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<p>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 (<sup>int</sup>FXR KO) and control mice were fed a high-fat, sucrose, and cholesterol-enriched diet (HFSC) for 24 weeks. Intestinal immune phenotyping, microarray, 16&#xa0;S rRNA sequencing, bile acid quantification and liver assessments (histology, biochemistry and single-cell RNA sequencing (scRNA-seq)) were performed. <sup>int</sup>FXR 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<sup>+</sup> 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 <sup>int</sup>FXR 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.</p>

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Intestinal FXR deficiency uncouples steatosis protection from liver inflammation and fibrosis in MASH-diet fed mice

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月10日

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  • Margaux Nawrot,
  • Simon Peschard,
  • Morgane M Thibaut,
  • Kévin Ory,
  • Emmanuelle Vallez,
  • Emilie Dorchies,
  • Véronique Touche,
  • Julie Dubois-Chevalier,
  • Céline Gheeraert,
  • Sandrine Caron,
  • Kadiombo Bantubungi,
  • Philippe Lefebvre,
  • Anne Tailleux,
  • Joel T Haas,
  • Laure B Bindels,
  • Isabelle Leclercq,
  • David Dombrowicz,
  • Sophie Lestavel,
  • Bart Staels

摘要

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.