ratas , Superóxidos/metabolismo , Factores de Tiempo , Factor de Crecimiento Transformador beta1/genética , Xantina Oxidasa/metabolismoRESUMEN
SAMP1/YitFcs mice serve as a model of Crohn's disease, and we have used them to assess gastritis. Gastritis was compared in SAMP1/YitFcs, AKR, and C57BL/6 mice by histology, immunohistochemistry, and flow cytometry. Gastric acid secretion was measured in ligated stomachs, while anti-parietal cell antibodies were assayed by immunofluorescence and enzyme-linked immunosorbent spot assay. SAMP1/YitFcs mice display a corpus-dominant, chronic gastritis with multifocal aggregates of mononuclear cells consisting of T and B lymphocytes. Relatively few aggregates were observed elsewhere in the stomach. The infiltrates in the oxyntic mucosa were associated with the loss of parietal cell mass. AKR mice, the founder strain of the SAMP1/YitFcs, also have gastritis, although they do not develop ileitis. Genetic studies using SAMP1/YitFcs-C57BL/6 congenic mice showed that the genetic regions regulating ileitis had comparable effects on gastritis. The majority of the cells in the aggregates expressed the T cell marker CD3 or the B cell marker B220. Adoptive transfer of SAMP1/YitFcs CD4(+) T helper cells, with or without B cells, into immunodeficient recipients induced a pangastritis and duodenitis. SAMP1/YitFcs and AKR mice manifest hypochlorhydria and anti-parietal cell antibodies. These data suggest that common genetic factors controlling gastroenteric disease in SAMP1/YitFcs mice regulate distinct pathogenic mechanisms causing inflammation in separate sites within the digestive tract.
Asunto(s)
Aclorhidria/inmunología , Enfermedades Autoinmunes/inmunología , Gastritis/inmunología , Ileítis/inmunología , Aclorhidria/genética , Aclorhidria/patología , Traslado Adoptivo , Animales , Autoanticuerpos/análisis , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/patología , Linfocitos B/inmunología , Linfocitos B/patología , Complejo CD3/análisis , Complejo CD3/inmunología , Femenino , Ácido Gástrico/metabolismo , Gastritis/genética , Gastritis/patología , Ileítis/genética , Ileítis/patología , Antígenos Comunes de Leucocito/análisis , Antígenos Comunes de Leucocito/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Linfocitos T/inmunología , Linfocitos T/patología , Linfocitos T Colaboradores-Inductores/inmunologíaRESUMEN
OBJECTIVE: In Orientals, deficient aldehyde dehydrogenase 2 (ALDH2) is associated with an increased risk for esophageal squamous cell carcinoma (ESCC). The local metabolism of carcinogenic acetaldehyde in the upper gastrointestinal tract could be involved in the association, but the underlying mechanism has not been fully elucidated. Since an anacidic stomach can promote bacteria-catalyzed local acetaldehyde production, the gastric acid level could also affect acetaldehyde metabolism. This study investigated whether ALDH2-related susceptibility to ESCC differs depending on the gastric secretion level. MATERIAL AND METHODS: Sixty-two patients with ESCC and sex- and age-matched normal controls were enrolled in this study. ALDH2 polymorphism was analyzed by polymerase chain-restriction fragment length polymorphism, and those with an inactive allele (ALDH2-1/2-2 or ALDH2-2/2-2) were defined as ALDH2 deficient. Gastrin-stimulated acid output was assessed by endoscopic gastrin test and hypochlorhydria was defined as 0.6 mEq/10 min or lower. Multiple logistic regression analyses were used to adjust for other potential confounders. RESULTS: ALDH2 deficiency or hypochlorhydria was more prevalent in ESCC compared with controls and both showed increased independent associations with ESCC in multivariate analysis. Stratified analysis by the gastric acid secretion level revealed that the associations between the ALDH2 genotype and ESCC differed according to the individual gastric acid secretion levels and that ALDH2 deficiency was a significant risk factor for ESCC exclusively in individuals with hypochlorhydria with an odds ratio (95% confidence interval): 5.0 (1.2-21.2). CONCLUSION: Microbial production of carcinogen acetaldehyde in the presence of gastric hypochlorhydria is most probably involved in the mechanism of ALDH2-related susceptibility to ESCC.
