Induction of farnesoid X receptor signaling in germ-free mice colonized with a human microbiota

J Lipid Res. 2017 Feb;58(2):412-419. doi: 10.1194/jlr.M072819. Epub 2016 Dec 12.

Abstract

The gut microbiota influences the development and progression of metabolic diseases partly by metabolism of bile acids (BAs) and modified signaling through the farnesoid X receptor (FXR). In this study, we aimed to determine how the human gut microbiota metabolizes murine BAs and affects FXR signaling in colonized mice. We colonized germ-free mice with cecal content from a mouse donor or feces from a human donor and euthanized the mice after short-term (2 weeks) or long-term (15 weeks) colonization. We analyzed the gut microbiota and BA composition and expression of FXR target genes in ileum and liver. We found that cecal microbiota composition differed between mice colonized with mouse and human microbiota and was stable over time. Human and mouse microbiota reduced total BA levels similarly, but the humanized mice produced less secondary BAs. The human microbiota was able to reduce the levels of tauro-β-muricholic acid and induce expression of FXR target genes Fgf15 and Shp in ileum after long-term colonization. We show that a human microbiota can change BA composition and induce FXR signaling in colonized mice, but the levels of secondary BAs produced are lower than in mice colonized with a mouse microbiota.

Keywords: bile acids and salts; biosynthesis and metabolism; enzyme mechanisms and regulation; farnesoid X receptor agonist; farnesoid X receptor antagonist; gut microbiota; humanized mouse models; intestine.

MeSH terms

  • Animals
  • Bile Acids and Salts / metabolism
  • Feces / microbiology
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism*
  • Gastrointestinal Microbiome / genetics*
  • Humans
  • Ileum / metabolism
  • Ileum / microbiology
  • Intestinal Mucosa / metabolism
  • Intestines / microbiology
  • Liver / metabolism
  • Liver / microbiology
  • Metabolic Diseases / genetics*
  • Metabolic Diseases / metabolism
  • Metabolic Diseases / microbiology
  • Metabolic Diseases / pathology
  • Mice
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • RNA-Binding Proteins / agonists
  • RNA-Binding Proteins / antagonists & inhibitors
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Taurocholic Acid / analogs & derivatives
  • Taurocholic Acid / metabolism

Substances

  • Bile Acids and Salts
  • Fxr1h protein, mouse
  • Nerve Tissue Proteins
  • RNA-Binding Proteins
  • fibroblast growth factor 15, mouse
  • synapto-pHluorin protein, mouse
  • tauromuricholic acid
  • Taurocholic Acid
  • Fibroblast Growth Factors