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

Abstract

Bile acids modulate cell functions in health and disease, however, the mechanisms underlying their actions on neoplastic cells in the gastrointestinal (GI) tract remain largely unknown. In this issue of the JCI, Noto et al. comprehensively analyzed how interactions between Helicobacter pylori infection, iron deficiency, and bile acids modulate gastric inflammation and carcinogenesis. The investigators used sophisticated models, including INS-GAS mice with elevated serum gastrin and gastric acid secretion, in which H. pylori infection mimics human disease progression, to show that selected bile acids potentiated the carcinogenic effects of H. pylori infection and iron depletion. This elegant work has broad translational implications for microbe-associated GI neoplasia. Importantly, bile acid sequestration robustly attenuated the combined effects of H. pylori infection and iron depletion on gastric inflammation and cancer.

Figure 1. In the setting of auspicious host and bacterial genetic features and a favorable microenvironment, gastric H. pylori infection promotes chronic inflammation, epithelial cell dysplasia, and neoplastic transformation.

(i) In the mucus gel adherent to the surface of gastric epithelial cells, cag-positive H. pylori with the type IV secretory system and additional virulence attributes (e.g., vacuolating cytotoxin) intoxicate the host cell cytosol, thereby activating multiple signaling pathways that control cell proliferation and polarity and other proneoplastic attributes. Notably, H. pylori–induced gastric mucosal inflammation and the progression to dysplasia and cancer are modulated by dietary micronutrients. As shown by Noto et al. (18, 19), serum iron depletion hastens the development of H. pylori–induced gastric inflammation and cancer. (ii) Gut microbes in other compartments of the GI tract may promote mucosal neoplasia by mechanisms like those of H. pylori. (iii) Gastric reflux of bile acids, modified by gut bacterial dehydroxylation and deconjugation, potentiates the proinflammatory and proneoplastic effects of H. pylori infection. (iv) Gastric cancer cells display intratumor heterogeneity and overexpress receptors for neurotransmitters and bioactive molecules, such as bile acids. (v) Healthy GI epithelial cells express and cancer cells overexpress a variety of GPCRs, including the bile acid receptors TGR5, M₃R, and S1PR2. (vi) H. pylori infection is associated with localized immune cell infiltrates in the proliferative zones of gastric pits. Local GI immune responses are regulated by specialized DCs. (vii) Secretory products of enteroendocrine cells modulate epithelial cell signaling. (viii) Likewise, components of the enteric nervous system modulate cellular and immune responses.