Asunto(s)
Aclorhidria/enzimología , Aldehído Deshidrogenasa/deficiencia , Carcinoma de Células Escamosas/genética , ADN de Neoplasias/genética , Neoplasias Esofágicas/genética , Polimorfismo Genético , Aclorhidria/epidemiología , Aclorhidria/patología , Anciano , Aldehído Deshidrogenasa/genética , Aldehído Deshidrogenasa Mitocondrial , Carcinoma de Células Escamosas/complicaciones , Carcinoma de Células Escamosas/epidemiología , Endoscopía Gastrointestinal , Neoplasias Esofágicas/epidemiología , Neoplasias Esofágicas/patología , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Humanos , Incidencia , Japón/epidemiología , Masculino , Reacción en Cadena de la Polimerasa , Prevalencia , Pronóstico , Estudios Retrospectivos , Factores de RiesgoRESUMEN
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.
Asunto(s)
Antígenos Bacterianos/genética , Proteínas Bacterianas/genética , Islas Genómicas , Helicobacter pylori/patogenicidad , Lesiones Precancerosas/inmunología , Lesiones Precancerosas/microbiología , Neoplasias Gástricas/microbiología , Aclorhidria/inmunología , Aclorhidria/microbiología , Aclorhidria/patología , Animales , Citocinas/genética , Citocinas/metabolismo , Gastrinas , Gastritis/inmunología , Gastritis/microbiología , Gastritis/patología , Gerbillinae/genética , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/genética , Infecciones por Helicobacter/patología , Helicobacter pylori/genética , Hipertrofia , Técnicas para Inmunoenzimas , Lesiones Precancerosas/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Radioinmunoensayo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Somatostatina , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/patología , Úlcera Gástrica/inmunología , Úlcera Gástrica/microbiología , Úlcera Gástrica/patologíaRESUMEN
The WTC-deafness Kyoto (dfk) rat is a new mutant characterized by deafness and abnormal, imbalanced behavior. WTC-dfk rats carry an intragenic deletion at the Kcnq1 gene; KCNQ1 plays an important role in K(+) homeostasis, and the mutation of Kcnq1 causes a cardiac long QT syndrome in humans. Here, we studied stomach lesions in these WTC-dfk rats. The most characteristic pathologic feature in the stomach was the appearance of hypertrophic gastric glands in the stomach body. The hypertrophic cells had many eosinophilic granules in their cytoplasm, and these granules were stained red with Azan stain; stained positively for trypsinogen, amylase, and chymotrypsin; and did not stain positively for pepsinogen when using immunohistochemical analysis. These staining results suggested a metaplasia toward a pancreatic acinar cells. Extensive fibrosis was found in the bottom part of the mucosa of 34-week-old WTC-dfk rats, suggesting a progression of stomach lesions with aging. Although cells that were positive for proliferating cell nuclear antigen were restricted in the area of the glandular neck in WTC control rats, positive cells in WTC-dfk rats were scattered throughout the mucosa. The parietal cells in WTC-dfk rats were negative for KCNQ1 immunohistochemical analysis. These findings indicate that a deficiency in rat Kcnq1 provokes an abnormal proliferation and differentiation of gastric glandular cells.
