Hepatic circadian clock oscillators and nuclear receptors integrate microbiome-derived signals
Open accessAbstract
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.
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The microbiota is required for correct integration of liver clock-oscillations, which in turn regulate metabolic gene expression for optimal liver function.
“Upon examination of circadian clock mRNA in GF mice, it was reported that the microbiota was required for correct integration of liver clock-oscillations, which in turn regulate metabolic gene expression for optimal liver function (Montagner et al., 2016).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Montagner et al., 2016
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Self-citationLimoRhyde: A Flexible Approach for Differential Analysis of Rhythmic Transcriptome Data
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At the Interface of Lifestyle, Behavior, and Circadian Rhythms: Metabolic Implications
Bae, S.-A., Fang, M., Rustgi, V. K., Zarbl, H., & Androulakis, I. P. (2019) · Frontiers in Nutrition · doi:10.3389/fnut.2019.00132 · Cited by 100 · see citing works
Circadian regulation of liver function: from molecular mechanisms to disease pathophysiology
Bolshette, N. B., Ibrahim, H., Reinke, H., & Asher, G. (2023) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-023-00792-1 · Cited by 99 · see citing works
Microbiome diurnal rhythmicity and its impact on host physiology and disease risk
Nobs, S. P., Tuganbaev, T., & Elinav, E. (2019) · EMBO Reports · doi:10.15252/embr.201847129 · Cited by 90 · see citing works
“Microbial metabolites, specifically short-chain fatty acids, directly modulate diurnal expression of circadian clock genes in hepatocytes [129], while germ-free and antibiotic-treated mice display altered daily oscillation of clock gene expression in the liver [79,172].”
BackgroundPhotobiomodulation of the microbiome: implications for metabolic and inflammatory diseases
Bicknell, B. T., Liebert, A. D., Johnstone, D. M., & Kiat, H. (2018) · Lasers in Medical Science · doi:10.1007/s10103-018-2594-6 · Cited by 89 · see citing works
“Photobiomics”: Can Light, Including Photobiomodulation, Alter the Microbiome?
Liebert, A. D., Bicknell, B. T., Johnstone, D. M., Gordon, L. C., Kiat, H., & Hamblin, M. R. (2019) · Photobiomodulation Photomedicine and Laser Surgery · doi:10.1089/photob.2019.4628 · Cited by 87 · see citing works
“…lipid metabolism, glucose metabolism, protein turnover, and redox balance as well as increasing biomarkers such as cholesterol, free fatty acids, fibroblast growth factor 21, bilirubin and lactate, 121 and inflammatory markers such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-a ).”
Khalyfa, A., Ericsson, A. C., Qiao, Z., Almendros, I., Farré, R., & Gozal, D. (2021) · EBioMedicine · doi:10.1016/j.ebiom.2021.103208 · Cited by 83 · see citing works
“The ever expanding extant literature clearly indicates that the GM influences multiple metabolic process in liver, intestine, brain, skeletal muscle, and vWAT [76-79], and that specific alterations in GM foster the development and progression of metabolic and cardiovascular diseases, as well as obesity [78, 80, 81].”
BackgroundPredicting drug-microbiome interactions with machine learning
McCoubrey, L. E., Gaisford, S., Orlu, M., & Basit, A. W. (2021) · Biotechnology Advances · doi:10.1016/j.biotechadv.2021.107797 · Cited by 80 · see citing works
Duszka, K., Gregor, A., Guillou, H., König, J. S., & Wahli, W. (2020) · Cells · doi:10.3390/cells9071708 · Cited by 82 · see citing works
Self-citationThe PPAR–microbiota–metabolic organ trilogy to fine‐tune physiology
Oh, H. Y. P., Visvalingam, V., & Wahli, W. (2019) · The FASEB Journal · doi:10.1096/fj.201802681rr · Cited by 78 · see citing works
Self-citationCircadian Clocks and Metabolism: Implications for Microbiome and Aging
Paschos, G. K., & FitzGerald, G. A. (2017) · Trends in Genetics · doi:10.1016/j.tig.2017.07.010 · Cited by 77 · see citing works
“Experiments in germ-free mice, confirm the requirement of the microbiome for hepatic circadian clock oscillators and identify changes in downstream nuclear receptors that regulate metabolic gene expression [65].”
