Long-term proton pump inhibitor administration worsens atrophic corpus gastritis and promotes adenocarcinoma development in Mongolian gerbils infected with Helicobacter pylori.

BACKGROUND: We investigated whether corpus atrophic gastritis worsens in Mongolian gerbils (MGs) after long-term administration of proton pump inhibitor (PPI). MGs are an excellent model for studying Helicobacter pylori-related gastritis and adenocarcinoma. METHODS: MGs were separated into four groups (n =15/group); H pylori (ATCC43504) was inoculated into the OPZ(omeprazole)+Hp (H pylori) and Hp groups, a PPI (OPZ) was administered to the OPZ+Hp and OPZ groups and the control group received no treatment. MGs had access to food containing omeprazole (100 mg/kg body weight/day) for 6 months, after which their stomachs were removed and cut into nine sections (six sections in the fundus and three sections in the antrum). Corpus atrophy was evaluated by the absence of parietal cells in the six sections in the fundus. First, we calculated a percentage of the area devoid of parietal cells in each haematoxylin and eosin-stained section, and then we scored the degree of atrophy by adding the percentages of the six sections. A full score was 600. RESULTS: Neutrophilic and lymphoid infiltrates were greater in the OPZ+Hp group than in the other groups. The corpus atrophy score in the OPZ+Hp group was significantly higher than that in the Hp group (p < 0.0048, Student t test). Significantly more adenocarcinomas were found in the OPZ+Hp (60%) than in the Hp (7%) group animals. CONCLUSION: Long-term PPI administration promotes development of adenocarcinoma, which is associated with the progression of atrophic corpus gastritis in MGs infected with H pylori.

Association of tannase-producing Staphylococcus lugdunensis with colon cancer and characterization of a novel tannase gene.

BACKGROUND: The relationship between Streptococcus (St.) bovis endocarditis and colon cancer is well known. In St. bovis, the biotype I strain (formerly, St. gallolyticus) produces tannase that degrades tannins. The aim of this study was to investigate the association of tannase-producing bacteria with colon cancer, and to identify the major tannase-producing bacteria and the gene involved. METHODS: Tannase-producing bacteria were isolated in tannic acid-treated selective agar medium from feces and rectal swabs of 357 patients who underwent colon endoscopy from 1999 to 2004. RESULTS: Tannase-producing bacteria were isolated more frequently from the colon cancer group (24.3%) than from the adenoma or normal groups (14.4%; P < 0.05). S. gallolyticus, Staphylococcus (S.) lugdunensis, Lactobacillus (L.) plantarum, and L. pentosus were all identified as tannase-producing bacteria. Of these, S. lugdunensis was significantly isolated from the advanced-stage cancer group (22.2%; P < 0.001) more than from the early-stage cancer (8.6%) or adenoma (4.9%) groups. The gene (tanA) for tannase in S. lugdunensis was cloned and sequenced. The tanA gene was associated with all S. lugdunensis but not with other bacteria by Southern blotting and polymerase chain reaction. CONCLUSIONS: Tannase-producing S. lugdunensis is associated with advanced-stage colon cancer, and the tanA gene is a useful marker for the detection of S. lugdunensis.

Two distinct etiologies of gastric cardia adenocarcinoma: interactions among pH, Helicobacter pylori, and bile acids.

Gastric cancer can be classified as cardia and non-cardia subtypes according to the anatomic site. Although the gastric cancer incidence has decreased steadily in several countries over the past 50 years, the incidence of cardia cancers and esophageal adenocarcinoma (EAC) continue to increase. The etiological factors involved in the development of both cardia cancers and EACs are associated with high animal fat intake, which causes severe obesity. Central obesity plays roles in cardiac-type mucosa lengthening and partial hiatus hernia development. There are two distinct etiologies of cardia cancer subtypes: one associated with gastroesophageal reflux (GER), which predominantly occurs in patients without Helicobacter pylori (H. pylori) infection and resembles EAC, and the other associated with H. pylori atrophic gastritis, which resembles non-cardia cancer. The former can be developed in the environment of high volume duodenal content reflux, including bile acids and a higher acid production in H. pylori-negative patients. N-nitroso compounds, which are generated from the refluxate that includes a large volume of bile acids and are stabilized in the stomach (which has high levels of gastric acid), play a pivotal role in this carcinogenesis. The latter can be associated with the changing colonization of H. pylori from the distal to the proximal stomach with atrophic gastritis because a high concentration of soluble bile acids in an environment of low acid production is likely to act as a bactericide or chemorepellent for H. pylori in the distal stomach. The manuscript introduces new insights in causative factors of adenocarcinoma of the cardia about the role of bile acids in gastro-esophageal refluxate based upon robust evidences supporting interactions among pH, H. pylori, and bile acids.

Proton pump inhibitors and helicobacter pylori-associated pathogenesis.

The fact that long-term use of proton pump inhibitors (PPIs) aggravates corpus atrophic gastritis in patients with Helicobacter pylori infection has been proven clinically and experimentally. Corpus atrophic gastritis is a known risk factor for gastric cancer. Therefore, gastric neoplasia might be associated with the long-term use of PPIs. One of the causes of worsening corpus atrophic gastritis, leading to the development of adenocarcinoma, might be bacterial overgrowth under conditions of hypochlorhydria. The production of potentially carcinogenic N-nitrosocompounds by nitrosating organisms under conditions of hypochlorhydria might be associated with carcinogenesis. Interactions between bile acids, pH, and H. pylori might also contribute to carcinogenicity, especially in patients with gastro-esophageal reflux disease (GERD). The concentration of soluble bile acids, which have bactericidal or chemorepellent properties toward H. pylori, in gastric contents is considerably higher in patients undergoing continuous PPI therapy than in healthy individuals with normal acid production. Under these circumstances, H. pylori might colonize the stomach body rather than the pyloric antrum. Hypergastrinemia induced by PPI administration might promote the development of gastric cancer. Because the main cause of corpus atrophic gastritis is H. pylori infection, and not PPI administration, H. pylori infection should be eradicated before starting long-term PPI therapy.