Asunto(s)
Aclorhidria/patología , Canal de Potasio KCNQ1/metabolismo , Páncreas/patología , Enfermedades de los Roedores/patología , Estómago/patología , Aclorhidria/metabolismo , Animales , Inmunohistoquímica/veterinaria , Metaplasia/metabolismo , Metaplasia/patología , Páncreas/metabolismo , Ratas , Ratas Endogámicas WKY , Enfermedades de los Roedores/metabolismo , Estómago/ultraestructuraRESUMEN
Gastric hypoacidity and hypergastrinaemia are seen in several conditions associated with an increased risk of gastric malignancy. Hypoacidity and hypergastrinaemia are closely related and their long-term effects are difficult to study separately in patients. Studies using animal models can provide valuable information about risk factors and mechanisms in gastric cancer development as the models allow a high degree of intervention when introducing or eliminating factors possibly affecting carcinogenesis. In this report, we briefly review findings from relevant animal studies on this topic. Animal models of gastric hypoacidity and hypergastrinaemia provide evidence hypergastrinaemia is a common causative factor in many otherwise diverse settings. In all species where sufficient hypoacidity and hypergastrinaemia have been induced, a proportion of the animals develop malignant lesions in the gastric oxyntic mucosa.
Asunto(s)
Aclorhidria/complicaciones , Ácido Gástrico/metabolismo , Mucosa Gástrica/metabolismo , Gastrinas/metabolismo , Neoplasias Gástricas/etiología , Aclorhidria/metabolismo , Aclorhidria/patología , Animales , Proliferación Celular , Transformación Celular Neoplásica/metabolismo , Modelos Animales de Enfermedad , Células Similares a las Enterocromafines/metabolismo , Humanos , Receptor de Colecistoquinina B/metabolismo , Medición de Riesgo , Factores de Riesgo , Estómago/patología , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologíaRESUMEN
Expression of sonic hedgehog (Shh), a morphogen for the gastric fundic glands, is reduced in the atrophic mucosa that develops in association with Helicobacter pylori infection, resulting in impaired differentiation of the fundic gland cells, increased expression of trefoil factor family 2 (TFF2) and the formation of spasmolytic polypeptide (SP)-expressing metaplasia (SPEM), a preneoplastic lesion. However, it is still unresolved whether H. pylori-induced inflammation and the resultant reduction in parietal cell number or reduced parietal cell function per se reduces Shh expression. The present study was designed to clarify the expression of Shh and TFF2 in the context of parietal cell dysfunction in the absence of inflammation, using histamine H(2) receptor-knockout (H(2)R-null) mice and an acid exposure model. Age-matched H(2)R-null mice and wild-type (WT) mice were used. The expression of Shh and TFF2 mRNA was quantified by quantitative RT-PCR. Immunohistochemistry was also performed to detect the expression of Shh, TFF2 and cell markers. To study the effects of acid exposure, HCl solution was administered to the animals. The H(2)R-null mice exhibited higher gastric pH, increased TFF2 expression and reduced Shh expression. Impaired mucous neck-to-zymogenic cell differentiation was observed in the H(2)R-null mice. Furthermore, Shh expression increased in the presence of gastric acid and showed a significant correlation with gastric surface pH. In conclusion, our results suggest that persistent parietal cell dysfunction alone (suppressed gastric acid secretion), in the absence of inflammation or parietal cell loss caused by H. pylori infection, may be sufficient to down-regulate Shh expression in TFF2-overexpressing preneoplastic lesions of the gastric fundus. Since exposure to acid restored fundic Shh expression, appropriate gastric acid secretion may play an important role in the morphogen dynamics involved in the maintenance of gastric fundic gland homeostasis.
