Iron deficiency accelerates Helicobacter pylori–induced carcinogenesis in rodents and humans
Jennifer M. Noto, … , Manuel R. Amieva, Richard M. Peek Jr.
Jennifer M. Noto, … , Manuel R. Amieva, Richard M. Peek Jr.
Published December 21, 2012
Citation Information: J Clin Invest. 2013;123(1):479-492. https://doi.org/10.1172/JCI64373.
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Iron deficiency accelerates Helicobacter pylori–induced carcinogenesis in rodents and humans

Abstract

Gastric adenocarcinoma is strongly associated with Helicobacter pylori infection; however, most infected persons never develop this malignancy. H. pylori strains harboring the cag pathogenicity island (cag+), which encodes CagA and a type IV secretion system (T4SS), induce more severe disease outcomes. H. pylori infection is also associated with iron deficiency, which similarly augments gastric cancer risk. To define the influence of iron deficiency on microbial virulence in gastric carcinogenesis, Mongolian gerbils were maintained on iron-depleted diets and infected with an oncogenic H. pyloricag+ strain. Iron depletion accelerated the development of H. pylori–induced premalignant and malignant lesions in a cagA-dependent manner. H. pylori strains harvested from iron-depleted gerbils or grown under iron-limiting conditions exhibited enhanced virulence and induction of inflammatory factors. Further, in a human population at high risk for gastric cancer, H. pylori strains isolated from patients with the lowest ferritin levels induced more robust proinflammatory responses compared with strains isolated from patients with the highest ferritin levels, irrespective of histologic status. These data demonstrate that iron deficiency enhances H. pylori virulence and represents a measurable biomarker to identify populations of infected persons at high risk for gastric cancer.

Authors

Jennifer M. Noto, Jennifer A. Gaddy, Josephine Y. Lee, M. Blanca Piazuelo, David B. Friedman, Daniel C. Colvin, Judith Romero-Gallo, Giovanni Suarez, John Loh, James C. Slaughter, Shumin Tan, Douglas R. Morgan, Keith T. Wilson, Luis E. Bravo, Pelayo Correa, Timothy L. Cover, Manuel R. Amieva, Richard M. Peek Jr.

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Figure 6

H. pylori harvested in iron-depleted conditions in vivo and in vitro increase expression and translocation of CagA into gastric epithelial cells and augment the host proinflammatory response.

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H. pylori harvested in iron-depleted conditions in vivo and in vitro in...
In vivo-adapted H. pylori strains harvested from iron-replete (n = 5) or iron-depleted (n = 5) gerbils 12 weeks after infection, as well as strain 7.13 grown in vitro under iron-replete, iron-restricted, or iron-restricted conditions with iron supplementation (Iron-restricted+), were cocultured with AGS human gastric epithelial cells for 6 hours. In vivo-adapted H. pylori isolated from iron-depleted gerbils (A and B) exhibited increased CagA expression (A and C) and translocation (pCagA) into gastric epithelial cells. (D–F) In vitro, CagA expression and translocation were increased under iron-restricted conditions, a phenotype that was abrogated following the addition of exogenous iron. (G and H) In vivo-adapted H. pylori isolated from iron-depleted gerbils induced increased IL-8 expression in gastric epithelial cells compared with strains isolated from iron-replete gerbils, a phenotype that was recapitulated under iron-restricted conditions in vitro (I). Data represent fold change over parental preinoculation strain 7.13 (B and C) or over uninfected control cells (G–I). Error bars indicate standard error of the mean from experiments performed on at least 3 independent occasions, and Student’s t tests and ANOVAs were used to determine statistical significance between groups.