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Sci Rep. 2016 Feb 16;6:20127. doi: 10.1038/srep20127.

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

Author information

1
INRA ToxAlim, UMR1331, Chemin de Tournefeuille, Toulouse Cedex, France.
2
Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
3
Department of Medicine, Division of Cardiology, UCLA, Los Angeles, USA.
4
Institut National de la Santé et de la Recherche Médicale, U855, Lyon, France.
5
Institut des Maladies Métaboliques et Cardiovasculaires, Hôpital Rangueil, Toulouse Cedex, France.
6
Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School, Singapore, Singapore.
7
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
8
Department of Health Sciences, College of Arts and Sciences, Qatar University, Daha, Qatar.
9
INRA, UMR1348 Pegase, Saint-Gilles, France.
10
Agrocampus Ouest, UMR1348 Pegase, France.
11
Rennes; Université Européenne de Bretagne, France.
12
Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore.
13
SCELSE microbiome centre, Nanyang Technological University, Singapore, Singapore.
14
Center for Integrative Genomics, University of Lausanne, Le Genopode, Lausanne, Switzerland.

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 regulating metabolic gene expression for optimal liver function.

PMID:
26879573
PMCID:
PMC4754633
DOI:
10.1038/srep20127
[Indexed for MEDLINE]
Free PMC Article

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