title: Hepatic circadian clock oscillators and nuclear receptors integrate microbiome-derived signals.
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.
authors.affiliation: INRA ToxAlim, UMR1331, Chemin de Tournefeuille, Toulouse Cedex, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Montagner
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
authors.forename: Agata
authors.initials: A
authors.lastname: Korecka
authors.affiliation: INRA ToxAlim, UMR1331, Chemin de Tournefeuille, Toulouse Cedex, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Polizzi
authors.affiliation: INRA ToxAlim, UMR1331, Chemin de Tournefeuille, Toulouse Cedex, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Lippi
authors.affiliation: Department of Medicine, Division of Cardiology, UCLA, Los Angeles, USA.
authors.forename: Yuna
authors.initials: Y
authors.lastname: Blum
authors.affiliation: INRA ToxAlim, UMR1331, Chemin de Tournefeuille, Toulouse Cedex, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Canlet
authors.affiliation: INRA ToxAlim, UMR1331, Chemin de Tournefeuille, Toulouse Cedex, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Tremblay-Franco
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U855, Lyon, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Gautier-Stein
authors.affiliation: Institut des Maladies Métaboliques et Cardiovasculaires, Hôpital Rangueil, Toulouse Cedex, France.
authors.forename: Rémy
authors.initials: R
authors.lastname: Burcelin
authors.affiliation: Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School, Singapore, Singapore.|Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Yen
authors.affiliation: Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School, Singapore, Singapore.|Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Hyunsoo Shawn
authors.initials: HS
authors.lastname: Je
authors.forename: Maha
authors.initials: M
authors.lastname: Al-Asmakh
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.|Department of Health Sciences, College of Arts and Sciences, Qatar University, Daha, Qatar.
authors.forename: Al-Asmakh
authors.initials: AA
authors.lastname: Maha
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U855, Lyon, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Mithieux
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
authors.forename: Velmurugesan
authors.initials: V
authors.lastname: Arulampalam
authors.affiliation: INRA, UMR1348 Pegase, Saint-Gilles, France.|Agrocampus Ouest, UMR1348 Pegase, France.|Rennes; Université Européenne de Bretagne, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Lagarrigue
authors.affiliation: INRA ToxAlim, UMR1331, Chemin de Tournefeuille, Toulouse Cedex, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Guillou
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.|Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore.|SCELSE microbiome centre, Nanyang Technological University, Singapore, Singapore.
authors.forename: Sven
authors.initials: S
authors.lastname: Pettersson
authors.affiliation: INRA ToxAlim, UMR1331, Chemin de Tournefeuille, Toulouse Cedex, France.|Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore.|Center for Integrative Genomics, University of Lausanne, Le Genopode, Lausanne, Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Wahli
mesh_terms: D000818:Animals; D015415:Biomarkers; D057906:Circadian Clocks / Q000235:genetics*; D005260:Female; D000069196:Gastrointestinal Microbiome; D041981:Gastrointestinal Tract / Q000378:metabolism / Q000382:microbiology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005943:Gluconeogenesis / Q000235:genetics; D008658:Inactivation, Metabolic / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D064307:Microbiota; D009928:Organ Specificity; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D015415:Biomarkers; D018160:Receptors, Cytoplasmic and Nuclear