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Does the Phytochemical Diversity of Wild Plants Like the Erythrophleumgenus Correlate with Geographical Origin?

Cédric Delporte, Nausicaa Noret, Cécile Vanhaverbeke, Olivier J. Hardy, Jean-François Martin, Marie Tremblay-Franco, David Touboul, Anais Gorel, Marie Faes, Caroline Stévigny, Pierre Van Van Antwerpen, Florence Souard
2021 Molecules  
Secondary metabolites are essential for plant survival and reproduction. Wild undomesticated and tropical plants are expected to harbor highly diverse metabolomes. We investigated the metabolomic diversity of two morphologically similar trees of tropical Africa, Erythrophleum suaveolens and E. ivorense, known for particular secondary metabolites named the cassaine-type diterpenoids. To assess how the metabolome varies between and within species, we sampled leaves from individuals of different
more » ... ographic origins but grown from seeds in a common garden in Cameroon. Metabolites were analyzed using reversed phase LC-HRMS(/MS). Data were interpreted by untargeted metabolomics and molecular networks based on MS/MS data. Multivariate analyses enabled us to cluster samples based on species but also on geographic origins. We identified the structures of 28 cassaine-type diterpenoids among which 19 were new, 10 were largely specific to E. ivorense and five to E. suaveolens. Our results showed that the metabolome allows an unequivocal distinction of morphologically-close species, suggesting the potential of metabolite fingerprinting for these species. Plant geographic origin had a significant influence on relative concentrations of metabolites with variations up to eight (suaveolens) and 30 times (ivorense) between origins of the same species. This shows that the metabolome is strongly influenced by the geographical origin of plants (i.e., genetic factors).
doi:10.3390/molecules26061668 pmid:33802747 pmcid:PMC8002556 fatcat:z7zfy363yvbtdigtnfl25odkxe

Metabolomics Tools for Describing Complex Pesticide Exposure in Pregnant Women in Brittany (France)

Nathalie Bonvallot, Marie Tremblay-Franco, Cécile Chevrier, Cécile Canlet, Charline Warembourg, Jean-Pierre Cravedi, Sylvaine Cordier, Daniel S. Sem
2013 PLoS ONE  
The use of pesticides and the related environmental contaminations can lead to human exposure to various molecules. In early-life, such exposures could be responsible for adverse developmental effects. However, human health risks associated with exposure to complex mixtures are currently under-explored. Objective: This project aims at answering the following questions: What is the influence of exposures to multiple pesticides on the metabolome? What mechanistic pathways could be involved in the
more » ... metabolic changes observed? Methods: Based on the PELAGIE cohort (Brittany, France), 83 pregnant women who provided a urine sample in early pregnancy, were classified in 3 groups according to the surface of land dedicated to agricultural cereal activities in their town of residence. Nuclear magnetic resonance-based metabolomics analyses were performed on urine samples. Partial Least Squares Regression-Discriminant Analysis (PLS-DA) and polytomous regressions were used to separate the urinary metabolic profiles from the 3 exposure groups after adjusting for potential confounders. Results: The 3 groups of exposure were correctly separated with a PLS-DA model after implementing an orthogonal signal correction with pareto standardizations (R2 = 90.7% and Q2 = 0.53). After adjusting for maternal age, parity, body mass index and smoking habits, the most statistically significant changes were observed for glycine, threonine, lactate and glycerophosphocholine (upward trend), and for citrate (downward trend). Conclusion: This work suggests that an exposure to complex pesticide mixtures induces modifications of metabolic fingerprints. It can be hypothesized from identified discriminating metabolites that the pesticide mixtures could increase oxidative stress and disturb energy metabolism.
doi:10.1371/journal.pone.0064433 pmid:23704985 pmcid:PMC3660334 fatcat:ogrzsjztmfhpxn5aamuxi3tnem

Effect of obesity and metabolic syndrome on plasma oxysterols and fatty acids in human

