Hepatic circadian clock oscillators and nuclear receptors integrate microbiome-derived signals

Scientific Reports
Alexandra MontagnerWalter Wahli

Abstract

The liver is a key organ of metabolic homeostasis with functions that oscillate in response to food intake. Although liver and gut microbiome crosstalk has been reported, microbiome-mediated effects on peripheral circadian clocks and their output genes are less well known. Here, we report that germ-free (GF) mice display altered daily oscillation of clock gene expression with a concomitant change in the expression of clock output regulators. Mice exposed to microbes typically exhibit characterized activities of nuclear receptors, some of which (PPARα, LXRβ) regulate specific liver gene expression networks, but these activities are profoundly changed in GF mice. These alterations in microbiome-sensitive gene expression patterns are associated with daily alterations in lipid, glucose, and xenobiotic metabolism, protein turnover, and redox balance, as revealed by hepatic metabolome analyses. Moreover, at the systemic level, daily changes in the abundance of biomarkers such as HDL cholesterol, free fatty acids, FGF21, bilirubin, and lactate depend on the microbiome. Altogether, our results indicate that the microbiome is required for integration of liver clock oscillations that tune output activators and their effectors, thereby re...Continue Reading

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Datasets Mentioned

BETA
GSE71628

Methods Mentioned

BETA
nuclear magnetic resonance
PCR
NMR

Software Mentioned

Expression Console
R function
R “ gplots
Bioconductor packages
JTK
WGCNA R package
LinRegPCRv2012
_ Cycle
P +
Affymetrix

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