Bacterial metabolites directly modulate farnesoid X receptor activity

Xianqin Zhang, Toshifumi Osaka, Satoshi Tsuneda

    Research output: Contribution to journalArticle

    10 Citations (Scopus)

    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.

    Original languageEnglish
    Article number48
    JournalNutrition and Metabolism
    Volume12
    Issue number1
    DOIs
    Publication statusPublished - 2015 Nov 24

    Fingerprint

    Obese Mice
    Liver
    Weight Gain
    Intestines
    Obesity
    Epithelial Cells
    Body Weight
    Eubacterium
    Gene Expression
    Bacteroides
    High Fat Diet
    Luciferases
    Lipid Metabolism
    Real-Time Polymerase Chain Reaction
    Triglycerides
    Transcription Factors
    Biomarkers
    Cholesterol
    Ligands
    Bacteria

    Keywords

    • Bacterial metabolites
    • Farnesoid X receptor
    • Luciferase reporter assay
    • Obesity

    ASJC Scopus subject areas

    • Medicine (miscellaneous)
    • Nutrition and Dietetics
    • Endocrinology, Diabetes and Metabolism

    Cite this

    Bacterial metabolites directly modulate farnesoid X receptor activity. / Zhang, Xianqin; Osaka, Toshifumi; Tsuneda, Satoshi.

    In: Nutrition and Metabolism, Vol. 12, No. 1, 48, 24.11.2015.

    Research output: Contribution to journalArticle

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