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 5

Exposure of H. pylori to iron-depleted conditions in vivo and in vitro augments the capacity to assembly pilus components of the cag T4SS.

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Exposure of H. pylori to iron-depleted conditions in vivo and in vitro a...
In vivo-adapted H. pylori strains isolated from iron-replete (n = 5) and iron-depleted (n = 5) gerbils 12 weeks after infection as well as the parental preinoculation strain 7.13 grown in vitro under iron-replete, iron-restricted, or iron-restricted conditions with iron supplementation (Iron-restricted+) were cocultured with AGS human gastric epithelial cells for 4 hours, and cag T4SS pili were visualized by scanning electron microscopy. Images of 10 independent H. pylori strains isolated from (A–E) iron-replete or (G–K) iron-depleted gerbils and a representative image of strain 7.13 grown in vitro under (F) iron-replete and (L) iron-restricted conditions during coculture with AGS cells are shown. Arrows designate representative cag T4SS pili. Scale bars: 1 μm (A–L). (M and N) The number of cag T4SS pili per bacterial cell was enumerated based on analysis of at least 20 high-powered fields. Each data point represents the number of T4SS pili per bacterial cell (M, analysis of output strains from iron-replete, n = 57 and iron-depleted gerbils, n = 99; N, analysis of the preinoculation strain 7.13 in vitro under varying iron conditions; replicates: iron-replete, n = 20; iron-restricted, n = 20; iron-restricted+, n = 20). Mean values are shown, and Student’s t tests were used to determine statistical significance between groups.