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

Xinyuan Wang, Li Cheng, Kehan Yin, Bo Wang, Xiujuan Yan, Shengliang Chen

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Article in Journal of translational medicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

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A 5:2 Intermittent Fasting Regimen Ameliorates High-Fat Diet-Induced MASLD-Associated Skeletal Muscle Impairment in Mice.Journal of cachexia, sarcopenia and muscle · 2026
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6 authors.

Xinyuan Wang *Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200001, China.

Li Cheng *Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200001, China.

Kehan YinDivision of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200001, China.

Bo WangDivision of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200001, China.

Xiujuan YanDivision of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200001, China.

Shengliang ChenDivision of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200001, China. chenslmd@shsmu.edu.cn.ORCID 0000-0001-7672-5014

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

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

methodsMice 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.

resultsLong-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.

conclusionsChronic 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.

Indexed as

Cell Self RenewalGastrointestinal MicrobiomeIntestinesLithocholic AcidProton Pump InhibitorsStem CellsAnimalsIntestinal MucosaMaleMice, Inbred C57BLOrganoidsRabeprazoleWnt Signaling PathwayLithocholic AcidProton Pump InhibitorsRabeprazole7-ketolithocholic acidFaecalibaculum rodentiumProton pump inhibitorsStem cells

Identifiers

PMID42316284

DOI10.1186/s12967-026-08448-9

PMCPMC13528042

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