Deoxycholic acid induces gastric intestinal metaplasia by activating STAT3 signaling and disturbing gastric bile acids metabolism and microbiota

Abstract

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.

The role of bile acid in intestinal metaplasia

“…Several studies have shown that lactobacillus is widely colonized in human gastric mucosa ( Hakalehto et al, 2011 ; Delgado et al, 2013 ). It metabolizes lactose into lactic acid, which acidifies the mucous layer of the stomach and then inhibits the secretion of gastrin and gastric acid by the G cells of the antrum ( Myllyluoma et al, 2007 ; Jin et al, 2022 ). Therefore, a higher relative abundance of Lactobacillus in the gastric microbiome may accelerate gastric mucosal atrophy, IM, and tumorigenesis ( Jin et al, 2022 ).…”

“…It metabolizes lactose into lactic acid, which acidifies the mucous layer of the stomach and then inhibits the secretion of gastrin and gastric acid by the G cells of the antrum ( Myllyluoma et al, 2007 ; Jin et al, 2022 ). Therefore, a higher relative abundance of Lactobacillus in the gastric microbiome may accelerate gastric mucosal atrophy, IM, and tumorigenesis ( Jin et al, 2022 ). In addition, a high abundance of Thermus and Anoxybacillus was also detected in gastric juices of IM patients ( Liu et al, 2022 ).…”

Effect of gut flora mediated-bile acid metabolism on intestinal immune microenvironment

“…In the case of bowel cancer, how FXR regulates tumor growth by affecting energy is worthy of further investigation. DCA activates the STAT3 signaling pathway, interferes with the gastric microbiome and BA metabolism, and induces gastrointestinal metaplasia 105 . DCA reduces the expression of FXR, activates the Wnt signaling pathway, increases the levels of β-catenin and c-Myc, and promotes the proliferation and migration of colon cancer cells.…”

Microbial metabolites in colorectal tumorigenesis and cancer therapy

“…In addition, SBAs also promote colorectal tumorigenesis by activating oncogenic pathways including TGR5/STAT3, WNT/β-catenin, and NF-kB signaling. 71–74 A recent study in 2022 reported that SBAs could enhance stemness of CRC stem cells, of which SBAs involving tauro-β-muricholic acid and DCA induce proliferation of Lgr5-expressing cancer stem cells, further driving malignant transformation and promoting the adenoma-carcinoma progression. 75 Consistently, oral administration of DCA to mice led to increased colonic expression of R-spondin 3, an important protein regulating stem cell fate, whereas depletion of R-spondin 3 prevented such DCA-induced stem cell proliferation.…”