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Iron deficiency linked to altered bile acid metabolism promotes Helicobacter pylori-induced inflammation-driven gastric carcinogenesis


AUTHORS

Noto JMJennifer M , Piazuelo MBM Blanca , Shah SCShailja C , Romero-Gallo JJudith , Hart JLJessica L , Di CChao , Carmichael JDJames D , Delgado AGAlberto G , Halvorson AEAlese E , Greevy RARobert A , Wroblewski LELydia E , Sharma AAyushi , Newton ABAnnabelle B , Allaman MMMargaret M , Wilson KTKeith T , Washington MKM Kay , Calcutt MWM Wade , Schey KLKevin L , Cummings BPBethany P , Flynn CRCharles R , Zackular JPJoseph P , Peek RMRichard M . The Journal of clinical investigation. 2022 5 16; 132(10).

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.