Bile Acids Induce Intestinal Metaplasia, Gastric Cancer, and Chemoprevention

The symptoms of Gastric Cancer (GC) are often nonspecific, which can delay diagnosis and lead to a poor prognosis. In Intestinal Metaplasia (IM), bile reflux (BR) replaces the gastric mucosal epithelium with intestinal epithelium. Chenodeoxycholic Acid (CDCA) and Deoxycholic Acid (DCA), among the Bile Acids (BAs) in BR fluid, can stimulate BA receptors in the stomach. CDCA activates FXR, while DCA activates both GPCRs and FXR. DCA, a significant risk factor for gastrointestinal cancer, damages gastric epithelial cells by disrupting the outer mitochondrial membrane. This disruption produces reactive oxygen and nitrogen species, leading to DNA and chromosomal damage. Additionally, DCA causes gastric epithelial cells to progress from complete IM to incomplete IM. DCA activates multiple oncogenes, especially β-catenin, contributing to gastric carcinogenesis. In patients with GC, DCA increases levels of Dickkopf-1 (DKK1), which plays a crucial role in epithelial-mesenchymal transition (EMT), immune evasion, resistance to chemotherapy and immunotherapy, and metastasis by activating the β-catenin/Myc/STAT3 pathways. The vitamin D receptor (VTDR) regulates anti-cancer actions by halting cell growth, promoting apoptosis and autophagy, preventing blood vessel formation, and modulating immune responses and metastasis in GC through the inhibition of β-catenin.