PUBLICATION

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

Authors

Wen, J., Mercado, G.P., Volland, A., Doden, H.L., Lickwar, C.R., Crooks, T., Kakiyama, G., Kelly, C., Cocchiaro, J.L., Ridlon, J.M., Rawls, J.F.

ID

ZDB-PUB-210728-13

Date

2021

Source

Science advances 7(30): (Journal)

Registered Authors

Lickwar, Colin, Mercado, Gilberto Padilla, Rawls, John F.

Keywords

none

Datasets

GEO:GSE173570

MeSH Terms

Animals
Bile Acids and Salts*/metabolism
Receptors, Cytoplasmic and Nuclear/genetics
Receptors, Cytoplasmic and Nuclear/metabolism
Zebrafish*/metabolism
Liver/metabolism
Mammals/metabolism
Transcription Factors/metabolism
Intestines

(all 9)

PubMed

34301599 Full text @ Sci Adv

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.

Genes / Markers

Figures

Show all Figures

Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT	chemical treatment by environment: cholic acid	Days 7-13	whole organism fabp6 expression increased amount, abnormal	Fig. 4
WT	chemical treatment by environment: cholic acid	Days 7-13	whole organism fgf19 expression increased amount, abnormal	Fig. 4
WT	chemical treatment by environment: taurocholic acid	Days 7-13	whole organism fabp6 expression increased amount, abnormal	Fig. 4
cyp7a1^rdu84/rdu84; rdu22Tg	standard conditions	Days 7-13	posterior intestine epithelium GFP expression decreased amount, abnormal	Fig. 4
cyp7a1^rdu84/rdu84; rdu22Tg	standard conditions	Days 7-13	posterior intestine epithelium GFP expression decreased amount, abnormal	Fig. 1
nr1h4^rdu81/rdu81	standard conditions	Days 7-13	digestive system abcb11b expression decreased amount, abnormal	Fig. 1
nr1h4^rdu81/rdu81	standard conditions	Days 7-13	digestive system fabp6 expression decreased amount, abnormal	Fig. 1
nr1h4^rdu81/rdu81	standard conditions	Days 7-13	digestive system fgf19 expression decreased amount, abnormal	Fig. 1
nr1h4^rdu81/rdu81	standard conditions	Days 7-13	digestive system slc10a2 expression decreased amount, abnormal	Fig. 1
nr1h4^rdu81/rdu81	standard conditions	Days 7-13	liver cyp7a1 expression increased amount, abnormal	Fig. 1

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
nc1Tg	Tg(6xHsa.NFKB:EGFP)	Transgenic Insertion
pd1000Tg	Tg(-4.5fabp2:DsRed)	Transgenic Insertion
pd1028Tg	TgBAC(tnfa:GFP)	Transgenic Insertion
pd1034Tg	TgBAC(cldn15la:GFP)	Transgenic Insertion
pd1117Tg	TgBAC(lamp2:RFP)	Transgenic Insertion
rdu22Tg	Tg(fabp6-Mmu.Fos:GFP)	Transgenic Insertion
rdu80Tg	Tg(fabp6:EGFP,cryaa:mCherry)	Transgenic Insertion
rdu81		Small Deletion	nr1h4
rdu82		Small Deletion	nr1h4
rdu83		Small Deletion	cyp7a1

1 - 10 of 12

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Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
cyp7a1	CRISPR2-cyp7a1	CRISPR
nr1h4	CRISPR1-nr1h4	CRISPR

Fish

Fish
cyp7a1^rdu84/rdu84; rdu22Tg
nr1h4^rdu81/rdu81
nr1h4^rdu81/rdu81; rdu22Tg
rdu22Tg
slc10a2^{sa2486/sa2486}; rdu22Tg
WT

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
DsRed	EFG	DsRed
EGFP	EFG	EGFP
GFP	EFG	GFP
mCherry	EFG	mCherry
RFP	EFG	RFP

Mapping

Wen et al., 2021 ZDB-PUB-210728-13 PMID:34301599

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

Wen et al., 2021

ZDB-PUB-210728-13
PMID:34301599