BackgroundThe microbiome stabilizes circadian rhythms in the gut
Zhang, Y., Li, Y., Barber, A. F., Noya, S. B., Williams, J. A., Li, F., Daniel, S. G., Bittinger, K. L., Fang, J., & Sehgal, A. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2217532120 · Cited by 73 · see citing works
Song, D., Yang, C. S., Zhang, X., & Wang, Y. (2020) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2020.1719473 · Cited by 70 · see citing works
Tan, C. K., Zhuang, Y., & Wahli, W. (2017) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2017.1280467 · Cited by 70 · see citing works
“Complex responses also depend on organ–organ cross talk and host–microbiome interactions, which also have an impact on PPARs [13,116].”
BackgroundSelf-citationMechanisms Involved in Gut Microbiota Regulation of Skeletal Muscle
Li, G., Jin, B., & Fan, Z. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/2151191 · Cited by 68 · see citing works
“Although several studies have revealed how the gut microbiota impacts the liver and intestinal metabolism [22], there are few reports on how the gut microbiota regulates skeletal muscle, which is also one of the key metabolic organs [23].”
BackgroundCodoñer‐Franch, P., Gombert, M., Martı́nez-Raga, J., & Cénit, M. C. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24087579 · Cited by 69 · see citing works
“In this context, obesity or type 2 diabetes (T2D) displays less rhythmicity in the gut microbiome in ways that are distinct between the two disorders [127].”
BackgroundMetronidazole Causes Skeletal Muscle Atrophy and Modulates Muscle Chronometabolism
Manickam, R., Oh, H. Y. P., Tan, C. K., Paramalingam, E., & Wahli, W. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19082418 · Cited by 63 · see citing works
“However, this time point was chosen based on our finding that in GF mice, the strongest alteration in the expression of clock and clock effector genes was observed at ZT6 [19].”
BackgroundSelf-citationNuclear Receptors Regulate Intestinal Inflammation in the Context of IBD
Klepsch, V., Moschen, A. R., Tilg, H., Baier, G., & Hermann‐Kleiter, N. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01070 · Cited by 63 · see citing works
“NRs contribute especially to gut homeostasis by shaping intestinal immune cells; on one side, they are constantly challenged in the face of stimulatory signals from nutrients and gut microbiota, and on the other, they shape the composition of the microbiota themselves (Figures 1, 2) (5, 13, 19, 28, 29).”
BackgroundThe Drosophila microbiome has a limited influence on sleep, activity, and courtship behaviors
Selkrig, J., Mohammad, F., Ng, S. H., Chua, J. Y., Tumkaya, T., Ho, J., Chiang, Y. N., Rieger, D., Pettersson, S., Helfrich‐Förster, C., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-28764-5 · Cited by 62 · see citing works
Self-citationZhang, Z., Wang, D., Qiao, S., Wu, X., Cao, S., Wang, L., Su, X., & Li, L. (2017) · Scientific Reports · doi:10.1038/s41598-017-04888-y · Cited by 60 · see citing works
Insights into the Role of PPARβ/δ in NAFLD
Chen, J., Montagner, A., Tan, N. S., & Wahli, W. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19071893 · Cited by 60 · see citing works
“Indeed, PPARα peaks at the end the light/resting period, while PPARβ/δ is highly expressed in the liver during the night/feeding period, according to [86,121], and Montagner et al.”
