Genetic or chemical hypochlorhydria is associated with inflammation that modulates parietal and G-cell populations in mice

Zavros, Yana; Rieder, Gabriele; Ferguson, Amy W.; Samuelson, Linda C.; Merchant, Juanita L.

doi:10.1053/gast.2002.30298

Cited by 117 publications

(138 citation statements)

References 39 publications

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“…In many patients with gastric cancer, H. pylori infection is often difficult to detect even with multiple modalities (91). This is consistent with the observation that gastrin-deficient mice, which are achlorhydric, housed in a conventional facility develop bacterial overgrowth and chronic atrophic gastritis and progress to antral gastric cancer (92,93). This pathological process is very similar to that which develops in H. felis-infected wild-type mice, again after long-standing achlorhydria and after Helicobacter spp.…”

Section: Achlorhydria and Bacterial Overgrowthsupporting

confidence: 66%

Inflammation, atrophy, and gastric cancer

Fox

Wang²

2007

J. Clin. Invest.

694

626

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The association between chronic inflammation and cancer is now well established. This association has recently received renewed interest with the recognition that microbial pathogens can be responsible for the chronic inflammation observed in many cancers, particularly those originating in the gastrointestinal system. A prime example is Helicobacter pylori, which infects 50% of the world's population and is now known to be responsible for inducing chronic gastric inflammation that progresses to atrophy, metaplasia, dysplasia, and gastric cancer. This Review provides an overview of recent progress in elucidating the bacterial properties responsible for colonization of the stomach, persistence in the stomach, and triggering of inflammation, as well as the host factors that have a role in determining whether gastritis progresses to gastric cancer. We also discuss how the increased understanding of the relationship between inflammation and gastric cancer still leaves many questions unanswered regarding recommendations for prevention and treatment.

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Section: Achlorhydria and Bacterial Overgrowthsupporting

confidence: 66%

Inflammation, atrophy, and gastric cancer

Fox

Wang²

2007

J. Clin. Invest.

694

626

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“…Zavros et al (39) have reported that transgenic gastrindeficient mice are susceptible to bacterial overgrowth when they are housed in conventional mouse facilities. While these authors isolated aerobic, facultative, and anaerobic bacteria from the stomachs of these mice, they did not quantify the susceptibility of individual mice to infection or the ability of specific pathogens to traverse the gastric environment and establish infection.…”

Section: Discussionmentioning

confidence: 99%

Influence of Gastric Acid on Susceptibility to Infection with Ingested Bacterial Pathogens

et al. 2008

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Despite the widely held belief that gastric acid serves as a barrier to bacterial pathogens, there are almost no experimental data to support this hypothesis. We have developed a mouse model to quantify the effectiveness of gastric acid in mediating resistance to infection with ingested bacteria. Mice that were constitutively hypochlorhydric due to a mutation in a gastric H ؉ /K ؉ -ATPase (proton pump) gene were infected with Yersinia enterocolitica, Salmonella enterica serovar Typhimurium, Citrobacter rodentium, or Clostridium perfringens cells or spores. Significantly greater numbers of Yersinia, Salmonella, and Citrobacter cells (P < 0.006) and Clostridium spores (P ‫؍‬ 0.02) survived in hypochlorhydric mice, resulting in reduced median infectious doses. Experiments involving intraperitoneal infection or infection of mice treated with antacids indicated that the increased sensitivity of hypochlorhydric mice to infection was entirely due to the absence of stomach acid. Apart from establishing the role of gastric acid in nonspecific immunity to ingested bacterial pathogens, our model provides an excellent system with which to investigate the effects of hypochlorhydria on susceptibility to infection and to evaluate the in vivo susceptibility to gastric acid of orally administered therapies, such as vaccines and probiotics.

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“…6 Emergence of a prominent mucous cell lineage (the so-called 'mucous cell metaplasia') was found to be one of the earliest histological changes in the fundic mucosa of these mice. 5 Mucosal changes bearing similar features have also been reported in a variety of pathological processes in human and mouse, which include H. pylori infection; [7][8][9] loss of parietal cells upon chemical administration; 10 treatment with a carcinogen, 11 mutation of the Kcnq1 gene encoding a potassium channel, 12 and constitutively active STAT3. 13 This type of mucosal change may therefore represent a common, and possibly reversible 10 response of the stomach, to mucosal injury and tissue inflammation triggered by various stimuli.…”

mentioning

confidence: 86%

“…5 A majority of these mice (60%) develop intestinal gastric adenocarcinoma by 12 months of age. 6 Emergence of a prominent mucous cell lineage (the so-called 'mucous cell metaplasia') was found to be one of the earliest histological changes in the fundic mucosa of these mice.…”

mentioning

confidence: 99%

Interferon gamma induction of gastric mucous neck cell hypertrophy

Kang

Rathinavelu

Samuelson

et al. 2005

Laboratory Investigation

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Chronic inflammation of the gastric epithelium is believed to induce mucosal changes that can eventually develop into gastric cancer. In gastrin-deficient (GÀ/À) mice exhibiting chronic inflammation in the hypochlorhydric stomach, we documented a prominent fundic mucous cell lineage sharing morphological similarity with preneoplastic changes reported in Helicobacter-infected mice. To study the identity and origin of this cell lineage, we screened for different gastric mucosal cell markers. The clusters of large, foamy cells stained for trefoil factor 2 (TFF2/SP), MUC6 and the lectin Griffonia Simplicifolia II (GSII), but not for the intestine-specific transcription factor Cdx2, suggested that they arise from gastric mucous neck cells. Ki67-labeled GSII-positive neck cells in Helicobacter felis-infected, but not GÀ/À stomachs, suggested that mucous neck cell proliferation accounted for expansion of this compartment in the H. felis model of gastritis, but not the GÀ/À model. Using RNase protection assays and quantitative PCR, we found that interferon gamma (IFNc) was the most abundant proinflammatory cytokine in the GÀ/À stomach. We also found that this Th1 cytokine can increase the abundance of mucous neck cells, since its infusion into mice recapitulated the appearance of these cells as observed in both GÀ/À and H. felis-infected mice. Using the human gastric cell line NCI-N87, we showed that IFNc induces the secretion of mucus and expression of MUC6, TFF2 and pepsinogen II, but not of pepsinogen I and intrinsic factor. In conclusion, our results demonstrate that inflammation, specifically the proinflammatory cytokine IFNc, induced expansion of the fundic mucous neck cell compartment, which likely represents both increased mucus production and cell number.

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Genetic or chemical hypochlorhydria is associated with inflammation that modulates parietal and G-cell populations in mice

Cited by 117 publications

References 39 publications

Inflammation, atrophy, and gastric cancer

Inflammation, atrophy, and gastric cancer

Influence of Gastric Acid on Susceptibility to Infection with Ingested Bacterial Pathogens

Interferon gamma induction of gastric mucous neck cell hypertrophy

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