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Circadian rhythms and the gut microbiota: from the metabolic syndrome to cancer


The metabolic syndrome is prevalent in developed nations and accounts for the largest burden of non-communicable diseases worldwide. The metabolic syndrome has direct effects on health and increases the risk of developing cancer. Lifestyle factors that are known to promote the metabolic syndrome generally cause pro-inflammatory alterations in microbiota communities in the intestine. Indeed, alterations to the structure and function of intestinal microbiota are sufficient to promote the metabolic syndrome, inflammation and cancer. Among the lifestyle factors that are associated with the metabolic syndrome, disruption of the circadian system, known as circadian dysrhythmia, is increasingly common. Disruption of the circadian system can alter microbiome communities and can perturb host metabolism, energy homeostasis and inflammatory pathways, which leads to the metabolic syndrome. This Perspective discusses the role of intestinal microbiota and microbial metabolites in mediating the effects of disruption of circadian rhythms on human health.

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Fig. 1: The bidirectional bacteria–host relationship.
Fig. 2: Microbiota signalling to the host circadian and metabolic systems occurs via both contact-dependent mechanisms and contact-independent mechanisms.


  1. 1.

    World Health Organization. Global Health Estimates 2016: Disease burden by Cause, Age, Sex, by Country and by Region, 2000–2016 (WHO, 2018).

  2. 2.

    Scholze, J. et al. Epidemiological and economic burden of metabolic syndrome and its consequences in patients with hypertension in Germany, Spain and Italy; a prevalence-based model. BMC Public. Health 10, 529 (2010).

    Google Scholar 

  3. 3.

    Pothiwala, P., Jain, S. K. & Yaturu, S. Metabolic syndrome and cancer. Metab. Syndr. Relat. Disord. 7, 279–288 (2009).

    CAS  Google Scholar 

  4. 4.

    Feigin, V. L. et al. Global burden of stroke and risk factors in 188 countries, during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet Neurol. 15, 913–924 (2016).

    Google Scholar 

  5. 5.

    Ogden, C. L., Carroll, M. D., Fryar, C. D. & Flegal, K. M. Prevalence of obesity among adults and youth: United States, 2011–2014. NCHS Data Brief 219, 1–8 (2015).

    Google Scholar 

  6. 6.

    Misra, A. & Khurana, L. Obesity and the metabolic syndrome in developing countries. J. Clin. Endocrinol. Metab. 93, S9–S30 (2008).

    CAS  Google Scholar 

  7. 7.

    Moreira, G. C., Cipullo, J. P., Ciorlia, L. A., Cesarino, C. B. & Vilela-Martin, J. F. Prevalence of metabolic syndrome: association with risk factors and cardiovascular complications in an urban population. PLoS One 9, e105056 (2014).

    Google Scholar 

  8. 8.

    Zhang, R., Lahens, N. F., Ballance, H. I., Hughes, M. E. & Hogenesch, J. B. A circadian gene expression atlas in mammals: implications for biology and medicine. Proc. Natl Acad. Sci. USA 111, 16219–16224 (2014).

    CAS  Google Scholar 

  9. 9.

    Mohawk, J. A., Green, C. B. & Takahashi, J. S. Central and peripheral circadian clocks in mammals. Annu. Rev. Neurosci. 35, 445–462 (2012).

    CAS  Google Scholar 

  10. 10.

    Stokkan, K. A., Yamazaki, S., Tei, H., Sakaki, Y. & Menaker, M. Entrainment of the circadian clock in the liver by feeding. Science. 291, 490–493 (2001).

  11. 11.

    Hoogerwerf, W. A. et al. Clock gene expression in the murine gastrointestinal tract: endogenous rhythmicity and effects of a feeding regimen. Gastroenterology 133, 1250–1260 (2007).

  12. 12.

    Bishehsari, F., Levi, F., Turek, F. W. & Keshavarzian, A. Circadian rhythms in gastrointestinal health and diseases. Gastroenterology 151, e1–e5 (2016).

    Google Scholar 

  13. 13.

    Touitou, Y., Touitou, D. & Reinberg, A. Disruption of adolescents’ circadian clock: the vicious circle of media use, exposure to light at night, sleep loss and risk behaviors. J. Physiol. Paris 110, 467–479 (2016).

    Google Scholar 

  14. 14.

    Mota, M. C., Silva, C. M., Balieiro, L. C. T., Fahmy, W. M. & Crispim, C. A. Social jetlag and metabolic control in non-communicable chronic diseases: a study addressing different obesity statuses. Sci. Rep. 7, 6358 (2017).