BackgroundSelf-citationThe Oscillating Gut Microbiome and Its Effects on Host Circadian Biology
Litichevskiy, L., & Thaiss, C. A. (2022) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-062320-111321 · Cited by 56 · see citing works
Daas, M. C., & de Roos, N. M. (2021) · Beneficial Microbes · doi:10.3920/bm2020.0149 · Cited by 54 · see citing works
Gut microbes and the liver circadian clock partition glucose and lipid metabolism
Frazier, K., Manzoor, S. S., Carroll, K., DeLeon, O., Miyoshi, S., Miyoshi, J., George, M. S., Tan, A., Chrisler, E. A., Izumo, M., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci162515 · Cited by 57 · see citing works
“14 in part, to differential regulation of hepatic PPAR signaling (Montagner et al., 2016) and may provide protection against high-fat diet-induced obesity.”
BackgroundFougerat, A., Bruse, J., Polizzi, A., Montagner, A., Guillou, H., & Wahli, W. (2024) · Progress in Lipid Research · doi:10.1016/j.plipres.2024.101303 · Cited by 54 · see citing works
“In line with this finding, it was also reported that germ-free mice show impaired expression of many PPAR α target genes, such as Fgf21 , in the liver [151].”
Self-citationInteractions between Gut Microbiota, Host Circadian Rhythms, and Metabolic Diseases
Zhang, M., Zhou, C., Li, X., Li, H., Han, Q., Chen, Z., Tang, W., & Yin, J. (2025) · Advances in Nutrition · doi:10.1016/j.advnut.2025.100416 · Cited by 53 · see citing works
“Speci fi cally, the expression patterns of Bmal1 , Per1/2 , and Cry1 exhibit distinct pro fi les in germ-free mice [64].”
InfluentialBeli, E., Prabakaran, S., Krishnan, P., Evans‐Molina, C., & Grant, M. B. (2019) · Nutrients · doi:10.3390/nu11102310 · Cited by 53 · see citing works
“The expression of many metabolic liver genes, including genes involved in sterol biosynthesis, fatty acid, and linoleic acid metabolism, PXR and LXR activation, and methionine metabolism, are altered in the absence of a gut microbiome [19,21,33].”
BackgroundA brief period of sleep deprivation leads to subtle changes in mouse gut microbiota
Aidy, S. E., Bolsius, Y. G., Raven, F., & Havekes, R. (2019) · Journal of Sleep Research · doi:10.1111/jsr.12920 · Cited by 50 · see citing works
“It is very important to consider the timing of sample collection when comparing studies of the gut microbiota as evidence for oscillation of these microbes and for a bidirectional interaction between their rhythm and the host circa‐ dian clock has now been well established (Montagner et al., 2016).”
BackgroundOh, J., Lee, J. H., Han, D.-H., Cho, S., & Lee, Y. J. (2017) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2017.04.071 · Cited by 49 · see citing works
Cardioprotective Properties of Phenolic Compounds: A Role for Biological Rhythms
Torres‐Fuentes, C., Suárez, M., Aragonès, G., Mulero, M., Ávila‐Román, J., Arola‐Arnal, A., Salvadó, M. J., Arola, L., Bravo, F. I., & Muguerza, B. (2022) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.202100990 · Cited by 49 · see citing works
The microbiota drives diurnal rhythms in tryptophan metabolism in the stressed gut
Gheorghe, C. E., Leigh, S., Tofani, G. S. S., Bastiaanssen, T. F. S., Lyte, J. M., Gardellin, E., Govindan, A., Strain, C., Martínez-Herrero, S., Goodson, M. S., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114079 · Cited by 51 · see citing works
The Microbiome Mediates Environmental Effects on Aging
Finlay, B. B., Pettersson, S., Melby, M. K., & Bosch, T. C. G. (2019) · BioEssays · doi:10.1002/bies.201800257 · Cited by 46 · see citing works
Self-citationRegulation of Mammalian Physiology by Interconnected Circadian and Feeding Rhythms
Atger, F., Mauvoisin, D., Weger, B. D., Gobet, C., & Gachon, F. (2017) · Frontiers in Endocrinology · doi:10.3389/fendo.2017.00042 · Cited by 46 · see citing works
Are There Circadian Clocks in Non-Photosynthetic Bacteria?
