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

Alexandra Montagner,Hervé Guillou,Velmurugesan Arulampalam,Amandine Gautier-Stein,Maha Al-Asmakh,Gilles Mithieux,Arnaud Polizzi,Yannick Lippi,Rémy Burcelin,Hyunsoo Shawn Je,Yuna Blum,Sandrine Lagarrigue,Yi-Chun Yen,Marie Tremblay-Franco,Walter Wahli,Agata Korecka,Cécile Canlet,Sven Pettersson

doi:10.1038/srep20127

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.

Highlights

Metabolism and modulate the abundance and distribution of various microbiome components[5]
Based on the recently established link between the peripheral clock in intestinal epithelial cells and the microbiome[12], we hypothesized that the microbiome impacts liver physiology possibly via the liver clock core, which consists of two interlocked feedback loops that comprise several clock genes[7]
Analysis of gene expression from liver samples showed that Bmal[1], Rev-erbα, Rev-erbβ, Per[1], Per[2], and Cry[1] displayed significantly different mRNA expression patterns in GF mice compared to specific pathogen–free (SPF) mice as demonstrated by analysis with the JTK_Cycle algorithm[16] (Fig. 1a,b; see Supplementary Tables S1 and S2 online)

Summary

Introduction

Metabolism and modulate the abundance and distribution of various microbiome components[5]. Antibiotic-induced depletion of the gut microbiome results in alteration of circadian gene expression in enterocytes and of rhythmic corticosterone production in the gut, with an ensuing hypercorticosterolism that causes hyperglycaemia, insulin resistance, and increased triglycerides and free fatty acids in plasma. Taken together, these data suggest that the gut microbiome is an integral component of mechanisms that synchronize the intestinal epithelial clock. These data indicate that the microbiome contributes to harvesting energy from nutrients and to collecting or producing signals that are essential to controlling the hepatic clock genes and their effectors such as nuclear receptors

Methods

Results

Conclusion