Helicobacter pylori infection and disease: from humans to animal models

Abstract

Informative and tractable animal models that are colonized by well-defined microbial pathogens represent ideal systems for the study of complex human diseases. Helicobacter pylori colonization of the stomach is a strong risk factor for peptic ulceration and distal gastric cancer. However, gastritis has no adverse consequences for most hosts and emerging evidence suggests that H. pylori prevalence is inversely related to gastroesophageal reflux disease and allergic disorders. These observations indicate that eradication may not be appropriate for certain populations due to the potentially beneficial effects conferred by persistent gastric inflammation. Animal models have provided an invaluable resource with which to study H. pylori pathogenesis and carcinogenesis, and have permitted the development of a focused approach to selectively target human populations at high-risk of disease.

Fig. 1. Molecular signaling alterations induced by intracellular delivery of CagA

After bacterial attachment, the cag secretion system translocates CagA, the product of the terminal gene in the cag island, into host epithelial cells. Intracellular CagA undergoes tyrosine phosphorylation by Src and Abl kinases, and activates a eukaryotic phosphatase (SHP-2) leading to morphological changes that are reminiscent of unrestrained stimulation by growth factors. Non-phosphorylated CagA also exerts effects within the cell, such as aberrant activation of β-catenin, leading to targeted, transcriptional upregulation of genes implicated in carcinogenesis.

Fig. 2. Relationships between the location of H. pylori-induced gastric inflammation, acid secretion, and disease

Antral-predominant gastritis with relative sparing of the acid-secreting corpus leads to increased acid secretion and an increased risk for duodenal ulcer disease. Corpus-predominant gastritis, a precursor lesion in the progression to gastric adenocarcinoma, is associated with reduced acid secretion and may represent a factor underpinning the inverse association between H. pylori infection and complications of gastroesophageal reflux disease.

Fig. 3. In vivo derivation of carcinogenic H. pylori strain 7.13

A gerbil infected with the human H. pylori clinical isolate B128 was sacrificed 3 weeks post-challenge, and a single colony output derivative (7.13) was used to infect an independent population of gerbils. Gerbils infected with strain 7.13, but not B128, developed gastric carcinoma.