Sartor, F., Eelderink-Chen, Z., Aronson, B., Bosman, J., Hibbert, L. E., Dodd, A. N., Kovács, Á. T., & Merrow, M. W. (2019) · Biology · doi:10.3390/biology8020041 · Cited by 46 · see citing works
Prokopienko, A. J., & Nolin, T. D. (2017) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2018.1378095 · Cited by 43 · see citing works
“Since these metabolites may be ligands for nuclear receptors, this could lead to altered hepatic gene expression [37,38].”
Nutrition, Microbiota and Role of Gut-Brain Axis in Subjects with Phenylketonuria (PKU): A Review
Verduci, E., Carbone, M. T., Borghi, E., Ottaviano, E., Burlina, A., & Biasucci, G. (2020) · Nutrients · doi:10.3390/nu12113319 · Cited by 41 · see citing works
“A few publications indicate how the microbiota may influence the CNS and consequently exert unwanted effects on metabolism [77,169], coordination [170], mood [171], behaviour [172], cognition [173], temperature control [174], and sensation [175].”
BackgroundDisruptions in gut microbial-host co-metabolism and the development of metabolic disorders
Rajani, C., & Jia, W. P. (2018) · Clinical Science · doi:10.1042/cs20171328 · Cited by 42 · see citing works
The Microbiome as a Circadian Coordinator of Metabolism
Alvarez, Y., Glotfelty, L., Blank, N., Dohnalová, L., & Thaiss, C. A. (2020) · Endocrinology · doi:10.1210/endocr/bqaa059 · Cited by 41 · see citing works
Mashaqi, S., & Gozal, D. (2020) · Sleep Medicine · doi:10.1016/j.sleep.2020.03.020 · Cited by 40 · see citing works
Bidirectional interactions between circadian rhythms and the gut microbiome
Bautista, J., Ojeda-Mosquera, S., Altamirano-Colina, A., Hidalgo‐Tinoco, C., Delgado, M. D. C., & López‐Cortés, A. (2025) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-025-13570-7 · Cited by 39 · see citing works
“Furthermore, the microbiota itself influences host rhythms by modulating gene expression in peripheral tissues such as the liver and intestine, partly through microbial metabolites and epigenetic remodeling of host chromatin (Montagner et al. 2016; Murakami et al. 2016; Y. Zhang et al. 2024a, b).”
Circadian control of metabolism and pathological consequences of clock perturbations
Mayeuf-Louchart, A., Zecchin, M., Staels, B., & Duez, H. (2017) · Biochimie · doi:10.1016/j.biochi.2017.07.017 · Cited by 35 · see citing works
Barretto, S. A., Lasserre, F., Huillet, M., Régnier, M., Polizzi, A., Lippi, Y., Fougerat, A., Person, E., Bruel, S., Bétoulières, C., et al. (2021) · Microbiome · doi:10.1186/s40168-021-01050-9 · Cited by 36 · see citing works
“[14], lipid metabolism [15] and xenobiotic metabolism [16, 17].”
BackgroundResultSelf-citationRegulation of systemic metabolism by tissue-resident immune cell circuits
Li, J. H., Hepworth, M. R., & O’Sullivan, T. E. (2023) · Immunity · doi:10.1016/j.immuni.2023.05.001 · Cited by 34 · see citing works
Interplay between Microbes and the Circadian ClockPreprint
Tognini, P., Murakami, M., & Sassone‐Corsi, P. (2017) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a028365 · Cited by 29 · see citing works
“The systemic oscillation of microbiota-derived metabolome reprograms the circadian transcriptome both locally and distally, thereby regulating host physiology such as metabolic function and drug detoxification (Leone et al. 2015; Montagner et al. 2016; Murakami et al. 2016; Thaiss et al. 2016).”
BackgroundCai, Y., Liu, Y., Wu, Z., Wang, J., & Zhang, X. (2023) · Nutrients · doi:10.3390/nu15122743 · Cited by 27 · see citing works
“By analyzing the gene expression of liver samples, the mRNA expression pattern of the biological-clock gene in the liver of infertile mice was significantly different from that of SPF mice [35].”