Asunto(s)
Aclorhidria/metabolismo , Fundus Gástrico/metabolismo , Proteínas Hedgehog/metabolismo , Mucinas/metabolismo , Proteínas Musculares/metabolismo , Péptidos/metabolismo , Aclorhidria/patología , Animales , Diferenciación Celular , Regulación hacia Abajo , Ácido Gástrico/metabolismo , Ácido Gástrico/fisiología , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas Hedgehog/genética , Ácido Clorhídrico/farmacología , Concentración de Iones de Hidrógeno/efectos de los fármacos , Masculino , Ratones , Ratones Noqueados , Mucinas/genética , Proteínas Musculares/genética , Células Parietales Gástricas/patología , Células Parietales Gástricas/fisiología , Péptidos/genética , ARN Mensajero/genética , Receptores Histamínicos H2/deficiencia , Receptores Histamínicos H2/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Factor Trefoil-2RESUMEN
Watery diarrhea, hypokalemia and achlorhydria (WDHA) syndrome caused by vasoactive intestinal polypeptide (VIP) -producing tumor only rarely occurs in patients with nonpancreatic disease. A 49-year-old woman was referred for evaluation of a right adrenal tumor incidentally diagnosed by abdominal ultrasound during the investigation of chronic watery diarrhea. Laboratory findings showed hypokalemia and excessive production of VIP and catecholamines. After surgical resection of the tumor, diarrhea subsided and both electrolytes and affected hormone levels normalized. Immunohistochemical examination confirmed a diagnosis of pheochromocytoma, which contained VIP-positive ganglion-like cells. We herein present the clinical and histogenetic implications of this rare clinical entity, with literature review.
Asunto(s)
Aclorhidria/etiología , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Diarrea/etiología , Hipopotasemia/etiología , Hallazgos Incidentales , Feocromocitoma/diagnóstico , Vipoma/diagnóstico , Aclorhidria/sangre , Aclorhidria/patología , Neoplasias de las Glándulas Suprarrenales/sangre , Neoplasias de las Glándulas Suprarrenales/complicaciones , Neoplasias de las Glándulas Suprarrenales/cirugía , Adrenalectomía , Catecolaminas/sangre , Diarrea/sangre , Diarrea/patología , Femenino , Humanos , Hipopotasemia/sangre , Hipopotasemia/patología , Persona de Mediana Edad , Feocromocitoma/sangre , Feocromocitoma/complicaciones , Feocromocitoma/cirugía , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Péptido Intestinal Vasoactivo/sangre , Vipoma/sangre , Vipoma/complicaciones , Vipoma/cirugíaRESUMEN
The KCNQ1 gene encodes a voltage-dependent potassium ion channel, and mutations in this gene are the most common cause of congenital long QT syndrome (LQTS). In the present study, we investigated the various phenotypic characteristics of vertigo 2 Jackson (C3H/HeJCrl-Kcnq1(vtg-2J)/J) mice with a Kcnq1 mutation. Both heterozygotes (vtg-2J/+) and homozygotes (vtg-2J/vtg-2J) showed prolonged QT intervals in electrocardiograms (ECGs) compared to C3H/HeJ control (+/+) mice. Furthermore, vtg-2J/vtg-2J mice showed gastric achlorhydria associated with elevation of their serum gastrin levels. The serum corticosterone levels were also significantly increased in vtg-2J/vtg-2J mice. In addition, vtg-2J/vtg-2J mice exhibited significantly higher blood pressure. These findings indicate that the Kcnq1 mutation in vtg-2J mice alters various physiological functions in the cardiac, gastric and adrenocortical systems, and suggest that vtg-2J mice may represent a useful model for studying Kcnq1 functions.
Asunto(s)
Aclorhidria/genética , Canal de Potasio KCNQ1/genética , Síndrome de QT Prolongado/genética , Aclorhidria/sangre , Aclorhidria/patología , Animales , Corticosterona/sangre , Modelos Animales de Enfermedad , Electrocardiografía , Femenino , Ácido Gástrico/metabolismo , Determinación de la Acidez Gástrica , Mucosa Gástrica/metabolismo , Gastrinas/sangre , Genotipo , Hipertensión/genética , Hipertensión/fisiopatología , Síndrome de QT Prolongado/patología , Síndrome de QT Prolongado/fisiopatología , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Mutantes , Mutación , Fenotipo , Estómago/patologíaAsunto(s)
Aclorhidria/patología , Tumor Carcinoide/patología , Gastritis Hipertrófica/diagnóstico , Hipoalbuminemia/diagnóstico , Neoplasias Primarias Múltiples/patología , Células Parietales Gástricas/patología , Neoplasias Gástricas/patología , Aclorhidria/sangre , Tumor Carcinoide/sangre , Tumor Carcinoide/complicaciones , Diagnóstico Diferencial , Gastritis Hipertrófica/sangre , Hiperplasia/sangre , Hiperplasia/complicaciones , Hiperplasia/patología , Hipoalbuminemia/sangre , Neoplasias Primarias Múltiples/sangre , Neoplasias Primarias Múltiples/complicaciones , Células Parietales Gástricas/metabolismo , Albúmina Sérica/análisis , Neoplasias Gástricas/sangre , Neoplasias Gástricas/complicacionesRESUMEN
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.
