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 2

Iron depletion augments and accelerates H. pylori–induced gastric inflammation and carcinogenesis.

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Iron depletion augments and accelerates H. pylori–induced gastric inflam...
(A) Gastric inflammation at 6–12 weeks after challenge was assessed and scored (0 to 12) in uninfected (UI) and H. pylori–infected gerbils. 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. (B) Correlation plot demonstrates an inverse relationship between the severity of gastric inflammation and H. pylori colonization density at 6–12 weeks after challenge. Each data point represents the inflammation score and colonization density from a single gerbil maintained on iron-replete (black symbols) or iron-depleted (gray symbols) diets. Spearman nonparametric correlations were used to determine the Spearman r correlation coefficient and statistical significance. (C and D) The percentage of gerbils that remained disease-free, as defined by absence of (C) dysplasia or (D) adenocarcinoma, at 2, 6, and 12 weeks after challenge is represented as Kaplan-Meier curves. Statistical differences were determined by log-rank tests.