Certain members of the gut microbiota exhibit diurnal variations in relative abundance and function to serve as non-canonical drivers of host circadian rhythms and metabolism. Also known as microbial oscillators, these microorganisms entrain upon non-photic cues, primarily dietary, to modulate host metabolism by providing input to both circadian clock-dependent and clock-independent host networks. Microbial oscillators are generally promoted by plant-based, low-fat (lean) diets, and most are abolished by low-fibre, high-sugar, high-fat (Western) diets. The changes in microbial oscillators under different diets then affect host metabolism by altering central and peripheral host circadian clock functions and/or by directly affecting other metabolic targets. Here, we review the unique role of the gut microbiota as a non-photic regulator of host circadian rhythms and metabolism. We describe genetic, environmental, dietary and other host factors such as sex and gut immunity that determine the composition and behaviour of microbial oscillators. The mechanisms by which these oscillators regulate host circadian gene expression and metabolic state are further discussed. Because of the gut microbiota’s unique role as a non-photic driver of host metabolism and circadian rhythms, the development and clinical application of novel gut microbiota-related diagnostics and therapeutics hold great promise for achieving and maintaining metabolic health.
The gut microbiome has an essential role in transducing dietary cues used by central and peripheral host circadian clocks to regulate and adapt to shifts in energy balance.
Low-fat (lean) diets promote diurnal ‘oscillations’ of certain microbial populations that are metabolically relevant circadian drivers.
Western diets high in fat and refined sugars, and low in fibre influence key microbial oscillators to disrupt host circadian rhythms and metabolism to promote obesity.
The effects of microbial oscillators on host circadian networks and metabolism might involve the production of bioactive small molecules and metabolites.
Activation of nuclear receptors by microbiome-derived mediators is one of many mechanisms to regulate host transcriptional and epigenetic pathways that influence host circadian control of energy balance.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Dodd, A. N. et al. Plant circadian clocks increase photosynthesis, growth, survival, and competitive advantage. Science 309, 630–633 (2005).
Fenske, M. P., Nguyen, L. P., Horn, E. K., Riffell, J. A. & Imaizumi, T. Circadian clocks of both plants and pollinators influence flower seeking behavior of the pollinator hawkmoth Manduca sexta. Sci. Rep. 8, 2842 (2018).
Helm, B. et al. Two sides of a coin: ecological and chronobiological perspectives of timing in the wild. Philos. Trans. R Soc. Lond. B Biol. Sci. 372, 20160246 (2017).
Sartor, F. et al. Are there circadian clocks in non-photosynthetic bacteria? Biology 8, 41 (2019).
Donaldson, G. P., Lee, S. M. & Mazmanian, S. K. Gut biogeography of the bacterial microbiota. Nat. Rev. Microbiol. 14, 20–32 (2016).
Gorkiewicz, G. & Moschen, A. Gut microbiome: a new player in gastrointestinal disease. Virchows Arch. 472, 159–172 (2018).
Cryan, J. F. & Dinan, T. G. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat. Rev. Neurosci. 13, 701–712 (2012).
Guinane, C. M. & Cotter, P. D. Role of the gut microbiota in health and chronic gastrointestinal disease: understanding a hidden metabolic organ. Ther. Adv. Gastroenterol. 6, 295–308 (2013).
Martinez-Guryn, K. et al. Small intestine microbiota regulate host digestive and absorptive adaptive responses to dietary lipids. Cell Host Microbe 23, 458–469.e5 (2018).
Takahashi, J. S., Hong, H. K., Ko, C. H. & McDearmon, E. L. The genetics of mammalian circadian order and disorder: implications for physiology and disease. Nat. Rev. Genet. 9, 764–775 (2008).
Rijo-Ferreira, F. & Takahashi, J. S. Genomics of circadian rhythms in health and disease. Genome Med. 11, 82 (2019).
Castanon-Cervantes, O. et al. Dysregulation of inflammatory responses by chronic circadian disruption. J. Immunol. 185, 5796–5805 (2010).
Chen, S. T. et al. Deregulated expression of the PER1, PER2 and PER3 genes in breast cancers. Carcinogenesis 26, 1241–1246 (2005).
Maury, E., Ramsey, K. M. & Bass, J. Circadian rhythms and metabolic syndrome: from experimental genetics to human disease. Circ. Res. 106, 447–462 (2010).
