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

Abstract

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 C27 bile alcohol and a C24 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.

A cell atlas of microbe-responsive processes in the zebrafish intestine

“…Nonetheless, our identification of Best4/Otop2 and tuft-like cells within the zebrafish intestinal epithelium underscores the similarities between fish and mammalian intestines. We further note that our datasets are in broad agreement with a recent study reporting single-cell profiles for sorted zebrafish IECs (Wen et al, 2021).…”

Management of Hypercholesterolemia Through Dietary ß-glucans–Insights From a Zebrafish Model

“…β-glucans lower the LDL, total cholesterol and serum triglyceride levels through the proliferation of intestinal microbes that possess bile salt hydrolase (BSH) activity ( 112 , 113 ). BSH activity can deconjugate bile acids, that are ligands for farnesoid X receptor (FXR), which is the intestinal bile acid sensor and the controller of liver bile acid production and lipid metabolism ( 114 ); this function of FXR is conserved in mammals and zebrafish ( 115 ). The positive effects of the β-glucan-driven increase in the BSH activity on gut physiology and lipid metabolism are not yet fully clarified.…”

Enteric nervous system modulation of luminal pH modifies the microbial environment to promote intestinal health

“…The ENS innervates the zebrafish intestine and pancreas in early larval stages, a process that fails to occur in sox10 mutants [ 7 , 91 ]. Zebrafish bile consists primarily of C 27 bile alcohol and C 24 bile acid which are released after lipid ingestion and could decrease luminal pH [ 92 ]. We show that sox10 mutants have a less alkaline intestinal lumen than their WT siblings independent of the microbiota.…”