Gastric inflammation, metaplasia, and tumor development in gastrin-deficient mice.

Abstract

BACKGROUND & AIMS:

Gastrin deficiency and proton pump inhibitor treatment cause achlorhydria, which predisposes to disease. To elucidate the underlying molecular biology, we examined the changes in gastric gene expression in both types of achlorhydria. We also explored the associated changes in the gastric microflora and the long-term consequences of gastrin-deficient achlorhydria.

METHODS:

Expression profiles were generated from gastric RNA from wild-type mice, gastrin knockout (KO) mice, gastrin KO mice after 1 week of gastrin infusion, and wild-type mice treated for 1 month with a proton pump inhibitor. The results were confirmed using real-time polymerase chain reaction and immunohistochemistry. Selective media were used to characterize the gastric microflora.

RESULTS:

The number of gastric bacteria was increased in both gastrin KO and PPI-treated mice. The expression profiles revealed activation of immune defense genes, interferon-regulated response genes, and intestinal metaplasia of the gastric mucosa. In young gastrin-deficient mice, gastrin infusions reversed the changes. Over time, the changes accumulated, became irreversible, and progressed into metaplasia and polyp development. Finally, the study showed that gastrin regulated the expression of genes encoding extracellular matrix proteins.

CONCLUSIONS:

Independently of gastrin, achlorhydria is associated with gastric bacterial overgrowth and intestinal gene expression patterns and is associated with predisposition to disease. Gastrin is therefore essential for prevention of gastric disease, mainly through control of acid secretion but to a lesser extent also through control of gastric gene expression. The gastrin-deficient mouse serves as a useful new model for gastric metaplasia and neoplasia.

• Authors: Lennart Friis-Hansen, Klaus Rieneck, Hans-Olof Nilsson, Torkel Wadström, Jens F Rehfeld
• Journal: Gastroenterology (Gastroenterology) Vol. 131 Issue 1 Pg. 246-58 (Jul 2006) ISSN: 0016-5085 [Print] United States
• PMID: 16831607 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CDX2 Transcription Factor
• Cdx1 protein, mouse
• Cdx2 protein, mouse
• DNA, Neoplasm
• Gastrins
• Homeodomain Proteins
• Hormones
• Transcription Factors

Topics

• Animals
• CDX2 Transcription Factor
• DNA, Neoplasm (genetics)
• Disease Models, Animal
• Female
• Gastric Mucosa (metabolism, pathology)
• Gastrins (deficiency, therapeutic use)
• Gastritis (genetics, metabolism, prevention & control)
• Gene Expression (drug effects)
• Homeodomain Proteins (genetics)
• Hormones (deficiency, therapeutic use)
• Immunohistochemistry
• Male
• Metaplasia (genetics, metabolism, prevention & control)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Polymerase Chain Reaction
• Stomach Neoplasms (genetics, metabolism, prevention & control)
• Transcription Factors (genetics)