    Google Scholar 

  15. 15.

    Kervezee, L., Kosmadopoulos, A. & Boivin, D. B. Metabolic and cardiovascular consequences of shift work: the role of circadian disruption and sleep disturbances. Eur. J. Neurosci. 51, 396–412 (2020).

    Google Scholar 

  16. 16.

    Moossavi, S. & Bishehsari, F. Microbes: possible link between modern lifestyle transition and the rise of metabolic syndrome. Obes. Rev. 20, 407–419 (2019).

    CAS  Google Scholar 

  17. 17.

    Bass, J. & Takahashi, J. S. Circadian integration of metabolism and energetics. Science 330, 1349–1354 (2010).

    CAS  Google Scholar 

  18. 18.

    Panda, S. et al. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109, 307–320 (2002).

    CAS  Google Scholar 

  19. 19.

    Rudic, R. D. et al. BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis. PLoS Biol. 2, e377 (2004).

    Google Scholar 

  20. 20.

    Marcheva, B. et al. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature 466, 627–631 (2010).

    CAS  Google Scholar 

  21. 21.

    Turek, F. W. et al. Obesity and metabolic syndrome in circadian clock mutant mice. Science 308, 1043–1045 (2005).

    CAS  Google Scholar 

  22. 22.

    Cho, H. et al. Regulation of circadian behaviour and metabolism by REV-ERB-α and REV-ERB-β. Nature 485, 123–127 (2012).

    CAS  Google Scholar 

  23. 23.

    Gale, J. E. et al. Disruption of circadian rhythms accelerates development of diabetes through pancreatic beta-cell loss and dysfunction. J. Biol. Rhythm. 26, 423–433 (2011).

    Google Scholar 

  24. 24.

    Qian, J., Block, G. D., Colwell, C. S. & Matveyenko, A. V. Consequences of exposure to light at night on the pancreatic islet circadian clock and function in rats. Diabetes 62, 3469–3478 (2013).

    CAS  Google Scholar 

  25. 25.

    Pappa, K. I. et al. Circadian clock gene expression is impaired in gestational diabetes mellitus. Gynecol. Endocrinol. 29, 331–335 (2013).

    CAS  Google Scholar 

  26. 26.

    Garcia-Rios, A. et al. Beneficial effect of CLOCK gene polymorphism rs1801260 in combination with low-fat diet on insulin metabolism in the patients with metabolic syndrome. Chronobiol. Int. 31, 401–408 (2014).

    CAS  Google Scholar 

  27. 27.

    Bracci, M. et al. Rotating-shift nurses after a day off: peripheral clock gene expression, urinary melatonin, and serum 17-β-estradiol levels. Scand. J. Work. Env. Health 40, 295–304 (2014).

    CAS  Google Scholar 

  28. 28.

    Wehrens, S. M. T. et al. Meal timing regulates the human circadian system. Curr. Biol. 27, 1768–1775 (2017).

    CAS  Google Scholar 

  29. 29.

    Leproult, R., Holmback, U. & Van, C. E. Circadian misalignment augments markers of insulin resistance and inflammation, independently of sleep loss. Diabetes 63, 1860–1869 (2014).

    CAS  Google Scholar 

  30. 30.

    Morikawa, Y. et al. Effect of shift work on body mass index and metabolic parameters. Scand. J. Work. Env. Health 33, 45–50 (2007).

    Google Scholar 

  31. 31.

    Bo, S. et al. Consuming more of daily caloric intake at dinner predisposes to obesity. A 6-year population-based prospective cohort study. PLoS ONE 9, e108467 (2014).

    Google Scholar 

  32. 32.

    McHill, A. W. et al. Caloric and macronutrient intake differ with circadian phase and between lean and overweight young adults. Nutrients 11, 587 (2019).

    CAS  Google Scholar 

  33. 33.

    McHill, A. W. et al. Later circadian timing of food intake is associated with increased body fat. Am. J. Clin. Nutr. 106, 1213–1219 (2017).

    CAS  Google Scholar 

  34. 34.

    McMullan, C. J., Curhan, G. C., Schernhammer, E. S. & Forman, J. P. Association of nocturnal melatonin secretion with insulin resistance in nondiabetic young women. Am. J. Epidemiol. 178, 231–238 (2013).

    Google Scholar 

  35. 35.

    Bass, J. Circadian topology of metabolism. Nature 491, 348–356 (2012).

