4.8 Article

Fxr signaling and microbial metabolism of bile salts in the zebrafish intestine

Journal

SCIENCE ADVANCES
Volume 7, Issue 30, Pages -

Publisher

AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abg1371

Keywords

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Funding

  1. USDA Hatch [ILLU-538-916]
  2. NIH [R01-DK093399, R01-DK081426, R01-DK121007]
  3. Pew Charitable Trusts
  4. David H. and Norraine A. Baker Graduate Fellowship in Animal Sciences
  5. NIH Ruth L. Kirschstein National Research Service Award Individual Predoctoral Fellowship [F31DK121392]
  6. NIH Ruth L. Kirschstein National Research Service Award Individual Postdoctoral Fellowship [F32-DK094592]

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Key components of hepatic bile salt synthesis and ileal transport pathways in zebrafish are conserved and controlled by Fxr. Zebrafish bile salts primarily consist of a C-27 bile alcohol and a C-24 bile acid, which undergo microbial modifications. Fxr plays significant roles in transcriptional and differentiation programs in zebrafish intestinal epithelium.
Bile salt synthesis, secretion into the intestinal lumen, and resorption in the ileum occur in all vertebrate classes. In mammals, bile salt composition is determined by host and microbial enzymes, affecting signaling through the bile salt-binding transcription factor farnesoid X receptor (Fxr). However, these processes in other vertebrate classes remain poorly understood. We show that key components of hepatic bile salt synthesis and ileal transport pathways are conserved and under control of Fxr in zebrafish. Zebrafish bile salts consist primarily of a C-27 bile alcohol and a C-24 bile acid that undergo multiple microbial modifications including bile acid deconjugation that augments Fxr activity. Using single-cell RNA sequencing, we provide a cellular atlas of the zebrafish intestinal epithelium and uncover roles for Fxr in transcriptional and differentiation programs in ileal and other cell types. These results establish zebrafish as a nonmammalian vertebrate model for studying bile salt metabolism and Fxr signaling.

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