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 2

Iron deficiency augments H. pylori–induced gastric inflammation and injury in INS-GAS mice.

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Iron deficiency augments H. pylori–induced gastric inflammation and inju...
Male INS-GAS mice were maintained on an iron-replete (n = 22) or iron-depleted (n = 33) diet and then challenged with Brucella broth (UI) or the H. pylori strain PMSS1. Mice were euthanized 8 weeks after challenge. (A) Gastric tissue was homogenized and plated for quantitative culturing. Colonization density is expressed as log CFU/g of tissue. (B) Gastric tissue was fixed, paraffin embedded, and stained with a modified Steiner stain. The percentage of H. pylori colonizing the antrum, transition zone, and corpus was assessed, and the average topographical H. pylori colonization density/mouse is shown. (C–K) Gastric tissue was fixed, paraffin embedded, and stained with H&E. (C) Levels of total gastric inflammation (score of 0–12). (D–G) Representative histologic images from the antrum of uninfected mice maintained on an iron-replete (D) or iron-depleted (E) diet and of H. pylori–infected mice maintained on an iron-replete (F) or iron-depleted (G) diet (original magnification, ×200; scale bars: 100 μm). Gastric tissue was scored separately for acute (H) and chronic (I) inflammation and disease incidence (J). Dysplasia was graded as indefinite dysplasia (borderline nuclear and architectural epithelial changes that do not completely fit the patterns of dysplasia), low-grade or high-grade dysplasia. (K) Representative histologic images of indefinite dysplasia. Original magnification, ×200 and ×400 (enlarged inset). Scale bar: 100 μm. Each point represents data from an individual animal from 3 independent experiments. Mean values are shown in the scatter dot plots. An unpaired parametric t test (A and B), 1-way ordinary ANOVA with Šidák’s multiple-comparison test (C, H, and I), and Fisher’s exact test (J) were used to determine statistical significance. *P < 0.05, ***P < 0.001, and ****P < 0.0001.