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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.

The pyloric antral hormone gastrin plays a role in remodeling of the gastric epithelium, but the specific targets of gastrin that mediate these effects are poorly understood. Glandular epithelial cells of the gastric corpus express matrix metalloproteinase (MMP)-1, which is a potential determinant of tissue remodeling; some of these cells express the CCK-2 receptor at which gastrin acts. We have now examined the hypothesis that gastrin stimulates expression of MMP-1 in the stomach. We determined MMP-1 transcript abundance in gastric mucosal biopsies from Helicobacter pylori negative human subjects with normal gastric mucosal histology, who had a range of serum gastrin concentrations due in part to treatment with proton pump inhibitors (PPI). The effects of gastrin were studied on gastric epithelial AGS-GR cells using Western blot and migration assays. In human subjects with increased serum gastrin due to PPI usage, MMP-1 transcript abundance was increased 2-fold; there was also increased MMP-7 transcript abundance but not MMP-3. In Western blots, gastrin increased proMMP-1 abundance, as well that of a minor band corresponding to active MMP-1, in the media of AGS-GR cells, and the response was mediated by protein kinase C and p42/44 MAP kinase. There was also increased MMP-1 enzyme activity. Gastrin-stimulated AGS-GR cell migration in both scratch wound and Boyden chamber assays was inhibited by MMP-1 immunoneutralization. We conclude that MMP-1 expression is a target of gastrin implicated in mucosal remodeling., (Copyright © 2015 the American Physiological Society.)

Gastric mucosal health is maintained in response to potentially damaging luminal factors. Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) disrupt protective mechanisms leading to bleeding and ulceration. The plasminogen activator system has been implicated in fibrinolysis following gastric ulceration, and an inhibitor of this system, plasminogen activator inhibitor (PAI)-1, is expressed in gastric epithelial cells. In Helicobacter pylori-negative patients with normal gastric histology taking aspirin or NSAIDs, we found elevated gastric PAI-1 mRNA abundance compared with controls; the increase in patients on aspirin was independent of whether they were also taking proton pump inhibitors. In the same patients, aspirin tended to lower urokinase plasminogen activator mRNA. Immunohistochemistry indicated PAI-1 localization to epithelial cells. In a model system using MKN45 or AGS-GR cells transfected with a PAI-1 promoter-luciferase reporter construct, we found no evidence for upregulation of PAI-1 expression by indomethacin, and, in fact, cyclooxygenase products such as PGE2 and PGI2 weakly stimulated expression. Increased gastric PAI-1 mRNA was also found in mice following gavage with ethanol or indomethacin, but plasma PAI-1 was unaffected. In PAI-1(-/-) mice, gastric hemorrhagic lesions in response to ethanol or indomethacin were increased compared with C57BL/6 mice. In contrast, in PAI-1-H/Kβ mice in which PAI-1 is overexpressed in parietal cells, there were decreased lesions in response to ethanol and indomethacin. Thus, PAI-1 expression is increased in gastric epithelial cells in response to mucosal irritants such as aspirin and NSAIDs probably via an indirect mechanism, and PAI-1 acts as a local autoregulator to minimize mucosal damage.

Although the pathogenesis of cervical inlet patch (CIP) is not fully understood, most authors consider it as a congenital abnormality, whereas others surmise it to be related to gastroesophageal reflux disease (GERD). We aimed to evaluate esophageal function and the prevalence of GERD and Barrett's esophagus in patients with CIP. GERD is defined by the presence of erosive esophagitis or an abnormal pH monitoring. Seventy-one consecutive patients with endoscopic and histological evidence of CIP were prospectively evaluated. Esophageal symptom analysis, 24-hour simultaneous biliary reflux and double-channel pH-monitoring, and esophageal manometry were carried out in 65/71 (92%) patients and in 25 matched controls. Six patients were not suitable for testing and were, therefore, excluded. The histological evaluation of the heterotopic islands showed cardia and/or oxyntic mucosa in 64/65 (98%) patients and specialized intestinal metaplasia (SIM) in one patient (2%). The cardia and/or oxyntic mucosa was accompanied by focally appearing pancreatic acinar metaplasia and pancreatic ductal metaplasia in 7/64 (11%) and in 1/64 (2%), superficial mucous glands in 6/64 (9%), and SIM in 2/64 (3%) cases. In total, SIM was present in three patients (5%), and one of them had low-grade dysplasia. At the gastroesophageal junction, 28 (43%) patients had columnar metaplasia, including nine (14%) patients with SIM. Erosive esophagitis was present in 37 (57%) cases. Thirty-two patients (49%) had abnormal acid reflux in the distal and 25 (38%) in the proximal esophagus. Abnormal biliary reflux was present in 25 (38%) cases. On the basis of endoscopic and pH studies, GERD was established in 44/65 (68%) patients. Typical reflux symptoms were common (33/65, 51%). The combined 24-hour biliary and double-channel pH-monitoring detected significantly more significant acidic reflux at both measurement points and significantly longer bile exposure time in the distal esophagus in patients with CIP. Acid secretion in the CIP was detected in three (5%) cases. Esophageal manometry revealed decreased LES pressure and prolonged relaxation with decreased peristaltic wave amplitude, and an increased number of simultaneous contractions in the esophageal body. The detailed evaluation of the esophageal morphology and function in subjects with CIP showed a high prevalence of GERD and Barrett's esophagus. Further studies are needed to evaluate whether combined acidic and biliary reflux is able to promote similar histomorphological changes in the CIP, as it is shown distally in patients with Barrett's esophagus., (© 2011 Copyright the Authors. Journal compilation © 2011, Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus.)