    CAS  Google Scholar 

  36. 36.

    Panda, S. Circadian physiology of metabolism. Science 354, 1008–1015 (2016).

    CAS  Google Scholar 

  37. 37.

    Faria, J. A. et al. Melatonin acts through MT1/MT2 receptors to activate hypothalamic Akt and suppress hepatic gluconeogenesis in rats. Am. J. Physiol. Endocrinol. Metab. 305, E230–E242 (2013).

    CAS  Google Scholar 

  38. 38.

    Bazwinsky-Wutschke, I., Wolgast, S., Muhlbauer, E., Albrecht, E. & Peschke, E. Phosphorylation of cyclic AMP-response element-binding protein (CREB) is influenced by melatonin treatment in pancreatic rat insulinoma β-cells (INS-1). J. Pineal Res. 53, 344–357 (2012).

    CAS  Google Scholar 

  39. 39.

    Bonnefond, A. et al. Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes. Nat. Genet. 44, 297–301 (2012).

    CAS  Google Scholar 

  40. 40.

    Masri, S. Sirtuin-dependent clock control: new advances in metabolism, aging and cancer. Curr. Opin. Clin. Nutr. Metab. Care 18, 521–527 (2015).

    CAS  Google Scholar 

  41. 41.

    Global Burden of Disease Cancer Collaboration. et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2016: a systematic analysis for the global burden of disease study. JAMA Oncol. 4, 1553–1568 (2018).

    Google Scholar 

  42. 42.

    Bishehsari, F., Mahdavinia, M., Vacca, M., Malekzadeh, R. & Mariani-Costantini, R. Epidemiological transition of colorectal cancer in developing countries: environmental factors, molecular pathways, and opportunities for prevention. World J. Gastroenterol. 20, 6055–6072 (2014).

    Google Scholar 

  43. 43.

    Feng, R. M., Zong, Y. N., Cao, S. M. & Xu, R. H. Current cancer situation in China: good or bad news from the 2018 global cancer statistics? Cancer Commun. 39, 22 (2019).

    Google Scholar 

  44. 44.

    Renehan, A. G., Tyson, M., Egger, M., Heller, R. F. & Zwahlen, M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 371, 569–578 (2008).

    Google Scholar 

  45. 45.

    Schernhammer, E. S. et al. Night-shift work and risk of colorectal cancer in the Nurses’ Health Study. J. Natl Cancer Inst. 95, 825–828 (2003).

    Google Scholar 

  46. 46.

    Carter, B. D., Diver, W. R., Hildebrand, J. S., Patel, A. V. & Gapstur, S. M. Circadian disruption and fatal ovarian cancer. Am. J. Prev. Med. 46, S34–S41 (2014).

    Google Scholar 

  47. 47.

    Altman, B. J. Cancer clocks out for lunch: disruption of circadian rhythm and metabolic oscillation in cancer. Front. Cell Dev. Biol. 4, 62 (2016).

    Google Scholar 

  48. 48.

    Kettner, N. M. et al. Circadian homeostasis of liver metabolism suppresses hepatocarcinogenesis. Cancer Cell 30, 909–924 (2016).

    CAS  Google Scholar 

  49. 49.

    Bishehsari, F. et al. Light/dark shifting promotes alcohol-induced colon carcinogenesis: possible role of intestinal inflammatory milieu and microbiota. Int. J. Mol. Sci. 17, 2017 (2016).

    Google Scholar 

  50. 50.

    Bishehsari, F. et al. Abnormal eating patterns cause circadian disruption and promote alcohol-associated colon carcinogenesis. Cell. Mol. Gastroenterol. Hepatol. 9, 219–237 (2020).

    Google Scholar 

  51. 51.

    Masri, S., Kinouchi, K. & Sassone-Corsi, P. Circadian clocks, epigenetics, and cancer. Curr. Opin. Oncol. 27, 50–56 (2015).

    CAS  Google Scholar 

  52. 52.

    Sulli, G. et al. Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence. Nature 553, 351–355 (2018).

    CAS  Google Scholar 

  53. 53.

    Papagiannakopoulos, T. et al. Circadian rhythm disruption promotes lung tumorigenesis. Cell Metab. 24, 324–331 (2016).

    CAS  Google Scholar 

  54. 54.

    Altman, B. J. et al. MYC disrupts the circadian clock and metabolism in cancer cells. Cell Metab. 22, 1009–1019 (2015).

    CAS  Google Scholar 

  55. 55.

