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

doi:10.1053/gast.2002.30298

Gastroenterology

Volume 122, Issue 1, January 2002, Pages 119-133

https://doi.org/10.1053/gast.2002.30298 Get rights and content

Abstract

Background & Aims: Reduced gastric acid predisposes the stomach to colonization by bacteria and inflammation. Therefore, we investigated how the chronic gastritis in mice made hypochlorhydric by either gastrin deficiency or omeprazole treatment modulates epithelial cell function. Methods: The gastric pathology of 16-week-old wild-type gastrin-expressing (G+/+) and gastrin-deficient (G−/−) mice maintained in conventional housing was compared. G−/− mice were then treated with antibiotics for 20 days. In a separate experiment, G+/+ mice were treated with omeprazole for 2 months or treated with omeprazole and antibiotics. Results: Compared with the G+/+ animals, the hypochlorhydric G−/− mice showed significant inflammation that resolved after 20 days of antibiotic treatment and correlated with a decrease in bacterial overgrowth. Elevated G- and parietal-cell numbers in the G−/− mice, quantified by flow cytometry, normalized after antibiotic treatment. G+/+ mice treated with omeprazole had increased bacteria and mucosal lymphocytes that resolved after antibiotic therapy. Quantitation of the gastric cells in these omeprazole-treated mice revealed a significant increase in G- and parietal-cell numbers. On resolution of the gastritis, a decrease in parietal and gastrin-expressing (G) cells was observed despite sustained hypochlorhydria in the presence of omeprazole. Conclusions: Genetic or chemical hypochlorhydria predisposes the stomach to bacterial overgrowth resulting in inflammation. The specific changes in parietal and G cells correlate with the presence of inflammation and not directly with gastric acid. Thus, the normal stomach responds to inflammation by increasing the number and function of cell types that are able to maximize gastric acid output.

GASTROENTEROLOGY 2002;122:119-133

Section snippets

Animals

G−/− (n = 12) mice and strain-matched (129/Sv) wild-type controls (gastrin-expressing [G+/+], n = 12) were bred by homozygous mating. Mice were kept in individual, sterile, microisolator cages in nonbarrier mouse rooms for 16 weeks (conventional housing). Food and water were not autoclaved. No additional procedures were used to house the mice in rooms separate from those that have been intentionally infected with other bacterial pathogens. All mice were fasted overnight with access to water ad

Mucosal inflammation in G−/− mice

The effect of hypochlorhydria on gastric pathology in the G−/− mice was evaluated. Sixteen-week-old G−/− mice showed mucosal thickening and significant inflammation (Figure 1B) compared with the G+/+ mice (Figure 1A).

. Representative H&E and PAS/alcian blue stains from mouse stomachs. Representative H&E-stained sections of inflamed stomach from a 16-week-old (A) G+/+ and (B) G−/− mouse with severe inflammation (arrow) and (C) metaplasia (open arrow), (D) neutral (red arrowhead) and acid (black

Discussion

The findings reported here show that a major consequence of hypochlorhydria induced genetically or chemically is the generation of an inflammatory response. In G−/− mice, lymphocytes were elevated above levels measured in the wild-type (G+/+) animals. Similarly, wild-type mice treated with omeprazole had increased numbers of lymphocytes, indicative of chronic inflammation. This result is consistent with prior studies showing that humans treated with omeprazole also become colonized with gastric

Acknowledgements

The authors thank the flow cytometry core in the University of Michigan Cancer Center (CA46952) and University of Michigan Multipurpose Arthritic Center (AR20557), and the assistance of the radioligand core of the University of Michigan Gastrointestinal Peptide Research Center (DK-34533) for their technical assistance. They also acknowledge the use of rabbit gastrin antibody #1296 from CURE DDRC/RIA Core (DK41301). The authors thank Chris Dickinson for synthesizing iodinated gastrin peptide,

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^☆: Address requests for reprints to: Juanita L. Merchant, M.D., Ph.D., 1150 West Medical Drive, MSRB I, 3510, Ann Arbor, Michigan 48109-0650. e-mail: [email protected]; fax: (734) 936-1400.

^**: Supported in part by Public Health Service grant DK-45729 (to J.L.M.) and DK48815 (to L.C.S.).

^★: Y.Z. is an associate and J.L.M. is an assistant investigator of the Howard Hughes Medical Institute.

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Basic ResearchGenetic or chemical hypochlorhydria is associated with inflammation that modulates parietal and G-cell populations in mice☆,**,★

Abstract

Section snippets

Animals

Mucosal inflammation in G−/− mice

Discussion

Acknowledgements

Lancet

J Biotechnol

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Cancer Lett

Gastroenterology

Gastroenterology

Parasitism by the “slow” bacterium Helicobacter pylori leads to altered gastric homeostasis and neoplasia

J Clin Invest

Helicobacter pylori infection is the primary cause of gastric cancer

J Gastroenterol

Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii

N Engl J Med

Cellular immune responses are essential for the development of Helicobacter felis-associated gastric pathology

J Immunol

Helicobacter pylori-induced mucosal inflammation is Th1 mediated and exacerbated in IL-4, but not IFN-gamma, gene-deficient mice

J Immunol

Expression of antral gastrin and somatostatin mRNA in Helicobacter pylori-infected subjects

Am J Gastroenterol

High-salt diet induces gastric epithelial hyperplasia and parietal cell loss, and enhances Helicobacter pylori colonization in C57BL/6 mice

Cancer Res

Helicobacter pylori infection and the risk of gastric carcinoma

N Engl J Med

Helicobacter pylori and non-Helicobacter pylori bacterial flora in gastric mucosal and tumour specimens of patients with primary gastric lymphoma

Eur J Clin Invest

Epidemiology of gastric cancer: an evaluation of available evidence

J Gastroenterol

Pernicious anaemia, intragastric bacterial overgrowth, and possible consequences

Scand J Gastroenterol

Intestinal barriers to bacteria and their toxins

Annu Rev Med

Specific detection of Helicobacter pylori and non-Helicobacter pylori flora in small- and large-cell primary gastric B-cell non-Hodgkin's lymphoma

Ann Oncol

Differential features of gastric cancer patients, either Helicobacter pylori positive or Helicobacter pylori negative

Ital J Gastroenterol Hepatol

Basic Research
Genetic or chemical hypochlorhydria is associated with inflammation that modulates parietal and G-cell populations in mice☆,**,★