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 7

Cholestyramine treatment significantly reduces H. pylori–induced inflammation and injury under conditions of iron deficiency in INS-GAS mice.

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Cholestyramine treatment significantly reduces H. pylori–induced inflamm...
Male INS-GAS mice were maintained on an iron-replete (n = 66) or iron-depleted (n = 65) diet supplemented with or without 2% cholestyramine (w/w) and then challenged with Brucella broth or the H. pylori strain PMSS1. Mice were euthanized 8 weeks after challenge. Whole blood was collected for CBC analysis from a subset of H. pylori–infected mice maintained on an iron-replete or iron-depleted diet with or without cholestyramine supplementation. (A) Hemoglobin, hematocrit, and mean corpuscular volume were assessed as parameters of iron deficiency. (B) Gastric tissue was processed for targeted bile acid analyses to assess DCA levels. (C) Gastric tissue was harvested for quantitative culturing. Colonization density is expressed as log CFU/g of tissue. (D–F) Gastric tissue was assessed for indices of inflammation (D) and disease incidence (E). Disease incidence includes normal histopathology, gastritis, and gastric dysplasia. Dysplasia was graded as indefinite dysplasia (borderline nuclear and architectural epithelial changes that do not completely fit the patterns of dysplasia), low-grade dysplasia, or high-grade dysplasia. (F) Representative histologic image of indefinite dysplasia is shown. Original magnification, ×200 and ×400 (enlarged inset). Scale bars: 100 μm. Each point represents data from an individual animal from 3 independent experiments. Mean values are shown in the scatter dot plots. Median values are shown in box-and-whisker plots, with whiskers designating minimum and maximum values. An unpaired parametric t test (A), 1-way ordinary ANOVA with Šidák’s multiple-comparison test (B–D), and Fisher’s exact test (E) were used to determine statistical significance. Only statistically significant comparisons are denoted. *P < 0.05, **P < 0.01, ***P < 0.005, and ****P < 0.0001.