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 8

Iron levels are inversely related to the severity of H. pylori–induced premalignant lesions and H. pylori virulence in a human population.

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Iron levels are inversely related to the severity of H. pylori–induced p...
(A) Serum samples, harvested from H. pylori–infected Colombian patients at high risk for gastric cancer, were segregated based on severity of gastric injury (non-atrophic gastritis, n = 55; atrophic gastritis, n = 40; intestinal metaplasia, n = 99) and analyzed for ferritin concentration by ELISA. Each data point represents the serum ferritin concentration from a single patient. (B and C) Strains harvested from patients with the lowest (n = 10) or highest (n = 10) serum ferritin concentrations from patients with gastritis alone (B) or intestinal metaplasia (C) were cocultured with AGS human gastric epithelial cells for 6 hours. Each strain was tested on 3 independent occasions and data points represent each independent replicate. Strains isolated from patients with the lowest ferritin concentrations (Low) induced significantly higher levels of IL-8 compared with strains isolated from patients with the highest ferritin concentrations (High) from both the gastritis alone and intestinal metaplasia groups. Mean values are shown and Mann-Whitney U tests were used to determine statistical significance between groups.