Turek, F. W. et al. Obesity and metabolic syndrome in circadian clock mutant mice. Science 308, 1043–1045 (2005).
Wulff, K., Gatti, S., Wettstein, J. G. & Foster, R. G. Sleep and circadian rhythm disruption in psychiatric and neurodegenerative disease. Nat. Rev. Neurosci. 11, 589–599 (2010).
Vinogradova, I. A., Anisimov, V. N., Bukalev, A. V., Semenchenko, A. V. & Zabezhinski, M. A. Circadian disruption induced by light-at-night accelerates aging and promotes tumorigenesis in rats. Aging 1, 855–865 (2009).
Huang, W., Ramsey, K. M., Marcheva, B. & Bass, J. Circadian rhythms, sleep, and metabolism. J. Clin. Invest. 121, 2133–2141 (2011).
Peek, C. B. et al. Circadian regulation of cellular physiology. Methods Enzymol. 552, 165–184 (2015).
Stephan, F. K. The "other" circadian system: food as a Zeitgeber. J. Biol. Rhythm. 17, 284–292 (2002).
Chaix, A., Manoogian, E. N. C., Melkani, G. C. & Panda, S. Time-restricted eating to prevent and manage chronic metabolic diseases. Annu. Rev. Nutr. 39, 291–315 (2019).
Sutton, E. F. et al. Early time-restricted feeding improves insulin sensitivity, blood pressure, and oxidative stress even without weight loss in men with prediabetes. Cell Metab. 27, 1212–1221.e3 (2018).
Wilkinson, M. J. et al. Ten-hour time-restricted eating reduces weight, blood pressure, and atherogenic lipids in patients with metabolic syndrome. Cell Metab. 31, 92–104.e5 (2020).
Damiola, F. et al. Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes Dev. 14, 2950–2961 (2000).
Cohen, S. E. & Golden, S. S. Circadian rhythms in cyanobacteria. Microbiol. Mol. Biol. Rev. 79, 373–385 (2015).
Tseng, R. et al. Structural basis of the day-night transition in a bacterial circadian clock. Science 355, 1174–1180 (2017).
Pattanayak, G. K., Lambert, G., Bernat, K. & Rust, M. J. Controlling the cyanobacterial clock by synthetically rewiring metabolism. Cell Rep. 13, 2362–2367 (2015).
Paulose, J. K., Cassone, C. V., Graniczkowska, K. B. & Cassone, V. M. Entrainment of the circadian clock of the enteric bacterium Klebsiella aerogenes by temperature cycles. iScience 19, 1202–1213 (2019).
Paulose, J. K., Wright, J. M., Patel, A. G. & Cassone, V. M. Human gut bacteria are sensitive to melatonin and express endogenous circadian rhythmicity. PLoS ONE 11, e0146643 (2016).
Leone, V. et al. Effects of diurnal variation of gut microbes and high-fat feeding on host circadian clock function and metabolism. Cell Host Microbe 17, 681–689 (2015). This study highlights the gut microbiota as transducers of dietary cues to affect host metabolism and suggests that microbial metabolites are one of the mediators.
Thaiss, C. A. et al. Microbiota diurnal rhythmicity programs host transcriptome oscillations. Cell 167, 1495–1510.e12 (2016). This study extensively investigated the relationship between microbial oscillations and host molecular network and metabolome.
Zarrinpar, A., Chaix, A., Yooseph, S. & Panda, S. Diet and feeding pattern affect the diurnal dynamics of the gut microbiome. Cell Metab. 20, 1006–1017 (2014).
Frazier, K. et al. High fat diet disrupts diurnal interactions between REG3γ and small intestinal gut microbes resulting in metabolic dysfunction. Preprint at bioRxiv https://doi.org/10.1101/2020.06.17.130393 (2020).
Thaiss, C. A. et al. Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis. Cell 159, 514–529 (2014).
Martinez, K. B., Leone, V. & Chang, E. B. Western diets, gut dysbiosis, and metabolic diseases: are they linked? Gut Microbes 8, 130–142 (2017).
Liang, X., Bushman, F. D. & FitzGerald, G. A. Rhythmicity of the intestinal microbiota is regulated by gender and the host circadian clock. Proc. Natl Acad. Sci. USA 112, 10479–10484 (2015).