Asunto(s)
Aclorhidria/microbiología , Gastrinas/genética , Neoplasias Gástricas/etiología , Aclorhidria/complicaciones , Aclorhidria/patología , Animales , Ácido Gástrico/metabolismo , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Gastrinas/deficiencia , Regulación de la Expresión Génica , Enfermedades Intestinales/patología , Metaplasia/microbiología , Metaplasia/patología , Ratones , Ratones Noqueados , Modelos Biológicos , Receptor de Colecistoquinina B/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/microbiologíaAsunto(s)
Aclorhidria/patología , Tumor Carcinoide/patología , Gastritis Hipertrófica/diagnóstico , Neoplasias Primarias Múltiples/patología , Células Parietales Gástricas/patología , Neoplasias Gástricas/patología , Aclorhidria/complicaciones , Aclorhidria/metabolismo , Albúminas/metabolismo , Tumor Carcinoide/complicaciones , Tumor Carcinoide/metabolismo , Diagnóstico Diferencial , Gastritis Hipertrófica/metabolismo , Hiperplasia/complicaciones , Hiperplasia/metabolismo , Hiperplasia/patología , Neoplasias Primarias Múltiples/complicaciones , Neoplasias Primarias Múltiples/metabolismo , Células Parietales Gástricas/metabolismo , Neoplasias Gástricas/complicaciones , Neoplasias Gástricas/metabolismoRESUMEN
BACKGROUND: Gastric neoplasia is common in humans, yet controversy remains over contributions of chronic achlorhydria, gastrinemia and hyperplasia, to cancer risk. To study this, mice lacking the gastric H/K-ATPase (Atp4a(-/-) mice) were used to determine whether chronic loss of acid secretion, with attendant hypergastrinemia, predisposes to cancer phenotype. METHODS: Atp4a(-/-) and Atp4a(+/+) mice, paired for age and gender, were examined at 3, 8, 12 and 20 months for histopathology, and for expression of the trefoil factor family (TFF)1-3, Reg IIIbeta, gamma and delta, osteopontin, CD44, chromogranin A, Crp-ductin, and galectin, all of which are important in cell growth. RESULTS: By 8 months, the glandular stomach of the Atp4a(-/-) mice doubled in weight and thickness, and several modulators of growth were increased. Female Atp4a(-/-) mice were more hyperplastic than Atp4a(-/-) males at 12 and 20 months. By 1 year, severe mucocystic hyperplasia, incomplete intestinal metaplasia, ciliated metaplasia, a shift in mucins from neutral to acidic, and inflammation were widespread. Cells in the mucus pit zone developed a pyloric-type appearance, containing large hyaline-like, periodic acid-Schiff (PAS)-negative/alcian blue-negative inclusions. But critical characteristics of gastric neoplasia, such as nuclear atypia, invasion into the muscularis mucosa, and metastases were absent. In Atp4a(-/-) mice, chromogranin A and histidine decarboxylase, RegIIIgamma and delta, TFF3, osteopontin and CD44 were upregulated while Reg IIIbeta, and TFF1 were reduced. CONCLUSIONS: Chronic achlorhydria and hypergastrinemia in aged Atp4a(-/-) mice produced progressive hyperplasia, mucocystic and incomplete intestinal metaplasia, and the upregulation of growth factors without histological evidence of neoplasia.
