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 8

TGR5 expression parallels the severity of gastric disease.

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TGR5 expression parallels the severity of gastric disease. (A) TGR5 prot...
(A) TGR5 protein expression was evaluated by IHC in human gastric tissues from a gastric cancer TMA. A single pathologist assessed the percentage of TGR5-positive cells and the intensity of TGR5 staining. The IHC score reflects the percentage of cells positive for TGR5, multiplied by the intensity of staining, as previously described (61). TGR5 staining was assessed in gastric tissue sections from patients with no pathology (normal, n = 11), nonatrophic gastritis (NAG, n = 7), multifocal atrophic gastritis (MAG, n = 11) without intestinal metaplasia, intestinal metaplasia (IM, n = 9), dysplasia (DYS, n = 3), or gastric cancer (GC, n = 40). (B–E) Representative images of TGR5 protein expression in normal gastric tissue sections (B) and gastric tissue sections with multifocal atrophic gastritis (C), intestinal metaplasia (D), and gastric cancer (E). Original magnification, ×200. Scale bars: 100 μm. (F) RNA was extracted from normal gastric tissue (n = 12), gastric tissue with gastritis alone (n = 12), and gastric tissue with gastric adenocarcinoma (n = 12). TGR5 mRNA expression levels were standardized to GAPDH mRNA expression levels and are shown as fold relative to normal [2^–(ΔΔCt)]. 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 < 0.0001.