Reitmeier, S. et al. Arrhythmic gut microbiome signatures predict risk of type 2 diabetes. Cell Host Microbe 28, 258–272.e6 (2020). This study demonstrates translational potential of microbial oscillations as predictive markers of metabolic disease by investigating human samples.
Khalif, I. L., Quigley, E. M. M., Konovitch, E. A. & Maximova, I. D. Alterations in the colonic flora and intestinal permeability and evidence of immune activation in chronic constipation. Dig. Liver Dis. 37, 838–849 (2005).
Voigt, R. M. et al. Circadian disorganization alters intestinal microbiota. PLoS ONE 9, e97500 (2014).
Weger, B. D. et al. The mouse microbiome is required for sex-specific diurnal rhythms of gene expression and metabolism. Cell Metab. 29, 362–382.e8 (2019). This study demonstrates that sex-specific characteristics of host circadian gene expression in different organs can be affected by the gut microbiome.
Froy, O. & Miskin, R. Effect of feeding regimens on circadian rhythms: implications for aging and longevity. Aging 2, 7–27 (2010).
Longo, V. D. & Panda, S. Fasting, circadian rhythms, and time-restricted feeding in healthy lifespan. Cell Metab. 23, 1048–1059 (2016).
Greenwell, B. J. et al. Rhythmic food intake drives rhythmic gene expression more potently than the hepatic circadian clock in mice. Cell Rep. 27, 649–657.e5 (2019).
Zeb, F. et al. Effect of time-restricted feeding on metabolic risk and circadian rhythm associated with gut microbiome in healthy males. Br. J. Nutr. 123, 1216–1226 (2020).
Gabel, K. et al. Effect of time restricted feeding on the gut microbiome in adults with obesity: a pilot study. Nutr. Health 26, 79–85 (2020).
Loonen, L. M. et al. REG3γ-deficient mice have altered mucus distribution and increased mucosal inflammatory responses to the microbiota and enteric pathogens in the ileum. Mucosal Immunol. 7, 939–947 (2014).
Belkaid, Y. & Hand, T. W. Role of the microbiota in immunity and inflammation. Cell 157, 121–141 (2014).
Scheiermann, C., Gibbs, J., Ince, L. & Loudon, A. Clocking in to immunity. Nat. Rev. Immunol. 18, 423–437 (2018).
Hand, L. E. et al. The circadian clock regulates inflammatory arthritis. FASEB J. 30, 3759–3770 (2016).
Pagel, R. et al. Circadian rhythm disruption impairs tissue homeostasis and exacerbates chronic inflammation in the intestine. FASEB J. 31, 4707–4719 (2017).
Yu, X. et al. TH17 cell differentiation is regulated by the circadian clock. Science 342, 727–730 (2013).
Tognini, P., Thaiss, C. A., Elinav, E. & Sassone-Corsi, P. Circadian coordination of antimicrobial responses. Cell Host Microbe 22, 185–192 (2017).
Gibbs, J. E. et al. The nuclear receptor REV-ERBα mediates circadian regulation of innate immunity through selective regulation of inflammatory cytokines. Proc. Natl Acad. Sci. USA 109, 582–587 (2012).
Mukherji, A., Kobiita, A., Ye, T. & Chambon, P. Homeostasis in intestinal epithelium is orchestrated by the circadian clock and microbiota cues transduced by TLRs. Cell 153, 812–827 (2013). This study suggests that TLRs are an important interface where the interplay between the host circadian clock and the gut microbiota is regulated, resulting in metabolic changes in the host.
Murakami, M. et al. Gut microbiota directs PPARγ-driven reprogramming of the liver circadian clock by nutritional challenge. EMBO Rep. 17, 1292–1303 (2016).
Wang, Y. et al. The intestinal microbiota regulates body composition through NFIL3 and the circadian clock. Science 357, 912–916 (2017). This study identifies a specific molecular pathway through which the gut microbiota regulates host metabolism, which also involves ILCs, suggesting that the intestinal immune system can be involved in the interactions between the gut microbiota and host circadian control of metabolism.
Montagner, A. et al. Hepatic circadian clock oscillators and nuclear receptors integrate microbiome-derived signals. Sci. Rep. 6, 20127 (2016).
Oh, H. Y. P. et al. Depletion of gram-positive bacteria impacts hepatic biological functions during the light phase. Int. J. Mol. Sci. 20, 812 (2019).
