Gastric inflammation, metaplasia, and tumor development in gastrin-deficient mice
Gastric inflammation, metaplasia, and tumor development in gastrin-deficient mice
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DOI：
10.1053/j.gastro.2006.04.031
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发表时间：
2006-07-01
期刊：
影响因子：
29.4
通讯作者：
Rehfeld, Jens F.
中科院分区：
文献类型：
--
作者：
Friis-Hansen, Lennart;Rieneck, Klaus;Rehfeld, Jens F.
背景与目的：胃泌素缺乏和质子泵抑制剂治疗会导致腹泻症，易患疾病。为了阐明潜在的分子生物学，我们检测了这两种类型的胃失弛缓症患者胃基因表达的变化。我们还探讨了胃微生物区系的相关变化和胃泌素缺乏性胃酸过少的长期后果。方法：从野生型小鼠、胃泌素基因敲除(KO)小鼠、胃泌素基因敲除(KO)小鼠、胃泌素基因敲除小鼠(GAS)注射胃泌素1周后和用质子泵抑制剂治疗1个月的野生型小鼠的胃RNA中获得表达谱。结果通过实时聚合酶链式反应和免疫组织化学得到证实。采用选择性培养基对胃微生物区系进行鉴定。结果：胃泌素KO组和PPI组小鼠胃细菌数量均明显增加。表达谱显示免疫防御基因、干扰素调节的反应基因和胃粘膜的肠化生被激活。在年轻的胃泌素缺乏的小鼠中，注射胃泌素逆转了这种变化。随着时间的推移，这些变化积累起来，变得不可逆转，并进展为化生和息肉发展。最后，研究表明胃泌素调节编码细胞外基质蛋白的基因的表达。结论：胃酸缺乏与胃泌素无关，与胃细菌过度生长和肠道基因表达模式有关，并与疾病易感性有关。因此，胃泌素对于预防胃病是必不可少的，主要是通过控制胃酸分泌，但在较小程度上也通过控制胃基因表达。胃泌素缺乏的小鼠是胃化生和肿瘤的有用的新模型。
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 I week of gastrin infusion, and wild-type mice treated for I month with a proton pump inhibitor. The results were confirmed using real-time polymerase chain reaction and immuno-histochemistry. 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.