Marie Tremblay-Franco, Chiara Zerbinati, Antonio Pacelli, Giuseppina Palmaccio, Carla Lubrano, Simon Ducheix, Hervé Guillou, Luigi Iuliano
2015 Steroids  
Background: Obesity and the related entity metabolic syndrome are characterized by altered lipid metabolism and associated with increased morbidity risk for cardiovascular disease and cancer. Oxysterols belong to a large family of cholesterol-derived molecules known to play crucial role in many signaling pathways underlying several diseases. Little is known on the potential effect of obesity and metabolic syndrome on oxysterols in human. Objectives: In this work, we questioned whether
more » ... g oxysterols might be significantly altered in obese patients and in patients with metabolic syndrome. We also tested the potential correlation between circulating oxysterols and fatty acids. Methods: 60 obese patients and 75 patients with metabolic syndrome were enrolled in the study along with 210 age-and sex-matched healthy subjects, used as control group. Plasma oxysterols were analyzed by isotope dilution GC/MS, and plasma fatty acids profiling was assessed by gas chromatography coupled with flame ionization detection. Results: We found considerable differences in oxysterols profiling in the two disease groups that were gender-related. Compared to controls, males showed significant differences only in 4a-and 4b-hydroxycholesterol levels in obese and metabolic syndrome patients. In contrast, females showed consistent differences in 7-oxocholesterol, 4a-hydroxycholesterol, 25-hydroxycholesterol and triol. Concerning fatty acids, we found minor differences in the levels of these variables in males of the three groups. Significant changes were observed in plasma fatty acid profile of female patients with obesity or metabolic syndrome. We found significant correlations between various oxysterols and fatty acids. In particular, 4b-hydroxycholesterol, which is reduced in obesity and metabolic syndrome, correlated with a number of saturated and mono-unsaturated fatty acids that are end-products of de novo lipogenesis. Conclusions: Our data provide the first evidence that obesity and metabolic syndrome are associated with major, gender-specific, changes in circulating oxysterols and fatty acids. These findings suggest a metabolic link between oxysterols and fatty acids, and that oxysterols may contribute to the epidemic diseases associated with obesity and metabolic syndrome in female.
doi:10.1016/j.steroids.2015.03.019 pmid:25896943 fatcat:nt6ydnxe2nbaleqn4g5ikiywtm

Untargeted Lipidomic Profiling of Dry Blood Spots Using SFC-HRMS

Pauline Le Faouder, Julia Soullier, Marie Tremblay-Franco, Anthony Tournadre, Jean-François Martin, Yann Guitton, Caroline Carlé, Sylvie Caspar-Bauguil, Pierre-Damien Denechaud, Justine Bertrand-Michel
2021 Metabolites  
Lipids are essential cellular constituents that have many critical roles in physiological functions. They are notably involved in energy storage and cell signaling as second messengers, and they are major constituents of cell membranes, including lipid rafts. As a consequence, they are implicated in a large number of heterogeneous diseases, such as cancer, diabetes, neurological disorders, and inherited metabolic diseases. Due to the high structural diversity and complexity of lipid species,
more » ... presence of isomeric and isobaric lipid species, and their occurrence at a large concentration scale, a complete lipidomic profiling of biological matrices remains challenging, especially in clinical contexts. Using supercritical fluid chromatography coupled with high-resolution mass spectrometry, we have developed and validated an untargeted lipidomic approach to the profiling of plasma and blood. Moreover, we have tested the technique using the Dry Blood Spot (DBS) method and found that it allows for the easy collection of blood for analysis. To develop the method, we performed the optimization of the separation and detection of lipid species on pure standards, reference human plasma (SRM1950), whole blood, and DBS. These analyses allowed an in-house lipid data bank to be built. Using the MS-Dial software, we developed an automatic process for the relative quantification of around 500 lipids species belonging to the 6 main classes of lipids (including phospholipids, sphingolipids, free fatty acids, sterols, and fatty acyl-carnitines). Then, we compared the method using the published data for SRM 1950 and a mouse blood sample, along with another sample of the same blood collected using the DBS method. In this study, we provided a method for blood lipidomic profiling that can be used for the easy sampling of dry blood spots.
doi:10.3390/metabo11050305 pmid:34064856 fatcat:xhik2i6s7rbn3a6wnyppismy2m

ASICS: an automatic method for identification and quantification of metabolites in complex 1D 1H NMR spectra

