title: Bacterial metabolites directly modulate farnesoid X receptor activity.
abstract: BACKGROUND
  The farnesoid X receptor (FXR), a ligand-activated transcription factor belonging to the adopted orphan receptor, plays an important role in maintaining health of the liver and intestine. In this study, we identified individual bacterial strains that directly modulated the activation of intestinal FXR.
  
  
  METHODS
  The FXR stimulatory potential of 38 bacterial strains was determined using a stable FXR reporter system derived from intestinal epithelial cells (IEC). The induction of FXR target genes by screened FXR stimulatory bacteria was determined by real-time PCR. In addition, a high fat diet (HFD)-induced obese mouse model was used to evaluate in vivo FXR stimulatory potential of bacterial metabolites screened in this study.
  
  
  RESULTS
  A luciferase assay with the FXR reporter cell line demonstrated that the FXR-stimulatory activity of most bacterial cell samples was less than 2-fold. The culture supernatants of Bacteroides dorei and Eubacterium limosum induced FXR activity and selectively regulated FXR target expression in the FXR reporter system. Treatment with B. dorei-derived metabolites strongly induced ileal bile acid binding protein (IBABP) (8.4-fold) and organic solute transporter (OST) α (3.1-fold) compared with E. limosum-derived metabolites. Furthermore, administration of B. dorei derived metabolites showed significant reduction in body weight gain, and both two bacterial metabolites reduced liver weight in obese mice compared to PBS-treated controls. Administration of each bacterial metabolites improved in serum levels of obesity-related metabolic biochemical markers such as ALT, AST, total cholesterol, and triglyceride. Furthermore, two bacterial metabolites enhanced the Fxr gene expression in the intestine and liver, and ileal Shp gene expression tended to be increased by treatment with the metabolites derived from B. dorei.
  
  
  CONCLUSIONS
  B. dorei and E. limosum secreted the bioactive substances that directly stimulate FXR in the intestinal epithelial cells. Administration of these bacterial FXR-stimulatory metabolites improves the obesity phenotype including body weight gain, liver damage, lipid metabolism in DIO mice.
authors.affiliation: Department of Life Science and Medical Bioscience, Waseda University, Tokyo, 162-8480 Japan.
authors.forename: Xianqin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Life Science and Medical Bioscience, Waseda University, Tokyo, 162-8480 Japan.|Department of Microbiology and Immunology, Tokyo Women's Medical University, Tokyo, 162-8666 Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Osaka
authors.affiliation: Department of Life Science and Medical Bioscience, Waseda University, Tokyo, 162-8480 Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tsuneda
keywords: Bacterial metabolites; Farnesoid X receptor; Luciferase reporter assay; Obesity