Asunto(s)
Aclorhidria/metabolismo , Mucosa Gástrica/metabolismo , ATPasa Intercambiadora de Hidrógeno-Potásio/deficiencia , Aclorhidria/patología , Factores de Edad , Animales , Modelos Animales de Enfermedad , Hiperplasia Endometrial/patología , Femenino , Mucosa Gástrica/patología , ATPasa Intercambiadora de Hidrógeno-Potásio/genética , Hiperplasia , Masculino , Metaplasia , Ratones , Ratones Noqueados , Factores Sexuales , Estómago/patologíaRESUMEN
We describe a 54-year-old woman who had multiple gastric carcinoid tumors arising in the setting of marked hypergastrinemia associated with a lack of acid production by hypertrophic parietal cells. The serum gastrin level was 1,400 pg/mL, and investigation revealed no evidence for either of the recognized causes for hypergastrinemia-associated carcinoids, autoimmune gastritis, and Zollinger-Ellision syndrome. Partial gastrectomy was performed. Pathologic examination showed multiple intramucosal and invasive carcinoid tumors of the body and fundus in a background of marked ECL cell hyperplasia. There were no gastric or duodenal ulcerations. One perigastric lymph node was metastatically involved. The oxyntic mucosa showed marked hyperplasia and hypertrophy of the parietal cells. Some of these cells were vacuolated, and many displayed protrusions of apical cytoplasm into dilated oxyntic glands filled with inspissated eosinophilic material. Similar findings have occurred in 1 other patient, strongly indicating that the clinicopathologic alterations in the 2 cases are not random but, on the contrary, represent a very rare disorder of gastric carcinoids associated with an intrinsic acid secretion abnormality of the parietal cells.
Asunto(s)
Aclorhidria/patología , Tumor Carcinoide/patología , Hiperplasia/patología , Neoplasias Primarias Múltiples/patología , Células Parietales Gástricas/patología , Neoplasias Gástricas/patología , Aclorhidria/complicaciones , Tumor Carcinoide/complicaciones , Tumor Carcinoide/metabolismo , Femenino , Humanos , Hiperplasia/complicaciones , Inmunohistoquímica , Metástasis Linfática/patología , Persona de Mediana Edad , Neoplasias Primarias Múltiples/complicaciones , Neoplasias Primarias Múltiples/metabolismo , Neoplasias Gástricas/complicaciones , Neoplasias Gástricas/metabolismoRESUMEN
BACKGROUND & AIMS: Epidemiological studies suggest that atrophic corpus-dominant gastritis is an increased risk factor for gastric carcinogenesis. The role of the Helicobacter pylori type IV secretion system (T4SS) for pathogenesis in the Mongolian gerbil model was explored. METHODS: Mongolian gerbils were infected for 32 weeks either with H. pylori type I strain B128 or with isogenic mutant strain B128delta cytotoxin-associated gene (cagY) or B128delta cagA , defective in T4SS or in the production of its effector protein CagA, respectively. Quantitative H. pylori reisolation was performed from the gastric antrum and corpus separately, cytokines were measured by quantitative reverse-transcription polymerase chain reaction, and gastric pH and hormones were determined. RESULTS: B128-infected gerbils harbored high numbers of bacteria in the gastric antrum and corpus, whereas B128delta cagY and B128delta cagA colonized the antrum more densely than the corpus. All infected animals showed a strong antral inflammation and epithelial cell proliferation. B128-infected, rather than mutant-infected, gerbils presented a severe transmural inflammation with huge lymph aggregates, increased proliferation, significant atrophy, and mucous gland metaplasia in the corpus. Plasma gastrin levels and gastric pH values were significantly increased only in B128-infected gerbils. In all infected animals, the expression of the proinflammatory cytokines interleukin 1beta, interferon gamma, and growth-regulated protein was considerably increased in the antrum, but only in wild type-infected animals was an increase seen in the corpus mucosa. CONCLUSIONS: The presence of an intact T4SS allows H. pylori to colonize the gastric corpus. This results in atrophic corpus-dominant gastritis, a severe precancerous condition, thus highlighting T4SS and CagA as major risk factors for gastric cancer development.