Patrick J. C. Tardivel, Cécile Canlet, Gaëlle Lefort, Marie Tremblay-Franco, Laurent Debrauwer, Didier Concordet, Rémi Servien
2017 Metabolomics  
an automatic method for identification and quantification of metabolites in complex 1D 1H NMR spectra. Metabolomics, Springer Verlag, 2017, <10. Abstract: Introduction Experiments in metabolomics rely on the identification and quantification of metabolites in complex biological mixtures. This remains one of the major challenges in NMR/mass spectrometry analysis of metabolic profiles. These features are mandatory to make metabolomics asserting a general approach to test a priori formulated
more » ... eses on the basis of exhaustive metabolome characterization rather than an exploratory tool dealing with unknown metabolic features. Objectives In this article we propose a method, named ASICS, based on a strong statistical theory that handles automatically the metabolites identification and quantification in proton NMR spectra. Methods A statistical linear model is built to explain a complex spectrum using a library containing pure metabolite spectra. This model can handle local or global chemical shift variations due to experimental conditions using a warping function. A statistical lasso-type estimator identifies and quantifies the metabolites in the complex spectrum. This estimator shows good statistical properties and handles peak overlapping issues. Results The performances of the method were investigated on known mixtures (such as synthetic urine) and on plasma datasets from duck and human. Results show noteworthy performances, outperforming current existing methods. Conclusion ASICS is a completely automated procedure to identify and quantify metabolites in 1 H NMR spectra of biological mixtures. It will enable empowering NMR-based metabolomics by quickly and accurately helping experts to obtain metabolic profiles.
doi:10.1007/s11306-017-1244-5 fatcat:s3v5qvmltjaorofrh3j3e4q6pa

Bisphenol A Exposure Disrupts Neurotransmitters Through Modulation of Transaminase Activity in the Brain of Rodents

Daniel Zalko, Ana M. Soto, Cecile Canlet, Marie Tremblay-Franco, Fabien Jourdan, Nicolas J. Cabaton
2016 Endocrinology  
Soto, Cecile Canlet, Marie Tremblay-Franco, Fabien Jourdan, and Nicolas J. Cabaton Toxalim (D.Z., C.C., M.T.  ... 
doi:10.1210/en.2016-1207 pmid:27149041 pmcid:PMC4870873 fatcat:27hlyuv2hvbrxobxoymogsiixu

Delayed Early Primary Visual Pathway Development in Premature Infants: High Density Electrophysiological Evidence

Emmanuel Tremblay, Phetsamone Vannasing, Marie-Sylvie Roy, Francine Lefebvre, Damelan Kombate, Maryse Lassonde, Franco Lepore, Michelle McKerral, Anne Gallagher, Zsolt Ablonczy
2014 PLoS ONE  
In the past decades, multiple studies have been interested in developmental patterns of the visual system in healthy infants. During the first year of life, differential maturational changes have been observed between the Magnocellular (P) and the Parvocellular (P) visual pathways. However, few studies investigated P and M system development in infants born prematurely. The aim of the present study was to characterize P and M system maturational differences between healthy preterm and fullterm
more » ... nfants through a critical period of visual maturation: the first year of life. Using a cross-sectional design, high-density electroencephalogram (EEG) was recorded in 31 healthy preterms and 41 fullterm infants of 3, 6, or 12 months (corrected age for premature babies). Three visual stimulations varying in contrast and spatial frequency were presented to stimulate preferentially the M pathway, the P pathway, or both systems simultaneously during EEG recordings. Results from early visual evoked potentials in response to the stimulation that activates simultaneously both systems revealed longer N1 latencies and smaller P1 amplitudes in preterm infants compared to fullterms. Moreover, preterms showed longer N1 and P1 latencies in response to stimuli assessing the M pathway at 3 months. No differences between preterms and fullterms were found when using the preferential P system stimulation. In order to identify the cerebral generator of each visual response, distributed source analyses were computed in 12-month-old infants using LORETA. Source analysis demonstrated an activation of the parietal dorsal region in fullterm infants, in response to the preferential M pathway, which was not seen in the preterms. Overall, these findings suggest that the Magnocellular pathway development is affected in premature infants. Although our VEP results suggest that premature children overcome, at least partially, the visual developmental delay with time, source analyses reveal abnormal brain activation of the Magnocellular pathway at 12 months of age.
doi:10.1371/journal.pone.0107992 pmid:25268226 pmcid:PMC4182425 fatcat:rsszxsqqhje7xhormwhoww3dni

Adaptive response under multiple stress exposure in fish: From the molecular to individual level