ResultShor, E. K., Brown, S. P., & Freeman, D. A. (2020) · Journal of Pineal Research · doi:10.1111/jpi.12696 · Cited by 26 · see citing works
Circadian de(regulation) in physiology: implications for disease and treatmentPreprint
de Assis, L. V. M., & Kramer, A. (2024) · Genes & Development · doi:10.1101/gad.352180.124 · Cited by 27 · see citing works
Barretto, S. A., Lasserre, F., Fougerat, A., Smith, L., Fougeray, T., Lukowicz, C., Polizzi, A., Smati, S., Régnier, M., Naylies, C., et al. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20153767 · Cited by 25 · see citing works
“the day, and is highest as zeitgeber time (ZT)6 [19].”
BackgroundSelf-citationDeota, S., Pendergast, J. S., Kolthur‐Seetharam, U., Esser, K. A., Gachon, F., Asher, G., Dibner, C., Benitah, S. A., Escobar, C., Muoio, D. M., et al. (2025) · Nature Metabolism · doi:10.1038/s42255-025-01237-6 · Cited by 23 · see citing works
Ding, L., & Xiao, X. (2020) · Chinese Medical Journal · doi:10.1097/cm9.0000000000000702 · Cited by 24 · see citing works
“[84] Montagner et al[85] reported that germ-free mice exhibited dynamic oscillation of circadian clock gene expression with concomitant alterations in the expression of clock output regulators, which are closely connected with daily alterations in glucose, lipids, and xenobiotic metabolism.”
BackgroundCircadian rhythms and the liver
Costa, R., Mangini, C., Domenie, E. D., Zarantonello, L., & Montagnese, S. (2023) · Liver International · doi:10.1111/liv.15501 · Cited by 23 · see citing works
Feng, C. T., Sarigaiqiqige, Liu, W., Chen, H., Dong, W., & Yang, J. (2021) · Comparative Biochemistry and Physiology Part C Toxicology & Pharmacology · doi:10.1016/j.cbpc.2021.109100 · Cited by 22 · see citing works
The microbiome and inborn errors of metabolism: Why we should look carefully at their interplay?
Colonetti, K., Roesch, L. F. W., & Schwartz, I. V. D. (2018) · Genetics and Molecular Biology · doi:10.1590/1678-4685-gmb-2017-0235 · Cited by 22 · see citing works
“The microbiome has wide-ranging influence on the CNS, with probable effects on metabolism (Fu et al., 2015; Montagner et al., 2016), coordination (Sampson et al.”
BackgroundSalaün, C., Courvalet, M., Rousseau, L., Cailleux, K., Breton, J., Bôle‐Feysot, C., Guérin, C., Huré, M., Goichon, A., do-Rego, J.-C., et al. (2024) · Biology of Sex Differences · doi:10.1186/s13293-023-00576-x · Cited by 21 · see citing works
“Germ-free mice exhibit changes in liver circadian genes expression, such as Cry1 , Per1 and Per2 [34].”
