Intestinal
metaplasia (IM) is the inevitable precancerous stage to develop intestinal-type
gastric cancer (GC).
Deoxycholic acid (DCA) is the main
bile acid (BA) component of
duodenogastric reflux and has shown an increased concentration during the transition from chronic
gastritis to IM associated with continued STAT3 activation. However, the mechanisms underlying how DCA facilitates IM in the gastric epithelium need exploration. We evaluated IM and
bile reflux in corpus tissues from 161 subjects undergoing GC screening. Cell survival and proliferation, proinflammatory
cytokine expression and TGR5/STAT3/KLF5 axis activity were measured in normal human gastric cells,
cancer cells, and organoid lines derived from C57BL/6, FVB/N and
insulin-
gastrin (INS-GAS) mice treated with DCA. The effects of DCA on IM development were determined in INS-GAS mice with long-term DCA supplementation, after which the gastric bacterial and BA metabolic profiles were measured by
16S rRNA gene sequencing and LC-MS. We revealed a BA-triggered TGR5/STAT3/KLF5 pathway in human gastric IM tissues. In gastric epithelial cells, DCA promoted proliferation and apoptotic resistance, upregulated proinflammatory
cytokines and IM markers, and facilitated STAT3 phosphorylation, nuclear accumulation and
DNA binding to the KLF5 promoter. DCA triggered STAT3 signaling and the downstream IM marker KLF5 in mouse gastric organoids in vitro and in vivo. In INS-GAS mice, DCA promoted the accumulation of serum total BAs and accelerated the stepwise development of gastric IM and dysplasia. DCA induced gastric environmental alterations involving abnormal BA metabolism and microbial
dysbiosis, in which the Gemmobacter and Lactobacillus genera were specifically enriched. Lactobacillus genus enrichment was positively correlated with increased levels of GCA, CA, T-α-MCA, TCA and β-MCA in DCA-administrated INS-GAS mice. DCA promotes nuclear STAT3 phosphorylation, which mediates KLF5 upregulation associated with gastric
inflammation and IM development. DCA disturbs the gastric microbiome and BA metabolism homeostasis during IM induction.