Tumor progression has been linked to changes in the stromal environment. Myofibroblasts are stromal cells that are often increased in tumors but their contribution to cancer progression is not well understood. Here, we show that the secretomes of myofibroblasts derived from gastric cancers [cancer-associated myofibroblasts (CAMs)] differ in a functionally significant manner from those derived from adjacent tissue [adjacent tissue myofibroblasts (ATMs)]. CAMs showed increased rates of migration and proliferation compared with ATMs or normal tissue myofibroblasts (NTMs). Moreover, conditioned medium (CM) from CAMs significantly stimulated migration, invasion and proliferation of gastric cancer cells compared with CM from ATMs or NTMs. Proteomic analysis of myofibroblast secretomes revealed decreased abundance of the extracellular matrix (ECM) adaptor protein like transforming growth factor-β-induced gene-h3 (TGFβig-h3) in CAMs, which was correlated with lymph node involvement and shorter survival. TGFβig-h3 inhibited IGF-II-stimulated migration and proliferation of both cancer cells and myofibroblasts, and suppressed IGF-II activation of p42/44 MAPkinase; TGFβig-h3 knockdown increased IGF-II- and CM-stimulated migration. Furthermore, administration of TGFβig-h3 inhibited myofibroblast-stimulated growth of gastric cancer xenografts. We conclude that stromal cells exert inhibitory as well as stimulatory effects on tumor cells; TGFβig-h3 is a stromal inhibitory factor that is decreased with progression of gastric cancers.

Background: EMR is a widely used treatment option for gastric adenoma and early gastric cancer, but, there are no data on its use in Hungary. The aim of this study was to assess the diagnostic and therapeutic efficacy of EMR., Patients: 44 patients (30 females, 14 males, mean age: 67 years) were studied between 1994 and 2005; 33 had severe concomitant diseases (liver cirrhosis or severe cardiovascular disease). Indigo carmine dye staining and electronic magnification was used in all cases, with endoscopic ultrasonography when indicated. 56 EMR-s were performed. The histological results on the biopsy and resected specimens were analyzed., Results: The morphology of the lesions was type I in 20, type IIa in 35, and type IIa-IIc in 1 case. The diagnosis at first biopsy was in situ carcinoma in 3, adenoma with no dysplasia in 19, adenoma with low-grade dysplasia in 2, adenoma with moderate-grade dysplasia in 6, adenoma with high-grade dysplasia in 7, and hyperplastic lesion in 17 cases. The histology of EMR revealed in situ carcinoma in 5, carcinoid in 1, gastrointestinal stromal tumor in 1, adenoma with no dysplasia in 14, adenoma with low-grade dysplasia in 3, adenoma with moderate-grade dysplasia in 9, adenoma with high-grade dysplasia in 1, hyperplastic lesion in 21, and no diagnosis in 1 case. However, the moderate- and high-grade dysplasia was diagnosed in different cases with the two methods. EMR was considered complete in all but 1 case. A Nd YAG laser was used in this patient with in situ carcinoma, where the resection margin was not free of cancer cells. Bleeding occurred in 3 cases; 1 required transfusion and had pneumonia postoperatively. There were no gastric cancer-related deaths during the median follow-up of 33 (1-90) months. In the follow up period we could not observe gastric malignancy in the previously hyperplastic polyp cases. Among adenoma cases one recurrence was seen in the same place and one in another location. One hyperplastic residuum occurred and in one case adenoma has grown in the same place., Conclusion: EMR, a facile and useful diagnostic and therapeutic technique, appears very safe in terms of complications even in patients with comorbidities. Biopsy is generally unreliable to diagnose gastric adenoma. Lesions should be fully resected by EMR for a final diagnosis and (depending on the lesion size and type) possibly definitive treatment.

