Bile Diversion Improves Metabolic Phenotype Dependent on Farnesoid X Receptor (FXR).

OBJECTIVE: The current study investigated whether bile diversion (BD) improves metabolic phenotype under farnesoid X receptor (FXR) deficiency.

METHODS: BD was performed in high-fat diet (HFD)-fed FXR knockout (FXRko) and wild-type (WT) animals. Metabolic phenotypes, circulating enteroendocrine hormones, total bile acids (BAs) and BA composition, and cecal gut microbiota were analyzed.

RESULTS: FXR-deficient mice were resistant to HFD-induced obesity; however, FXR-deficient mice also developed hyperglycemia and exhibited increased liver weight, liver steatosis, and circulating triglycerides. BD increased circulating total BAs and taurine-b-muricholic acid, which were in line with normalized hyperglycemia and improved glucose tolerance in HFD-fed WT mice. FXR deficiency also increased total BAs and taurine-b-muricholic acid, but these animals remained hyperglycemic. While BD improved metabolic phenotype in HFD-fed FXRko mice, these improvements were not as effective as in WT mice. BD increased liver expression of fibroblast growth factor 21 and peroxisome proliferator-activated receptor γ coactivator-1β and elevated circulating glucagon-like peptide-1 levels in WT mice but not in FXRko mice. FXR deficiency altered gut microbiota composition with a specific increase in phylum Proteobacteria that may act as a possible microbial signature of some diseases. These cellular and molecular changes in FXRko mice may contribute to resistance toward improved metabolism.

CONCLUSIONS: FXR signaling plays a pivotal role in improved metabolic phenotype following BD surgery.