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

Duochen Jin; Keting Huang; Miao Xu; Hongjin Hua; Feng Ye; Jin Yan; Guoxin Zhang; Yun Wang

doi:10.1080/19490976.2022.2120744

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

Gut Microbes. 2022 Jan-Dec;14(1):2120744. doi: 10.1080/19490976.2022.2120744.

Authors

Duochen Jin^{1

2}, Keting Huang^{1

2}, Miao Xu^{1

2}, Hongjin Hua³, Feng Ye¹, Jin Yan¹, Guoxin Zhang^{1

2}, Yun Wang¹

Affiliations

¹ Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, Nanjing China.
² First Clinical Medical College, Nanjing Medical University, Nanjing, China.
³ Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

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.

Keywords: Deoxycholic acid; KLF5; STAT3; TGR5; bile acids metabolic profiling; carcinogenesis; gastric intestinal metaplasia; gastric microbiota.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bile Acids and Salts
Deoxycholic Acid / toxicity
Gastrointestinal Microbiome*
Humans
Metaplasia / chemically induced
Mice
Mice, Inbred C57BL
Microbiota*
Precancerous Conditions*
RNA, Ribosomal, 16S
STAT3 Transcription Factor / genetics
STAT3 Transcription Factor / metabolism

Substances

Bile Acids and Salts
RNA, Ribosomal, 16S
STAT3 Transcription Factor
STAT3 protein, human
Deoxycholic Acid

Grants and funding

This study was supported in part by the National Nature Science Foundation of China (No. 81770561, and No. 81970499) and Jiangsu Province Leading Talents and Innovation Team (CXTDA2017033).