IRON DEFICIENCY PROMOTES HELICOBACTER PYLORI-INDUCED GASTRIC CARCINOGENESIS BY ENABLING RECIPROCITY BETWEEN CARCINOGENIC SECONDARY BILE ACIDS AND PROTECTIVE LONG-CHAIN FATTY ACIDS.

Abstract

Helicobacter pylori (Hp) is the strongest known risk factor for gastric adenocarcinoma. We previously demonstrated that iron deficiency, a condition of the exposome, augments Hp-induced carcinogenesis. To define mechanisms driving this phenotype, we performed targeted metabolomics in mice which revealed that Hp significantly increased levels of deoxycholic acid (DCA), a carcinogenic secondary bile acid, exclusively under iron-deficient conditions. Further, DCA directly promoted Hp-induced dysplasia. Because bile acids and fatty acids can exert opposing effects on disease, fatty acids were also assessed within the context of iron deficiency and infection. In contrast to bile acids, long-chain fatty acids (LCFAs) were significantly downregulated by Hp under iron-deficient conditions, including levels of palmitic acid, a LCFA with therapeutic potential against gastric cancer. These data indicate that Hp increases levels of carcinogenic secondary bile acids with concordant reductions in protective LCFAs under iron-deficient conditions, suggesting an active interplay between these effectors in cancer risk.