Bacterial metabolites directly modulate farnesoid X receptor activityReport as inadecuate

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Nutrition and Metabolism

, 12:48

First Online: 24 November 2015Received: 29 July 2015Accepted: 18 November 2015


BackgroundThe 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.

MethodsThe 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.

ResultsA 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.

ConclusionsB. 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.

KeywordsFarnesoid X receptor Bacterial metabolites Luciferase reporter assay Obesity AbbreviationsFXRFarnesoid X receptor

ShpSmall heterodimer partner

6ECDCA6α-ethyl-chenodeoxycholic acid

BAsBile acids

FXREFXR element

DMSODimethyl sulfoxide

PBSPhosphate-buffered saline

GapdhGlyceraldehyde-3-phosphate dehydrogenase

RLURelative luminescent unit

MCAsMuricholic acids

IbabpIleal bile acid binding protein

OstαOrganic solute transporter α

Fgf19Fibroblast growth factor 19

Fgf15Fibroblast growth factor 15

HFDHigh fat diet

IbatIleal bile acid transport

BsepBile salt export pump

Cyp8b1Sterol 12-α-hydroxylase

Cyp7b125-hydroxycholesterol 7-α-hydroxylase

Cyp7a1Cholesterol 7-α-hydroxylase

NtcpNa+-taurocholate cotransporting polypeptide

IECIntestinal epithelial cells

TβMCATauro-β-muricholic acid

IBDIntestinal bowel disease

Xianqin Zhang and Toshifumi Osaka contributed equally to this work.

Electronic supplementary materialThe online version of this article doi:10.1186-s12986-015-0045-y contains supplementary material, which is available to authorized users.

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Author: Xianqin Zhang - Toshifumi Osaka - Satoshi Tsuneda



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