Allison Gandar, Pascal Laffaille, Cécile Canlet, Marie Tremblay-Franco, Roselyne Gautier, Annie Perrault, Laure Gress, Pierre Mormède, Nathalie Tapie, Hélène Budzinski, Séverine Jean
2017 Chemosphere  
., Tremblay-Franco, M., Gautier, R., Perrault, A., Gress, L., Mormède, P., Tapie, N., Budzinski, Jean, S. (2017).  ...  Comment citer ce document : Gandar, A., Laffaille, P., Canlet, C., Tremblay-Franco, M., Gautier, R., Perrault, A., Gress, L., Mormède, P., Tapie, N., Budzinski, Jean, S. (2017).  ... 
doi:10.1016/j.chemosphere.2017.08.089 pmid:28869847 fatcat:p4xi7uunnvg7fbm2vxeu46rifu

Osmolality-based normalization enhances statistical discrimination of untargeted metabolomic urine analysis: results from a comparative study

Loïc Mervant, Marie Tremblay-Franco, Emilien L. Jamin, Emmanuelle Kesse-Guyot, Pilar Galan, Jean-François Martin, Françoise Guéraud, Laurent Debrauwer
2021 Metabolomics  
Because of its ease of collection, urine is one of the most commonly used matrices for metabolomics studies. However, unlike other biofluids, urine exhibits tremendous variability that can introduce confounding inconsistency during result interpretation. Despite many existing techniques to normalize urine samples, there is still no consensus on either which method is most appropriate or how to evaluate these methods. To investigate the impact of several methods and combinations of methods
more » ... tionally used in urine metabolomics on the statistical discrimination of two groups in a simple metabolomics study. We applied 14 different strategies of normalization to forty urine samples analysed by liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). To evaluate the impact of these different strategies, we relied on the ability of each method to reduce confounding variability while retaining variability of interest, as well as the predictability of statistical models. Among all tested normalization methods, osmolality-based normalization gave the best results. Moreover, we demonstrated that normalization using a specific dilution prior to the analysis outperformed post-acquisition normalization. We also demonstrated that the combination of various normalization methods does not necessarily improve statistical discrimination. This study re-emphasized the importance of normalizing urine samples for metabolomics studies. In addition, it appeared that the choice of method had a significant impact on result quality. Consequently, we suggest osmolality-based normalization as the best method for normalizing urine samples. NCT03335644.
doi:10.1007/s11306-020-01758-z pmid:33389209 fatcat:7ehimtyej5bcnopasiredc7xvu

Specific Metabolic Fingerprint of a Dietary Exposure to a Very Low Dose of Endosulfan

Cécile Canlet, Marie Tremblay-Franco, Roselyne Gautier, Jérôme Molina, Benjamin Métais, Florence Blas-Y Estrada, Laurence Gamet-Payrastre
2013 Journal of Toxicology  
Like other persistent organochlorine pesticides, endosulfan residues have been detected in foods including fruit, vegetables, and fish. The aim of our study was to assess the impact of a dietary exposure to low doses of endosulfan from foetal development until adult age on metabolic homeostasis in mice and to identify biomarkers of exposure using an1H-NMR-based metabonomic approach in various tissues and biofluids. We report in both genders an increase in plasma glucose as well as changes in
more » ... els of factors involved in the regulation of liver oxidative stress, confirming the prooxidant activities of this compound. Some metabolic changes were distinct in males and females. For example in plasma, a decrease in lipid LDL and choline content was only observed in female. Lactate levels in males were significantly increased. In conclusion, our results show that metabolic changes in liver could be linked to the onset of pathologies like diabetes and insulin resistance. Moreover from our results it appears that the NMR-based metabonomic approach could be useful for the characterization in plasma of a dietary exposure to low dose of pesticide in human.
doi:10.1155/2013/545802 pmid:23431292 pmcid:PMC3569910 fatcat:lujrxuzstjfovl24ktriyefkry

Investigating the Postprandial Metabolome after Challenge Tests to Assess Metabolic Flexibility and Dysregulations Associated with Cardiometabolic Diseases