BackgroundCircadian Rhythm Effects on the Molecular Regulation of Physiological Systems
Crislip, G. R., Johnston, J. G., Douma, L. G., Costello, H. M., Juffre, A., Boyd, K., Li, W. W., Maugans, C. C., Gutierrez‐Monreal, M. A., Esser, K. A., et al. (2021) · Comprehensive physiology · doi:10.1002/cphy.c210011 · Cited by 33 · see citing works
Origins and functions of microbiome rhythms
Kießling, S., Liu, S., Haller, D., & Thaiss, C. A. (2025) · Cell Host & Microbe · doi:10.1016/j.chom.2025.05.017 · Cited by 17 · see citing works
Dimorphic metabolic and endocrine disorders in mice lacking the constitutive androstane receptor
Lukowicz, C., Ellero‐Simatos, S., Régnier, M., Oliviero, F., Lasserre, F., Polizzi, A., Montagner, A., Smati, S., Boudou, F., Lenfant, F., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-56570-0 · Cited by 17 · see citing works
Self-citationdos Santos, A., & Vasylyshyn, A. (2025) · Frontiers in Physiology · doi:10.3389/fphys.2025.1595057 · Cited by 16 · see citing works
Andjelković, A., Kemppainen, K. K., & Jacobs, H. T. (2016) · G3 Genes Genomes Genetics · doi:10.1534/g3.116.030882 · Cited by 16 · see citing works
Kiani, P., Khodadadi, E. S., Nikdasti, A., Yarahmadi, S., Gheibi, M., Yousefi, Z., Ehtiati, S., Yahyazadeh, S., Shafiee, S. M., Taghizadeh, M., et al. (2025) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-025-05207-0 · Cited by 16 · see citing works
Yan, R., Yang, C. S., & Zhang, X. (2021) · Trends in Food Science & Technology · doi:10.1016/j.tifs.2021.01.007 · Cited by 16 · see citing works
O’Neil, D. S., Stewart, C. J., Chu, D. M., Goodspeed, D. M., Gonzalez‐Rodriguez, P. J., Shope, C. D., & Aagaard, K. M. (2017) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2017.03.024 · Cited by 15 · see citing works
“Work in the germ-free mouse has demonstrated that the 166 peripheral circadian clock, particularly in the liver, is potentially regulated by the gut microbiome, as mice devoid of any 167 microbes demonstrate altered patterns of hepatic circadian gene expression (32,33).”
BackgroundCircadian orchestration of host and gut microbiota in infection
Xia, Y., Ding, X., Wang, S., & Ren, W. (2022) · Biological reviews/Biological reviews of the Cambridge Philosophical Society · doi:10.1111/brv.12898 · Cited by 14 · see citing works
“(2016) demonstrated messenger RNA (mRNA) expression of Baml1, Rev-erbα/β, Per1/2, and Cry1 in germ-free (GF) mouse liver in comparison to specific pathogen-free (SPF) mice (Montagner et al., 2016).”
BackgroundDepletion of Gram-Positive Bacteria Impacts Hepatic Biological Functions During the Light Phase
Oh, H. Y. P., Ellero‐Simatos, S., Manickam, R., Tan, N. S., Guillou, H., & Wahli, W. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20040812 · Cited by 14 · see citing works
“Strikingly, vancomycin—a narrow spectrum glycopeptide antibiotic that eliminates gram-positive bacteria—perturbed the liver clock at the ZT4–6 time point that was chosen for this study based on our previous work [17].”
BackgroundResultInfluentialSelf-citationBijnens, S., & Depoortere, I. (2023) · Physiology & Behavior · doi:10.1016/j.physbeh.2023.114103 · Cited by 16 · see citing works
Circadian Rhythm Effects on the Molecular Regulation of Physiological Systems
Crislip, G. R., Johnston, J. G., Douma, L. G., Costello, H. M., Juffre, A., Boyd, K., Li, W. W., Maugans, C. C., Gutierrez‐Monreal, M. A., Esser, K. A., et al. (2021) · Comprehensive physiology · doi:10.1002/j.2040-4603.2022.tb00198.x · Cited by 13 · see citing works
“Cyp3a11 and Cyp2b10 , which encode a xeno-biotic and a drug/steroid metabolizing enzyme, respectively, demonstrated very low hepatic expressions in germ-free male mice, with no or very dampened daily oscillations (186).”
An overview of basic pathophysiological interactions between gut bacteria and their host
Simonson, M., Simonson, T., & Nobécourt, E. (2025) · Frontiers in Nutrition · doi:10.3389/fnut.2025.1565609 · Cited by 14 · see citing works
“Effects of the GMB on the circadian rhythm of the liver were linked to several nuclear receptors (126), some activated by cholesterol analogs and possibly BAs.”
