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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Research Article

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 7

Increased virulence of H. pylori isolated from iron-depleted gerbils is abrogated under conditions of iron repletion in vivo.

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Increased virulence of H. pylori isolated from iron-depleted gerbils is ...
(A) Colonization density (log CFU/g of gastric tissue) was similar among gerbils infected with wild-type parental strain 7.13 or the in vivo-adapted strain isolated from an iron-depleted gerbil that developed cancer. (B) Gastric inflammation induced by parental strain 7.13 and the in vivo-adapted strain 6 weeks after challenge was assessed and scored (0 to12). Each data point represents the inflammation score from a single gerbil. Mean values are shown and Mann-Whitney U tests were used to determine statistical significance between groups. (C) The percentage of gerbils with gastritis or carcinoma is shown. Statistical differences were assessed by χ2 tests. (D) Readapted H. pylori strains induce similar levels of IL-8 expression in gastric epithelial cells compared with output strains from parental strain 7.13-infected gerbils. Data represent fold change over uninfected control cells. Error bars indicate standard error of the mean from experiments performed on at least 3 independent occasions, and Mann-Whitney U tests were used to determine statistical significance between groups.