Kennedy, E. A., King, K. Y. & Baldridge, M. T. Mouse microbiota models: comparing germ-free mice and antibiotics treatment as tools for modifying gut bacteria. Front. Physiol. 9, 1534 (2018).
Govindarajan, K. et al. Unconjugated bile acids influence expression of circadian genes: a potential mechanism for microbe-host crosstalk. PLoS ONE 11, e0167319 (2016).
Martinez, K. B., Pierre, J. F. & Chang, E. B. The gut microbiota: the gateway to improved metabolism. Gastroenterol. Clin. North. Am. 45, 601–614 (2016).
Zwighaft, Z. et al. Circadian clock control by polyamine levels through a mechanism that declines with age. Cell Metab. 22, 874–885 (2015).
Zarrinpar, A. et al. Antibiotic-induced microbiome depletion alters metabolic homeostasis by affecting gut signaling and colonic metabolism. Nat. Commun. 9, 2872 (2018).
Luo, Y. et al. Gut microbiota regulates mouse behaviors through glucocorticoid receptor pathway genes in the hippocampus. Transl. Psychiatry 8, 187 (2018).
Neufeld, K. M., Kang, N., Bienenstock, J. & Foster, J. A. Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol. Motil. 23, 255–264, e119 (2011).
Yan, X. et al. Intestinal flora modulates blood pressure by regulating the synthesis of intestinal-derived corticosterone in high salt-induced hypertension. Circ. Res. 126, 839–853 (2020).
Yang, X. et al. Nuclear receptor expression links the circadian clock to metabolism. Cell 126, 801–810 (2006).
Zhong, X. et al. Circadian clock regulation of hepatic lipid metabolism by modulation of m6A mRNA methylation. Cell Rep. 25, 1816–1828.e4 (2018).
Eckel-Mahan, K. L. et al. Reprogramming of the circadian clock by nutritional challenge. Cell 155, 1464–1478 (2013).
Kuang, Z. et al. The intestinal microbiota programs diurnal rhythms in host metabolism through histone deacetylase 3. Science 365, 1428–1434 (2019).
Solt, L. A., Kojetin, D. J. & Burris, T. P. The REV-ERBs and RORs: molecular links between circadian rhythms and lipid homeostasis. Future Med. Chem. 3, 623–638 (2011).
Solt, L. A. et al. Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature 485, 62–68 (2012).
Chen, L. & Yang, G. PPARs integrate the mammalian clock and energy metabolism. PPAR Res. 2014, 653017 (2014).
Guerre-Millo, M. et al. PPAR-α-null mice are protected from high-fat diet-induced insulin resistance. Diabetes 50, 2809–2814 (2001).
Rosen, E. D. et al. PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol. Cell 4, 611–617 (1999).
Barak, Y. et al. Effects of peroxisome proliferator-activated receptor δ on placentation, adiposity, and colorectal cancer. Proc. Natl Acad. Sci. USA 99, 303–308 (2002).
Luquet, S. et al. Roles of PPAR delta in lipid absorption and metabolism: a new target for the treatment of type 2 diabetes. Biochim. Biophys. Acta 1740, 313–317 (2005).
Monsalve, F. A., Pyarasani, R. D., Delgado-Lopez, F. & Moore-Carrasco, R. Peroxisome proliferator-activated receptor targets for the treatment of metabolic diseases. Med. Inflamm. 2013, 549627 (2013).
Bellet, M. M. et al. Circadian clock regulates the host response to Salmonella. Proc. Natl Acad. Sci. USA 110, 9897–9902 (2013).
Carroll, R. G., Timmons, G. A., Cervantes-Silva, M. P., Kennedy, O. D. & Curtis, A. M. Immunometabolism around the clock. Trends Mol. Med. 25, 612–625 (2019).
The authors’ research is supported by grants from NIDDK (R01DK115221) and the Center for Interdisciplinary Study of Inflammatory Intestinal Diseases (P30 DK42086).
The authors declare no competing interests.
Peer review information
Nature Reviews Gastroenterology & Hepatology thanks D. Haller, A. Zarrinpar and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Choi, H., Rao, M.C. & Chang, E.B. Gut microbiota as a transducer of dietary cues to regulate host circadian rhythms and metabolism. Nat Rev Gastroenterol Hepatol (2021). https://doi.org/10.1038/s41575-021-00452-2