The Metronome of Symbiosis: Interactions Between Microbes and the Host Circadian Clock
Heath-Heckman, E. (2016) · Integrative and Comparative Biology · doi:10.1093/icb/icw067 · Cited by 13 · see citing works
“It was later shown that the microbiome is necessary for both the presence and amplitude of normal transcriptional rhythms in the liver as well as its metabolomic output (Montagner et al. 2016).”
BackgroundHewitt, O. H., & Shaikh, H. M. (2021) · Frontiers in Marine Science · doi:10.3389/fmars.2021.744169 · Cited by 13 · see citing works
Brignardello, J., Fountana, S., Posma, J. M., Chambers, E. S., Nicholson, J. K., Wist, J., Frost, G. S., García‐Pérez, I., & Holmes, E. C. (2021) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqab211 · Cited by 13 · see citing works
“Interindividual differences in the temporal variation of serum SCFA concentrations were evident, consistent with previous studies (31, 32, 53).”
Atypical behavioral and thermoregulatory circadian rhythms in mice lacking a microbiome
Leone, V., Onishi, K. G., Kennedy, M. S., Riggle, J. P., Pierre, J. F., Maneval, A. C., Spedale, M., Theriault, B. R., Chang, E. B., & Prendergast, B. J. (2022) · Scientific Reports · doi:10.1038/s41598-022-18291-9 · Cited by 13 · see citing works
Regulation of fatty acid trafficking in liver by thioesterase superfamily member 1
Desai, A., Alves‐Bezerra, M., Li, Y., Ozdemir, C., Bare, C. J., Li, Y., Hagen, S. J., & Cohen, D. E. (2017) · Journal of Lipid Research · doi:10.1194/jlr.m081455 · Cited by 12 · see citing works
Weger, B. D., Rawashdeh, O., & Gachon, F. (2019) · BioEssays · doi:10.1002/bies.201900059 · Cited by 12 · see citing works
The cytokine MIF controls daily rhythms of symbiont nutrition in an animal–bacterial association
Koch, E. J., Bongrand, C., Bennett, B. D., Lawhorn, S., Moriano‐Gutierrez, S., Pende, M., Vadiwala, K., Dodt, H., Raible, F., Goldman, W. E., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2016864117 · Cited by 11 · see citing works
Metabolic Homeostasis: It’s All in the Timing
Brubaker, P. L., & Martchenko, A. (2021) · Endocrinology · doi:10.1210/endocr/bqab199 · Cited by 12 · see citing works
Wang, Y., Sharma, A., Weber, K. M., Topper, E. T., Appleton, A. A., Gustafson, D., Clish, C. B., Kaplan, R. C., Burk, R. D., Qi, Q., et al. (2023) · Menopause The Journal of The North American Menopause Society · doi:10.1097/gme.0000000000002287 · Cited by 10 · see citing works
I "Gut" Rhythm: the microbiota as a modulator of the stress response and circadian rhythms
Tofani, G. S. S., Clarke, G. A., & Cryan, J. F. (2025) · FEBS Journal · doi:10.1111/febs.17400 · Cited by 10 · see citing works
“Lastly, disruption of the gut microbiota by antibiotic or GF status have been reported to alter clock gene expression in the liver and the gut [203,209,212].”
PPARs as Key Transcription Regulators at the Crossroads of Metabolism and Inflammation
Vázquez‐Carrera, M., & Wahli, W. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25084467 · Cited by 8 · see citing works
“Furthermore, host–microbiota interactions not only influence PPAR responses, but are also impacted by them [33].”
BackgroundSelf-citationTicking in Place for the Microbiome to Message Out
Liang, X., & Bultman, S. J. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.11.015 · Cited by 8 · see citing works
“…this finding is contrary to previous studies, where a loss of gut microbiota disrupted the level and rhythmic expression of circadian clock genes such as Bmal1, Clock, Per2, and Cry1 in the intestinal epithelium (Mukherji et al., 2013) and in the liver (Leone et al., 2015; Montagner et al., 2016).”
