| The gut microbiota is associated with metabolic diseases including obesity, insulin resistance and fatty liver disease, as demonstrated by correlative studies and by transplantation of microbiota from obese humans and mice into germ-free mice. Modification of the microbiota by treatment of high-fat diet (HFD)-fed mice with tempol or antibiotics resulted in decreased adverse HFD-induced metabolic phenotypes. This was due to lower levels of the genera Lactobacillus and decreased bile salt hydrolase (BSH) activity. The decreased BSH resulted in increased levels of tauro-β-muricholic acid, a substrate of BSH and an antagonist for the farnesoid X receptor (FXR). A potent intestinal FXR antagonist, glycine-muricholic acid (Gly-MCA), that is resistant to BSH, was developed that when administered to HFD-fed mice, mimics the effect of the altered microbiota on HFD-induced metabolic disease. Gly-MCA had similar effects on genetically obese leptin-deficient mice, decreasing obesity insulin resistance and fatty liver. Gly-MCA also reduced experimental non-alcoholic steatohepatitis. The decrease in adverse metabolic phenotypes by tempol, antibiotics and Gly-MCA is due to the lowering of serum ceramides. FXR intestine-null mice also have lower serum ceramides, are metabolic fit and resistant to HFD-induced metabolic disease, and this is reversed by injection of C16:0 ceramide. In ileum of obese mice, due to the presence of endogenous FXR agonists produced in the liver, FXR target genes involved in ceramide synthesis are induced, and when Gly-MCA is administered, they are repressed, which accounts for the decrease in serum ceramides. These studies reveal that ceramides produced in the ileum under control of FXR, influence metabolic diseases. A recent study found that metformin, through modulation of a pathway similar to that described above involving get bacteria, bile acids and FXR signaling, modulates hyperglycemia. |