Gaïa Lépine, Marie Tremblay-Franco, Sabrine Bouder, Laurianne Dimina, Hélène Fouillet, François Mariotti, Sergio Polakof
2022 Nutrients  
This review focuses on the added value provided by a research strategy applying metabolomics analyses to assess phenotypic flexibility in response to different nutritional challenge tests in the framework of metabolic clinical studies. We discuss findings related to the Oral Glucose Tolerance Test (OGTT) and to mixed meals with varying fat contents and food matrix complexities. Overall, the use of challenge tests combined with metabolomics revealed subtle metabolic dysregulations exacerbated
more » ... ing the postprandial period when comparing healthy and at cardiometabolic risk subjects. In healthy subjects, consistent postprandial metabolic shifts driven by insulin action were reported (e.g., a switch from lipid to glucose oxidation for energy fueling) with similarities between OGTT and mixed meals, especially during the first hours following meal ingestion while differences appeared in a wider timeframe. In populations with expected reduced phenotypic flexibility, often associated with increased cardiometabolic risk, a blunted response on most key postprandial pathways was reported. We also discuss the most suitable statistical tools to analyze the dynamic alterations of the postprandial metabolome while accounting for complexity in study designs and data structure. Overall, the in-depth characterization of the postprandial metabolism and associated phenotypic flexibility appears highly promising for a better understanding of the onset of cardiometabolic diseases.
doi:10.3390/nu14030472 pmid:35276829 pmcid:PMC8840206 fatcat:fakbojg4tzdava7iucth365m5u

Proton NMR Enables the Absolute Quantification of Aqueous Metabolites and Lipid Classes in Unique Mouse Liver Samples

Aurélien Amiel, Marie Tremblay-Franco, Roselyne Gautier, Simon Ducheix, Alexandra Montagner, Arnaud Polizzi, Laurent Debrauwer, Hervé Guillou, Justine Bertrand-Michel, Cécile Canlet
2019 Metabolites  
Hepatic metabolites provide valuable information on the physiological state of an organism, and thus, they are monitored in many clinical situations. Typically, monitoring requires several analyses for each class of targeted metabolite, which is time consuming. The present study aimed to evaluate a proton nuclear magnetic resonance (1H-NMR) method for obtaining quantitative measurements of aqueous and lipidic metabolites. We optimized the extraction protocol, the standard samples, and the
more » ... c solvents for the absolute quantification of lipid species. To validate the method, we analyzed metabolic profiles in livers of mice fed three different diets. We compared our results with values obtained with conventional methods and found strong correlations. The 1H-NMR protocol enabled the absolute quantification of 29 aqueous metabolites and eight lipid classes. Results showed that mice fed a diet enriched in saturated fatty acids had higher levels of triglycerides, cholesterol ester, monounsaturated fatty acids, lactate, 3-hydroxy-butyrate, and alanine and lower levels of glucose, compared to mice fed a control diet. In conclusion, proton NMR provided a rapid overview of the main lipid classes (triglycerides, cholesterol, phospholipids, fatty acids) and the most abundant aqueous metabolites in liver.
doi:10.3390/metabo10010009 pmid:31877749 pmcid:PMC7023327 fatcat:5u2lpfjr4bdqfnmugc5kdogqyu

Dynamic Metabolic Disruption in Rats Perinatally Exposed to Low Doses of Bisphenol-A