BackgroundResultLiver as a nexus of daily metabolic cross talk
Litwin, C., & Koronowski, K. B. (2024) · International review of cytology · doi:10.1016/bs.ircmb.2024.06.001 · Cited by 8 · see citing works
Bigliardi, P. L., Junnarkar, S., Markale, C., Lo, S. F., Bigliardi, E., Kalyuzhny, A., Ong, S. L. M., Dunn, N. R., Wahli, W., & Bigliardi‐Qi, M. (2024) · Cells · doi:10.3390/cells13030232 · Cited by 6 · see citing works
“[27,28]. bind to this These sequences are targets for the binding of the BMAL1 and Clock heterodimer which then induce the rhythmic expression of their target genes. heterodimer and PER2 is known to bind to this heterodimer and thus inhibit the expression of the target genes DEC2, DBP and TEF .”
BackgroundSelf-citationJiao, X., Li, Y., Hu, Y., Yan, R., Fu, T., Liu, J., & Li, Z. (2025) · Mucosal Immunology · doi:10.1016/j.mucimm.2025.01.010 · Cited by 6 · see citing works
Basic Biology of Rhythms and the Microbiome
Heinemann, M., Ratiner, K., & Elinav, E. (2021) · Springer eBooks · doi:10.1007/978-3-030-72158-9_16 · Cited by 6 · see citing works
- Authors
- Montagner, A., Korecka, A., Polizzi, A., Lippi, Y., Blum, Y., Canlet, C., Tremblay-Franco, M., Gautier-Stein, A., Burcelin, R., Yen, Y.-C., Je, H. S., Al-Asmakh, M., Mithieux, G., Arulampalam, V., Lagarrigue, S., Guillou, H., Pettersson, S., & Wahli, W.
- Affiliations
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
- Karolinska Institutet (SE)
- University of California, Los Angeles (US)
- Hôpital Rangueil (FR)
- National University of Singapore (SG)
- Inserm (FR)
- Université Européenne de Bretagne (FR)
- Nanyang Technological University (SG)
- Corresponding author
- Guillou, Hervé
- Pettersson, Sven
- Wahli, Walter
- ORCID
- Venue
- Scientific Reports
- Published
- 2016-02-16
- Volume
- 6
- Issue
- 1
- Pages
- 20127-20127
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC4754633
- OpenAlex
- W2428071229
- Cited by
- 137
- References
- 58
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 12 · 2023: 10 · 2022: 7 · 2021: 26 · 2020: 15 · 2019: 19 · 2018: 9 · 2017: 14 · 2016: 6
- FWCI
- 10.18
- Type
- journal article
- Language
- en
- Update notices
- erratum (2016-04-20)
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- SERVAL (Université de Lausanne) (publishedVersion, cc-by)
- HAL (submittedVersion, cc-by)
- IRIS (submittedVersion, cc-by)
- National University of Singapore (submittedVersion, cc-by)
- DR-NTU (Nanyang Technological University) (submittedVersion, cc-by)
- Qatar University QSpace (Qatar University) (submittedVersion, cc-by)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- National Science Foundation
- Canadian Institute for Advanced Research
- Nanyang Technological University
- Agence Nationale de la Recherche (ANR-15-CE14-0026)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Karolinska Institutet
- Université de Lausanne
- Conseil Régional Midi-Pyrénées
- Medical Research Council
- Lee Kong Chian School of Medicine, Nanyang Technological University
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- gut microbiota, germ-free mice, clock gene expression, nuclear receptors, PPARα, LXRβ, hepatic metabolome, lipid metabolism, glucose metabolism, xenobiotic metabolism, redox homeostasis, FGF21, bilirubin, lactate, HDL cholesterol, free fatty acids
- MeSH terms
- Gastrointestinal Microbiome, Animals, Female, Gene Expression Regulation, Gluconeogenesis, Liver, Male, Inactivation, Metabolic, Organ Specificity, Signal Transduction, Biomarkers, Receptors, Cytoplasmic and Nuclear, Gene Expression Profiling, Gastrointestinal Tract, Mice, Circadian Clocks, Transcriptome, Microbiota
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