Capsaicin ameliorates cholestasis through modulation of the FXR-SHP and FXR-FGF15 gut-liver axis in mice

Hui Du; Yue Luo; Ning Zhou; Tong Wang; Ruiyu Wang; Yang Wang; Chuanzhu Lv

doi:10.1016/j.phymed.2025.157130

Capsaicin ameliorates cholestasis through modulation of the FXR-SHP and FXR-FGF15 gut-liver axis in mice

Phytomedicine. 2025 Oct:146:157130. doi: 10.1016/j.phymed.2025.157130. Epub 2025 Aug 5.

Authors

Hui Du¹, Yue Luo¹, Ning Zhou², Tong Wang³, Ruiyu Wang⁴, Yang Wang⁵, Chuanzhu Lv⁶

Affiliations

¹ School of Medicine, University of Electronic Science and Technology of China, Chengdu 610054, PR China; Department of Emergency Medicine Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610064, PR China.
² Department of Emergency, Central People's Hospital of Zhanjiang, Zhanjiang 524045, PR China.
³ Department of Emergency, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518003, PR China.
⁴ Department of Emergency Medicine Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610064, PR China.
⁵ Department of Emergency Medicine Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610064, PR China. Electronic address: young0416@163.com.
⁶ Department of Emergency Medicine Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610064, PR China; Research Unit of Island Emergency Medicine, Chinese Academy of Medical Sciences (No. 2019RU013), Hainan Medical University, Haikou 571199, PR China. Electronic address: lvchuanzhu677@126.com.

PMID: 40782765
DOI: 10.1016/j.phymed.2025.157130

Abstract

Background: Cholestasis, including primary sclerosing cholangitis (PSC), remains a challenging condition with limited treatment options. The gut-liver axis and FXR signaling pathways play critical roles in maintaining bile acid homeostasis and preventing liver injury. Capsaicin, a natural compound with anti-inflammatory properties, has the potential to modulate these pathways and offer therapeutic benefits for cholestasis.

Purpose: In this study, capsaicin-loaded nanoparticles were developed and evaluated in a PSC mouse model to investigate the therapeutic effects and underlying mechanisms of action.

Methods: Capsaicin-loaded nanoparticles (CAP@NPs) were synthesized via a solvent evaporation method and thoroughly characterized. Using a DDC-induced primary sclerosing cholangitis (PSC) mouse model, we evaluated their therapeutic effects on liver injury through serum biochemistry and histopathology. TRPV1 expression in fibrotic liver tissue was assessed via qRT-PCR, immunohistochemistry, and immunofluorescence. Inflammation, immune responses, and fibrosis were analyzed using molecular, histological, and cytometric techniques. Effects on bile acid metabolism were investigated by profiling hepatic and ileal gene expression, while gut microbiota shifts and colon injury markers were examined to elucidate underlying mechanisms. Biosafety was confirmed by hematological and pathological assessments.

Results: Our findings revealed that administration of CAP@NPs attenuated liver injury, inflammation, fibrosis, and bile duct hyperplasia. Mechanistically, CAP@NPs activated hepatic FXR-SHP and ileal FXR-FGF15 pathways to suppress Cyp7A1 expression, modulated gut microbiota composition (increased Clostridia, decreased Bacteroidia), enhanced intestinal barrier integrity, and reduced endotoxin translocation.

Conclusion: This study represents a novel approach to treating cholestasis through targeted modulation of bile acid metabolism and inflammatory pathways, offering hope for new therapeutic strategies in liver disease.

Keywords: Capsaicin; Cholestatic liver disease; FXR; Gut-liver axis.

MeSH terms

Animals
Bile Acids and Salts / metabolism
Capsaicin* / pharmacology
Cholangitis, Sclerosing / drug therapy
Cholestasis* / drug therapy
Cholestasis* / metabolism
Disease Models, Animal
Fibroblast Growth Factors / metabolism
Gastrointestinal Microbiome / drug effects
Liver / drug effects
Liver / metabolism
Liver / pathology
Male
Mice
Mice, Inbred C57BL
Nanoparticles / chemistry
RNA-Binding Proteins
Receptor, Farnesoid X-Activated
Receptors, Cytoplasmic and Nuclear* / metabolism
Signal Transduction / drug effects
TRPV Cation Channels / metabolism

Substances

Fibroblast Growth Factors
Receptors, Cytoplasmic and Nuclear
Capsaicin
Bile Acids and Salts
TRPV Cation Channels
RNA-Binding Proteins
Receptor, Farnesoid X-Activated
fibroblast growth factor 15, mouse
Fxr1h protein, mouse
TRPV1 protein, mouse