Potential mechanism of corpus-predominant gastritis after PPI therapy in Helicobacter pylori-positive patients with GERD.

The long-term use of proton pump inhibitors (PPIs) exacerbates corpus atrophic gastritis in patients with Helicobacter pylori (H. pylori) infection. To identify a potential mechanism for this change, we discuss interactions between pH, bile acids, and H. pylori. Duodenogastric reflux, which includes bile, occurs in healthy individuals, and bile reflux is increased in patients with gastroesophageal reflux disease (GERD). Diluted human plasma and bile acids have been found to be significant chemoattractants and chemorepellents, respectively, for the bacillus H. pylori. Although only taurine conjugates, with a pKa of 1.8-1.9, are soluble in an acidic environment, glycine conjugates, with a pKa of 4.3-5.2, as well as taurine-conjugated bile acids are soluble in the presence of PPI therapy. Thus, the soluble bile acid concentrations in the gastric contents of patients with GERD after continuous PPI therapy are considerably higher than that in those with intact acid production. In the distal stomach, the high concentration of soluble bile acids is likely to act as a bactericide or chemorepellent for H. pylori. In contrast, the mucous layer in the proximal stomach has an optimal bile concentration that forms chemotactic gradients with plasma components required to direct H. pylori to the epithelial surface. H. pylori may then colonize in the stomach body rather than in the pyloric antrum, which may explain the occurrence of corpus-predominant gastritis after PPI therapy in H. pylori-positive patients with GERD.

Rebamipide contributes to reducing adverse effects of long-term administration of omeprazole in rats.

Proton pump inhibitors (PPIs) have become of great importance for the treatment of peptic ulcer disease and gastroesophageal reflux disease. However, these drugs have several adverse effects, including worsening of corpus atrophic gastritis in patients with H. pylori infection, various histological changes including fundic gland-type polyps, inhibition of glycoprotein production, and hypergastrinemia. On the other hand, it has been reported that rebamipide, a gastroprotective drug, has the potential to increase mucous secretion and basically regulate physiological defensive functions aimed to maintain tissue integrity. In this study, we attempted to clarify whether rebamipide improves morphological changes and hypergastrinemia after administration of omeprazole (OPZ) for 1 year in rats. Eight-week-old male Wistar rats were used. Rats were divided into four groups according to diet as follows: 100 mg/kg body weight OPZ group, 100 mg/kg body weight OPZ and 30 mg/kg body weight rebamipide (OPZ + trebanipide group), 30 mg/kg body weight rebamipide, and normal diet (CRF-1). Morphological changes in gastric mucosa in all groups were studied using hematoxylin and eosin staining, periodic acid-Schiff staining, and immunohistochemical staining for alpha-amylase. Serum gastrin level and basal acid secretion were also examined. In the OPZ group, cystic degenerations with amorphous eosinophilic contents, decreased mucous secretion, decreased chief cells, and development of pancreatic acinar cell metaplasia were detected. However, in the OPZ+rebamipide group, these morphological changes were significantly milder than in the OPZ group. Serum gastrin level and basal acid secretion in the OPZ group increased significantly compared to those in the control group. But these factors in the OPZ+rebamipide group were almost normalized (similar to those of control animals). In conclusion, long-term OPZ treatment causes various morphological changes, hypergastrinemia, and basal acid hypersecretion. The present results suggest that rebamipide contributes to reducing these adverse effects caused by long-term OPZ treatment in rats.

Development of pancreatic acinar cell metaplasia after successful administration of omeprazole for 6 months in rats.

Long-term use of proton pump inhibitors (PPIs) has been reported to worsen corpus atrophic gastritis in patients with Helicobacter pylori infection. On the other hand, PPIs have been associated with fundic gland-type gastric polyps and various histological changes. In the present study, we attempted to establish a protocol for omeprazole (OPZ) administration to rats over a longer period and examined the morphological changes in the gastric mucosa after administration of OPZ for 6 months. A total of 34 Wistar rats (8 weeks old) were used. In a preliminary experiment to determine the appropriate dose of OPZ, the rats had ad libitum access to food containing different doses of OPZ for 1 month. We found an approximate dose of 100 mg/kg body weight/day of OPZ to be most suitable from the point of view of intragastric pH, body weight, and serum gastrin level. In the experiment proper, rats were divided into two groups, either control or OPZ diets, and morphological changes in the gastric mucosa in each group were then examined by hematoxylin and eosin and immunohistochemical staining with alpha-amylase, trypsin, and chromogranin A. Multiple vacuolar degeneration of parietal cells and numerous small mucous cells were evident at 1 month after treatment with OPZ. At 6 months after treatment with OPZ, cystic degeneration and acinar-cell-like cells containing red granules positive for alpha-amylase and trypsin and negative for chromogranin A were detected in the OPZ rats. The serum gastrin level in the OPZ group was significantly higher than that in the control group. We have established a protocol for long-term administration of OPZ in rats that is a useful model for analyzing morphological changes after long-term PPI therapy. Long-term OPZ treatment causes hypergastrinemia and pancreatic acinar cell metaplasia in this animal model.