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.

Gastrointestinal neoplasia: carcinogenic interaction between bile acids and Helicobacter pylori in the stomach

“…In their current, scientifically rigorous work in this issue of the JCI , Noto et al ( 19 ) greatly extended their previous work by using INS-GAS mice to confirm that iron deficiency exacerbates H . pylori –induced gastritis and dysplasia and elucidated the underlying mechanisms.…”

“…pylori –infected C57BL/6 and INS-GAS mice, Noto et al found that, compared with infected mice under iron-replete conditions, variants of muricholic acid, cholic acid, and deoxycholic acid (DCA) were markedly increased by H . pylori infection in iron-deficient animals ( 19 ). As proof of principle, treating INS-GAS mice with DCA augmented, while bile acid sequestration attenuated, H .…”

“…As proof of principle, treating INS-GAS mice with DCA augmented, while bile acid sequestration attenuated, H . pylori –induced gastric inflammation and injury ( 19 ). As a measure of clinical relevance, using a retrospective database analysis, the authors found that the use of bile acid sequestrants in humans was associated with reduced gastric cancer risk, and expression of a bile acid receptor, TGR5, paralleled disease severity.…”

“…Nonetheless, the levels of Tgr5 expression in mice did not alter the severity of H . pylori –induced gastric inflammation, suggesting other mechanisms were at play ( 19 ). For example, the authors found that coculturing H .…”

“…For example, the authors found that coculturing H . pylori with DCA increased the translocation of CagA into host cells by a yet obscure mechanism ( 19 ). Notably, TGR5 is not the only bile acid receptor whose expression may be relevant to gastric cancer; for example, other investigators reported a functional increase in M 3 subtype muscarinic receptor (M 3 R) expression in gastric adenocarcinoma ( 8 , 9 ).…”