Iron deficiency linked to altered bile acid metabolism promotes Helicobacter pylori–induced inflammation–driven gastric carcinogenesis
Jennifer M. Noto, … , Joseph P. Zackular, Richard M. Peek Jr.
Jennifer M. Noto, … , Joseph P. Zackular, Richard M. Peek Jr.
Published March 22, 2022
Citation Information: J Clin Invest. 2022;132(10):e147822. https://doi.org/10.1172/JCI147822.
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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 6

DCA treatment significantly augments H. pylori–induced gastric inflammation and injury.

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DCA treatment significantly augments H. pylori–induced gastric inflammat...
Male INS-GAS mice were maintained on an iron-replete standard diet and then challenged with Brucella broth (n = 28) or the H. pylori strain PMSS1 (n = 25). Two weeks after infection, mice received water alone or water supplemented with 100 μM DCA throughout the course of the experiment. Mice were euthanized 6 weeks after challenge. (A) Average water consumption was measured. (B) Gastric tissue was harvested for quantitative culturing. Colonization density is expressed as log CFU/gram of tissue. Gastric tissue was assessed for indices of gastric inflammation (C) and disease incidence (D). Disease incidence includes normal histopathology, gastritis, and gastric dysplasia. Dysplasia was graded as indefinite dysplasia, low-grade dysplasia, or high-grade dysplasia. (E) Representative histologic image of low-grade dysplasia. Original magnification, ×200 and ×400 (enlarged inset). Scale bars: 100 μm. (F) The average number of Foxp3-positive cells was assessed by IHC from 5 high-powered fields (×400). Each point represents data from an individual animal from 3 independent experiments. (G–I) Gastric epithelial cells were cocultured with the H. pylori strain PMSS1 and then treated with either vehicle control or 50 μM DCA for 6 hours, and protein lysates were harvested for Western blot analysis. Levels of phosphorylated CagA (G) and the ratio of phosphorylated CagA (pCagA) to total CagA (H). Representative Western blots (I). Mean values are shown in the scatter dot plots. An unpaired parametric t test (B, G, and H), 1-way ordinary ANOVA with Šidák’s multiple-comparison test (A, C, and F), and Fisher’s exact test (D) were used to determine statistical significance. Only statistically significant comparisons are denoted. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.