Related Experiment Video
Updated: Jul 12, 2026
Mouse Model of Metabolic Dysfunction-Associated Steatotic Liver Disease with Fibrosis
Published on: July 18, 2025
Intestinal FXR deficiency uncouples steatosis protection from liver inflammation and fibrosis in MASH-diet fed mice
Margaux Nawrot1,2, Simon Peschard3, Morgane M Thibaut4
1Univ. Lille, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Inserm, Lille, F- 59000, France. margaux.nawrot@inserm.fr.
Abstract:
The Farnesoid X Receptor (FXR), a nuclear bile acid (BA) receptor highly expressed in the liver and intestine, is a potential pharmacological target for Metabolic dysfunction-Associated SteatoHepatitis (MASH). While intestinal FXR inhibition reduces high-fat diet (HFD)-induced hepatic steatosis, its role in MASH progression remains unclear. This study investigates the impact of intestinal FXR-deficiency on MASH development in a diet-induced murine model. Intestinal FXR-deficient (intFXR KO) and control mice were fed a high-fat, sucrose, and cholesterol-enriched diet (HFSC) for 24 weeks. Intestinal immune phenotyping, microarray, 16 S rRNA sequencing, bile acid quantification and liver assessments (histology, biochemistry and single-cell RNA sequencing (scRNA-seq)) were performed. intFXR KO mice were protected against HFSC diet-induced obesity and hepatic steatosis but exhibited altered expression of intestinal barrier-associated genes, with increased cytotoxic CD8+ T-lymphocytes. Microbiota composition and bile acid profiles were altered, including reduced Lachnospiraceae species correlating negatively with liver hyocholic acid levels. Despite a protection against hepatic steatosis, liver inflammation and fibrosis were unchanged in intFXR KO mice. Transcriptomic and Immune cell scRNA-seq analysis revealed alteration in immune-related pathways with an increased neutrophil proportion and higher cDC1:cDC2 and CD4:CD8 T cell ratios. Thus, intestinal FXR-deficiency limits steatosis but promote a distinct hepatic immune-inflammatory response and does not prevent progression to MASH.
Insights
Intestinal Farnesoid X Receptor (FXR) deficiency protects against obesity and fatty liver but does not prevent Metabolic dysfunction-Associated SteatoHepatitis (MASH) progression, despite altering immune responses.
Area of Science:
- Hepatology
- Gastroenterology
- Immunology
Background:
- The Farnesoid X Receptor (FXR) is a bile acid receptor crucial in liver and intestinal metabolism.
- FXR is a potential therapeutic target for Metabolic dysfunction-Associated SteatoHepatitis (MASH).
- The role of intestinal FXR in MASH progression is not fully understood.
Purpose of the Study:
- To investigate the impact of intestinal FXR deficiency on MASH development in a diet-induced murine model.
- To determine if targeting intestinal FXR can prevent MASH progression.
Main Methods:
- Utilized intestinal FXR-deficient (intFXR KO) and control mice fed a high-fat, sucrose, and cholesterol-enriched diet (HFSC) for 24 weeks.
- Performed comprehensive analyses including intestinal immune phenotyping, transcriptomics (microarray, scRNA-seq), 16S rRNA sequencing, bile acid profiling, and liver assessments.
- Evaluated obesity, hepatic steatosis, inflammation, fibrosis, gut barrier function, and immune cell populations.
Main Results:
- Intestinal FXR deficiency protected against diet-induced obesity and hepatic steatosis.
- Observed altered intestinal barrier gene expression and increased cytotoxic CD8+ T-lymphocytes.
- Microbiota composition and bile acid profiles were modified, with reduced Lachnospiraceae correlating with lower liver hyocholic acid.
- Despite steatosis protection, liver inflammation and fibrosis were not ameliorated.
- Transcriptomic and scRNA-seq revealed distinct hepatic immune alterations, including increased neutrophils and altered DC and T cell ratios.
Conclusions:
- Intestinal FXR deficiency limits hepatic steatosis but promotes a unique hepatic immune-inflammatory response.
- Targeting intestinal FXR does not prevent MASH progression and may exacerbate certain immune dysregulations.
- FXR's role in MASH is complex, with intestinal deficiency not offering a complete protective strategy.
