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

Abstract

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 BAs and BA composition and cecal gut microbiota were analyzed.Results.FXR deficient mice are resistant to HFD-induced obesity; however, FXR deficient mice also develop hyperglycemia and exhibit increased liver weight, liver steatosis, and circulating triglycerides. BD increases circulating total BAs and taurine-b-muricholic acid (TbMCA), in line with normalized hyperglycemia and improved glucose tolerance in HFD-fed WT mice. FXR deficiency also increases total BA and TbMCA, but these animals remain hyperglycemic. While BD improved metabolic phenotype in HFD-FXRko mice, these improvements were not as effective as in WT mice. BD increased liver expression of FGF21 and PGC1ß and elevated circulating GLP-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 towards improved metabolism.Conclusions.FXR signaling plays a pivotal role in improved metabolic phenotype following BD surgery.