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 1

Dietary iron depletion results in decreased hepatic iron, serum ferritin, hemoglobin, hematocrit, and gastric iron.

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Dietary iron depletion results in decreased hepatic iron, serum ferritin...
MRI was utilized to assess relative levels of hepatic iron in gerbils maintained on iron-replete or iron-depleted diets for 12 weeks. A representative (A) coronal scan (white box outlines liver tissue), (B) axial scan, (C) heat map, and (D) echo series (blue lines outline liver margins) are shown from an iron-replete gerbil. (E) Signal decay over time demonstrated that iron-depleted gerbils have a slower rate of signal decay, which is inversely proportional to the level of hepatic iron. (F) The cumulative rate of signal decay demonstrated that gerbils maintained on iron-depleted diets have significantly slower rates of signal decay, representing lower levels of hepatic iron. (G) ICP-DRC-MS indicated that hepatic iron concentration is significantly lower in gerbils maintained on iron-depleted diets (n = 65) versus iron-replete diets (n = 65) at 6 and 12 weeks. (H) ELISAs demonstrated that serum ferritin concentrations are significantly lower in gerbils maintained on iron-depleted (n = 40) versus iron-replete (n = 40) diets at 6 and 12 weeks. (I) Hemoglobin and (J) hematocrit values were assessed from blood isolated from gerbils maintained on iron-replete (n = 8) versus iron-depleted (n = 8) diets at 6 weeks. (K) ICP-MS demonstrated that gerbils maintained on iron-depleted diets (n = 8) have significantly lower levels of gastric iron versus gerbils maintained on iron-replete diets (n = 7) at 6 weeks. Data points represent values from individual gerbil samples. Mean values are shown, and error bars indicate standard error. Student’s t tests were used to determine statistical significance.