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 4

Wild-type H. pylori strain 7.13 colonizes multiple sites within gerbil gastric tissue and colonizes gastric glands to higher levels under iron-depleted conditions.

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Wild-type H. pylori strain 7.13 colonizes multiple sites within gerbil g...
Immunofluorescence and confocal microscopy were performed on gastric tissue from gerbils infected with H. pylori for 6 weeks. For all images, tissue sections were stained for H. pylori (green), actin (red), and cellular nuclei (blue). H. pylori was distributed throughout the entire glandular stomach, including the (A) corpus and (B) antrum. (C–E) Boxes designate representative areas shown at higher magnification. H. pylori localized to multiple sites within the gastric gland, including the (C) apical region, (D) glandular pit, and (E) glandular neck, and (F) formed microcolonies. Scale bars: 40 μm (A and B) and 10 μm (C–F). Representative examples of infected gastric glands from (G) iron-replete and (H) iron-depleted gerbils used for quantification of H. pylori. Scale bar: 10 μm (G and H). (I) The number of H. pylori in a subset of iron-replete (n = 31) and iron-depleted (n = 39) gastric glands were quantified and expressed as log CFU/gland.