Iron deficiency linked to altered bile acid metabolism promotes Helicobacter pylori–induced inflammation–driven gastric carcinogenesis
Jennifer M. Noto, M. Blanca Piazuelo, Shailja C. Shah, Judith Romero-Gallo, Jessica L. Hart, Chao Di, James D. Carmichael, Alberto G. Delgado, Alese E. Halvorson, Robert A. Greevy, Lydia E. Wroblewski, Ayushi Sharma, Annabelle B. Newton, Margaret M. Allaman, Keith T. Wilson, M. Kay Washington, M. Wade Calcutt, Kevin L. Schey, Bethany P. Cummings, Charles R. Flynn, Joseph P. Zackular, Richard M. Peek Jr.
Jennifer M. Noto, M. Blanca Piazuelo, Shailja C. Shah, Judith Romero-Gallo, Jessica L. Hart, Chao Di, James D. Carmichael, Alberto G. Delgado, Alese E. Halvorson, Robert A. Greevy, Lydia E. Wroblewski, Ayushi Sharma, Annabelle B. Newton, Margaret M. Allaman, Keith T. Wilson, M. Kay Washington, M. Wade Calcutt, Kevin L. Schey, Bethany P. Cummings, Charles R. Flynn, Joseph P. Zackular, Richard M. Peek Jr.
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Research Article Gastroenterology Infectious disease

Iron deficiency linked to altered bile acid metabolism promotes Helicobacter pylori–induced inflammation–driven gastric carcinogenesis

Abstract

Gastric carcinogenesis is mediated by complex interactions among Helicobacter pylori, host, and environmental factors. Here, we demonstrate that H. pylori augmented gastric injury in INS-GAS mice under iron-deficient conditions. Mechanistically, these phenotypes were not driven by alterations in the gastric microbiota; however, discovery-based and targeted metabolomics revealed that bile acids were significantly altered in H. pylori–infected mice with iron deficiency, with significant upregulation of deoxycholic acid (DCA), a carcinogenic bile acid. The severity of gastric injury was further augmented when H. pylori–infected mice were treated with DCA, and, in vitro, DCA increased translocation of the H. pylori oncoprotein CagA into host cells. Conversely, bile acid sequestration attenuated H. pylori–induced injury under conditions of iron deficiency. To translate these findings to human populations, we evaluated the association between bile acid sequestrant use and gastric cancer risk in a large human cohort. Among 416,885 individuals, a significant dose-dependent reduction in risk was associated with cumulative bile acid sequestrant use. Further, expression of the bile acid receptor transmembrane G protein–coupled bile acid receptor 5 (TGR5) paralleled the severity of carcinogenic lesions in humans. These data demonstrate that increased H. pylori–induced injury within the context of iron deficiency is tightly linked to altered bile acid metabolism, which may promote gastric carcinogenesis.

Authors

Jennifer M. Noto, M. Blanca Piazuelo, Shailja C. Shah, Judith Romero-Gallo, Jessica L. Hart, Chao Di, James D. Carmichael, Alberto G. Delgado, Alese E. Halvorson, Robert A. Greevy, Lydia E. Wroblewski, Ayushi Sharma, Annabelle B. Newton, Margaret M. Allaman, Keith T. Wilson, M. Kay Washington, M. Wade Calcutt, Kevin L. Schey, Bethany P. Cummings, Charles R. Flynn, Joseph P. Zackular, Richard M. Peek Jr.

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Figure 4

H. pylori induces proinflammatory responses in C57BL/6 and INS-GAS mice within the context of iron deficiency.

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H. pylori induces proinflammatory responses in C57BL/6 and INS-GAS mice...
Male and female C57BL/6 and male INS-GAS mice were maintained on an iron-replete or iron-depleted diet and then challenged with Brucella broth (UI) or the H. pylori strain PMSS1. Mice were euthanized 8 weeks after challenge. Gastric tissue was analyzed using a cytokine/chemokine multiplex bead array. Data were acquired and analyzed using the Millipore software platform and expressed as picograms of chemokine per milligram of gastric tissue. Levels of KC (A), MIP-2 (B), MIP-1α (C), MIP-1β (D), IP-10 (E), and RANTES (F) were significantly increased by H. pylori infection in C57BL/6 mice under conditions of iron deficiency compared with infected mice maintained on an iron-replete diet. Levels of MIP-1α (G) and IL-17 (H) were significantly increased in H. pylori–infected INS-GAS mice under conditions of iron deficiency compared with infected mice maintained on an iron-replete diet. Each point represents data from an individual animal from 3 independent experiments. C57BL/6 mice: iron-replete UI (n = 5) and PMSS1 (n = 17); iron-depleted UI (n = 5) and PMSS1 (n = 17). INS-GAS mice: iron-replete UI (n = 4) and PMSS1 (n = 9); iron-depleted UI (n = 7) and PMSS1 (n = 17). Mean values are shown in the scatter dot plots. A 1-way ordinary ANOVA with Šidák’s multiple-comparison test was used to determine statistical significance. Only statistically significant comparisons are denoted. *P < 0.05, **P < 0.01, and ***P < 0.001.