An Intestinal Microbiota–Farnesoid X Receptor Axis Modulates Metabolic Disease

Abstract

The gut microbiota is associated with metabolic diseases including obesity, insulin resistance and non-alcoholic fatty liver disease (NAFLD), as demonstrated by correlative studies and by transplant 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 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 (T-β-MCA), a substrate of BSH and a potent farnesoid X receptor (FXR) antagonist. Mice lacking expression of FXR in the intestine were resistant to HFD-induced obesity, insulin resistance and NAFLD thus confirming that intestinal FXR is involved in the potentiation of metabolic disease. A potent intestinal FXR antagonist glycine-β-muricholic acid (Gly-MCA) that is resistant to BSH, was developed that when administered to HFD-treated mice, mimics the effect of the altered microbiota on HFD-induced metabolic disease. Gly-MCA had similar effects on genetically obese leptin-deficient mice. The decreased in adverse metabolic phenotype by tempol, antibiotics and Gly-MCA was due to decreased serum ceramides. Mice lacking FXR in intestine 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 mouse ileum, due to the presence of endogenous FXR agonists produced in the liver, FXR target genes involved in ceramide synthesis are activated and when Gly-MCA is administered, they are repressed, which likely accounts for the decrease in serum ceramides. These studies reveal that ceramides produced in the ileum under control of FXR, influence metabolic diseases.

An Intestinal Farnesoid X Receptor–Ceramide Signaling Axis Modulates Hepatic Gluconeogenesis in Mice

“…Thus, modification of bacterial bile acid metabolism by use of a BSH inhibitor may represent a promising therapeutic strategy to treat type 2 diabetes–associated hyperglycemia. However, it needs to be emphasized that there are significant differences between the mechanism of metabolic disease between humans and mice and that some of the findings in the current study may not be directly translatable to humans, in particular the interaction between the intestinal microbiota, bile acid metabolites, and intestinal FXR signaling (38). Furthermore, whether activation or inhibition of intestinal FXR will be of more benefit to the treatment of metabolic disease is an area of intense interest (38,39).…”

Engineered FGF19 eliminates bile acid toxicity and lipotoxicity leading to resolution of steatohepatitis and fibrosis in mice

“…Furthermore, ceramide is proposed as a common molecular intermediate linking metabolic stress to the induction of insulin resistance . Recent reports have shown that genes that increase ceramide production, including Smpd3 and Sptlc2 , have upstream FXR binding sites and were identified as direct FXR target genes in reporter gene assays . Notably, T‐βMCA, a naturally occurring FXR antagonist, was enriched in livers harvested from FGF19‐ and M70‐treated mice and could directly suppress hepatic ceramide production through FXR inhibition.…”

Intestinal microbiota and nonalcoholic steatohepatitis

“…Bile acids are important regulators of glucose and lipid metabolism, thermogenesis and inflammation (recent reviews [38, 39]). The bile acid derivative 6-ethylchenodeoxycholic acid (obeticholic acid) is a potent activator of FXR.…”