Unlabelled: Helicobacter pylori infection in humans causes gastritis. The infection elicits a complex immune response in which the activation of mast cells and histamine release is of particular importance. Histamine further promotes the immune response and stimulates gastric acid secretion. The inflammatory effects of H. pylori can be studied in intragastrically infected mice. The aim of this study was to compare the local cytokine responses of histamine-deficient, histidine decarboxylase knock-out (HDC KO) and wild-type (WT) mice following H. pylori infection., Methods: H. pylori was administered intragastrically to HDC KO and WT mice. The animals were infected three times in a 1-week-period and were sacrificed 8 weeks after the first intervention. The local TNF-alpha, IL-6 and IL-10 cytokine levels in gastric mucosal specimens were determined by ELISA. Gastric mucosa sections were also analysed for histological signs of inflammation. To investigate the antibody response following H. pylori infection, the total anti-H. pylori IgG and the ratio of IgG1/IgG2a isotypes were determined in the serum by ELISA., Results: H. pylori induced considerable cytokine production in the infected groups. The TNF-alpha and IL-6 levels were significantly higher in the WT mice than in the HDC KO mice, whereas the IL-10 levels did not differ between the groups. Anti-H. pylori IgG was detected only in the infected groups and the titre was higher in the WT mice. A higher IgG1/IgG2a ratio was observed in the H. pylori infected HDC KO group. Histological analysis revealed that the grades of inflammation were less severe in the infected HDC KO animals., Conclusions: The results suggest that H. pylori induces lower TNF-alpha and IL-6 secretion in the gastric mucosa in the HDC KO mice than in the WT animals, while the levels of induction of IL-10 were similar. The imbalance between Th1/Th2 is less pronounced in the HDC KO mice, which might explain the milder inflammation in the gastric mucosa. These results provide further information on the role of histamine in the pathomechanism of H. pylori-induced gastritis.

Background: This study was designed to investigate the role of bile in a large animal model of acute esophageal reflux disease., Methods: An agar electrode was used to measure the transmucosal potential difference of the esophagus in anaesthetized dogs. The vascular permeability index and the epithelial permeability index of the mucosa were evaluated by means of the Evans blue and the sodium-fluorescein clearance method, respectively. The tissue adenosine triphosphate (ATP) level and the myeloperoxidase activity were determined from tissue biopsies, while the degree of mucosal damage was evaluated histologically on a grade 0-100 scale. Group 1 (n = 8) served as saline-treated control; groups 2 (n = 8), 3 (n = 5) and 4 (n = 5) were exposed for 4 h to canine bile alone, to hydrochloric acid + bile, or to hydrochloric acid alone, respectively., Results: In Groups 2, 3 and 4 the degree of mucosal damage was significantly increased, and a 4-fold elevation in myeloperoxidase activity was observed. The transmucosal potential difference was decreased significantly below the control level, while the vascular and epithelial permeability indices were significantly increased compared with the control values. Bile, but not hydrochloric acid, evoked a significant (40%) decrease in the ATP level of the esophageal tissue., Conclusions: We propose that mucosal dysfunction, structural damage and leukocyte invasion during hydrochloric acid-induced esophageal injury are exacerbated by bile-induced changes in tissue ATP concentrations during experimental esophageal reflux disease.

Background: Acetylsalicylic acid (ASA)-induced gastric injury is reduced when ASA is administered along with phosphatidylcholine. The hydrolysis of endogenous phosphatidylcholine leads to the production of betaine, which may participate in the maintenance of cellular homeostasis. The present aims were to investigate the effects of exogenous betaine and its palmitic acid complex (betaine-palmitate) in the protection of the gastric mucosa in ASA-induced subacute damage. Methods: Repeated doses of ASA were given intragastrically to male Wistar rats. Control rats were given vehicle only, while treated animals were challenged with ASA or with ASA along with betaine, palmitic acid or betaine-palmitate. The gastric mucosa was examined after 3 days and the nature of any microscopic mucosal injury was assessed by histology. The extent of macroscopic damage, changes in permeability (assessed by Evans blue method) and tissue ATP concentrations were determined in separate series. Results: ASA induced a significant fall in the ATP content of the mucosa, which was not affected by the other drugs used in the study. However, the ASA-induced mucosal permeability increase could be completely reversed by betaine-palmitate supplementation. The extent of severity of the macroscopic and microscopic lesions was 33% and 2.45, respectively, for ASA, as compared with 15% and 2.2 for betaine, 14% and 1.9 for palmitic acid and 3% and 1.4 for betaine-palmitate. Conclusions: Betaine-palmitate affords a significant protective effect against ASA-induced injury, without influencing the ATP synthesis, and this suggests that the defence is due to its ability to prevent secondary damage. [ABSTRACT FROM AUTHOR]