Marie Tremblay-Franco, Nicolas J. Cabaton, Cécile Canlet, Roselyne Gautier, Cheryl M. Schaeberle, Fabien Jourdan, Carlos Sonnenschein, Florence Vinson, Ana M. Soto, Daniel Zalko, Yann Gibert
2015 PLoS ONE  
Along with the well-established effects on fertility and fecundity, perinatal exposure to endocrine disrupting chemicals, and notably to xeno-estrogens, is strongly suspected of modulating general metabolism. The metabolism of a perinatally exposed individual may be durably altered leading to a higher susceptibility of developing metabolic disorders such as obesity and diabetes; however, experimental designs involving the long term study of these dynamic changes in the metabolome raise novel
more » ... llenges. 1 H-NMR-based metabolomics was applied to study the effects of bisphenol-A (BPA, 0; 0.25; 2.5, 25 and 250 μg/kg BW/ day) in rats exposed perinatally. Serum and liver samples of exposed animals were analyzed on days 21, 50, 90, 140 and 200 in order to explore whether maternal exposure to BPA alters metabolism. Partial Least Squares-Discriminant Analysis (PLS-DA) was independently applied to each time point, demonstrating a significant pair-wise discrimination for liver as well as serum samples at all time-points, and highlighting unequivocal metabolic shifts in rats perinatally exposed to BPA, including those exposed to lower doses. In BPA exposed animals, metabolism of glucose, lactate and fatty acids was modified over time. To further explore dynamic variation, ANOVA-Simultaneous Component Analysis (A-SCA) was used to separate data into blocks corresponding to the different sources of variation (Time, Dose and Time*Dose interaction). A-SCA enabled the demonstration of a dynamic, time/age dependent shift of serum metabolome throughout the rats' lifetimes. Variables responsible for the discrimination between groups clearly indicate that BPA modulates energy metabolism, and suggest alterations of neurotransmitter signaling, the latter finding being compatible with the neurodevelopmental effect of this xenoestrogen. In conclusion, long lasting metabolic effects of BPA could be characterized over 200 days, despite physiological (and thus metabolic) changes connected with sexual maturation and aging. samples; Right column: Liver extracts. Each dot represents an observation (animal), projected onto first (horizontal axis) and second (vertical axis) PLS-DA variables. BPA doses are shown in different colors: Control in black, BPA0.25 colored dark grey, BPA2.5 in middle grey, BPA25 in light grey and BPA250 in white. The black ellipse determines the 95% confidence interval, which is drawn using Hotelling's T 2 statistic. A. PND21 serum samples (A = 2, R 2 = 49.4, Q 2 = 0.484). B. PND50 serum samples (A = 3, R 2 = 69.7, Q 2 = 0.644). C. PND90 serum samples (A = 2, R 2 = 47.0, Q 2 = 0.449). D. PND140 serum samples Lasting Metabolic Disruption in Rats Exposed to BPA PLOS ONE |
doi:10.1371/journal.pone.0141698 pmid:26517871 pmcid:PMC4627775 fatcat:i33cfamne5dm7fdunbb4fd2sza

Postprandial NMR-Based Metabolic Exchanges Reflect Impaired Phenotypic Flexibility across Splanchnic Organs in the Obese Yucatan Mini-Pig

Marie Tremblay-Franco, Nathalie Poupin, Aurélien Amiel, Cécile Canlet, Didier Rémond, Laurent Debrauwer, Dominique Dardevet, Fabien Jourdan, Isabelle Savary-Auzeloux, Sergio Polakof
2020 Nutrients  
The postprandial period represents one of the most challenging phenomena in whole-body metabolism, and it can be used as a unique window to evaluate the phenotypic flexibility of an individual in response to a given meal, which can be done by measuring the resilience of the metabolome. However, this exploration of the metabolism has never been applied to the arteriovenous (AV) exploration of organs metabolism. Here, we applied an AV metabolomics strategy to evaluate the postprandial flexibility
more » ... across the liver and the intestine of mini-pigs subjected to a high fat–high sucrose (HFHS) diet for 2 months. We identified for the first time a postprandial signature associated to the insulin resistance and obesity outcomes, and we showed that the splanchnic postprandial metabolome was considerably affected by the meal and the obesity condition. Most of the changes induced by obesity were observed in the exchanges across the liver, where the metabolism was reorganized to maintain whole body glucose homeostasis by routing glucose formed de novo from a large variety of substrates into glycogen. Furthermore, metabolites related to lipid handling and energy metabolism showed a blunted postprandial response in the obese animals across organs. Finally, some of our results reflect a loss of flexibility in response to the HFHS meal challenge in unsuspected metabolic pathways that must be further explored as potential new events involved in early obesity and the onset of insulin resistance.
doi:10.3390/nu12082442 pmid:32823827 fatcat:elpk5niltbfjbglwxadm7k6mam

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

Alexandra Montagner, Agata Korecka, Arnaud Polizzi, Yannick Lippi, Yuna Blum, Cécile Canlet, Marie Tremblay-Franco, Amandine Gautier-Stein, Rémy Burcelin, Yi-Chun Yen, Hyunsoo Shawn Je, Maha Al-Asmakh (+6 others)
2016 Scientific Reports  
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 germfree (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
more » ... d 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 microbiomesensitive 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.
doi:10.1038/srep20127 pmid:26879573 pmcid:PMC4754633 fatcat:ygvypnz3wzesdek5zvzdlywh2y
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