Scholarlink

Background <p>Long-term proton pump inhibitor (PPI) use is associated with increased intestinal disease risk, but its damaging mechanisms remain unclear.</p> Methods <p>Mice were administered rabeprazole (Rab) for 4 weeks before dextran sulfate sodium (DSS) or ionizing radiation (IR) injury. We employed RNA sequencing, metabolomics, and metagenomics, evaluated intestinal stem cell (ISC) function, and used organoids for validation.</p> Results <p>Long-term Rab induced small intestinal mucosal injury and exacerbated DSS/IR-induced damage, manifesting as crypt/villus atrophy and reduced ISC numbers. Mechanistically, Rab downregulated the Wnt pathway and impaired mucosal defense and regeneration. Microbiota involvement was indicated by fecal transplantation. Integrated metagenomic and metabolomic analyses revealed that Rab induced intestinal dysbiosis and reduced ileal bile acids, particularly 7-ketolithocholic acid (7KLCA) and chenodeoxycholic acid (CDCA). <i>Faecalibaculum rodentium </i> supplementation restored ISC self-renewal by converting CDCA to 7KLCA. In vitro, 7KLCA activated Wnt signaling to rescue Rab-induced stem cell impairment. In vivo, both 7KLCA and Gly-β-MCA (intestinal FXR antagonists) suppressed the FXR-FGF15 axis, restored the expression of hepatic bile acid synthesis enzymes, and promoted epithelial repair, thereby mitigating DSS-induced injury.</p> Conclusions <p>Chronic PPI use impairs ISC self-renewal by disrupting the microbiota-7KLCA-Wnt axis. <i>F. rodentium</i> or 7KLCA supplementation ameliorates PPI-induced effects, highlighting a microbe-metabolite axis as a pivotal mechanism and potential therapies for PPI-associated intestinal damage.</p> Graphical Abstract <p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Chronic proton pump inhibitor exposure aggravates intestinal injury by impairing intestinal stem cell self-renewal through the microbiota-7-ketolithocholic acid Axis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月18日

查看全文
  • Xinyuan Wang,
  • Li Cheng,
  • Kehan Yin,
  • Bo Wang,
  • Xiujuan Yan,
  • Shengliang Chen

摘要

Background

Long-term proton pump inhibitor (PPI) use is associated with increased intestinal disease risk, but its damaging mechanisms remain unclear.

Methods

Mice were administered rabeprazole (Rab) for 4 weeks before dextran sulfate sodium (DSS) or ionizing radiation (IR) injury. We employed RNA sequencing, metabolomics, and metagenomics, evaluated intestinal stem cell (ISC) function, and used organoids for validation.

Results

Long-term Rab induced small intestinal mucosal injury and exacerbated DSS/IR-induced damage, manifesting as crypt/villus atrophy and reduced ISC numbers. Mechanistically, Rab downregulated the Wnt pathway and impaired mucosal defense and regeneration. Microbiota involvement was indicated by fecal transplantation. Integrated metagenomic and metabolomic analyses revealed that Rab induced intestinal dysbiosis and reduced ileal bile acids, particularly 7-ketolithocholic acid (7KLCA) and chenodeoxycholic acid (CDCA). Faecalibaculum rodentium supplementation restored ISC self-renewal by converting CDCA to 7KLCA. In vitro, 7KLCA activated Wnt signaling to rescue Rab-induced stem cell impairment. In vivo, both 7KLCA and Gly-β-MCA (intestinal FXR antagonists) suppressed the FXR-FGF15 axis, restored the expression of hepatic bile acid synthesis enzymes, and promoted epithelial repair, thereby mitigating DSS-induced injury.

Conclusions

Chronic PPI use impairs ISC self-renewal by disrupting the microbiota-7KLCA-Wnt axis. F. rodentium or 7KLCA supplementation ameliorates PPI-induced effects, highlighting a microbe-metabolite axis as a pivotal mechanism and potential therapies for PPI-associated intestinal damage.

Graphical Abstract