    Sonnenburg, J. L. & Sonnenburg, E. D. Vulnerability of the industrialized microbiota. Science 366, eaaw9255 (2019).

    CAS  Google Scholar 

  56. 56.

    Bishehsari, F. & Keshavarzian, A. Microbes help to track time. Science 365, 1379–1380 (2019).

    CAS  Google Scholar 

  57. 57.

    Furuya, S. & Yugari, Y. Daily rhythmic change of L-histidine and glucose absorptions in rat small intestine in vivo. Biochim. Biophys. Acta 343, 558–564 (1974).

    CAS  Google Scholar 

  58. 58.

    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).

    CAS  Google Scholar 

  59. 59.

    Thaiss, C. A. et al. Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis. Cell 159, 514–529 (2014).

    CAS  Google Scholar 

  60. 60.

    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).

    Google Scholar 

  61. 61.

    Thaiss, C. A. et al. Microbiota diurnal rhythmicity programs host transcriptome oscillations. Cell 167, 1495–1510 (2016).

    CAS  Google Scholar 

  62. 62.

    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).

    CAS  Google Scholar 

  63. 63.

    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).

    CAS  Google Scholar 

  64. 64.

    Chaix, A., Zarrinpar, A., Miu, P. & Panda, S. Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges. Cell Metab. 20, 991–1005 (2014).

    CAS  Google Scholar 

  65. 65.

    Chaix, A., Lin, T., Le, H. D., Chang, M. W. & Panda, S. Time-restricted feeding prevents obesity and metabolic syndrome in mice lacking a circadian clock. Cell Metab. 29, 303–319 (2019).

    CAS  Google Scholar 

  66. 66.

    Nobs, S. P., Tuganbaev, T. & Elinav, E. Microbiome diurnal rhythmicity and its impact on host physiology and disease risk. EMBO Rep. 20, e47129 (2019).

    Google Scholar 

  67. 67.

    Tahara, Y. et al. Gut microbiota-derived short chain fatty acids induce circadian clock entrainment in mouse peripheral tissue. Sci. Rep. 8, 1395 (2018).

    Google Scholar 

  68. 68.

    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).

    CAS  Google Scholar 

  69. 69.

    Parkar, S. G., Kalsbeek, A. & Cheeseman, J. F. Potential role for the gut microbiota in modulating host circadian rhythms and metabolic health. Microorganisms 7, 41 (2019).

    CAS  Google Scholar 

  70. 70.

    Kuang, Z. et al. The intestinal microbiota programs diurnal rhythms in host metabolism through histone deacetylase 3. Science 365, 1428–1434 (2019).

    CAS  Google Scholar 

  71. 71.

    Wang, Z. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57–63 (2011).

    CAS  Google Scholar 

  72. 72.

    Tang, W. H. et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N. Engl. J. Med. 368, 1575–1584 (2013).

    CAS  Google Scholar 

  73. 73.

    Wu, X. et al. Regulation of circadian rhythms by NEAT1 mediated TMAO-induced endothelial proliferation: a protective role of asparagus extract. Exp. Cell Res. 382, 111451 (2019).

    CAS  Google Scholar 

  74. 74.

    Ley, R. E. et al. Obesity alters gut microbial ecology. Proc. Natl Acad. Sci. USA 102, 11070–11075 (2005).

    CAS  Google Scholar 

  75. 75.

    Backhed, F. et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl Acad. Sci. USA 101, 15718–15723 (2004).

    Google Scholar 

  76. 76.

    Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006).

    Google Scholar 

  77. 77.

    Verdam, F. J. et al. Human intestinal microbiota composition is associated with local and systemic inflammation in obesity. Obesity 21, E607–E615 (2013).

    CAS  Google Scholar 

  78. 78.

    Karlsson, F. H. et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 498, 99–103 (2013).

    CAS  Google Scholar 

  79. 79.

    Fei, N. & Zhao, L. An opportunistic pathogen isolated from the gut of an obese human causes obesity in germfree mice. ISME J. 7, 880–884 (2013).

    CAS  Google Scholar 

  80. 80.

    Cortes-Martin, A., Iglesias-Aguirre, C. E., Meoro, A., Selma, M. V. & Espin, J. C. There is no distinctive gut microbiota signature in the metabolic syndrome: contribution of cardiovascular disease risk factors and associated medication. Microorganisms 8, 416 (2020).

    CAS  Google Scholar 

  81. 81.

    Liou, A. P. et al. Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity. Sci. Transl Med. 5, 178ra41 (2013).

  82. 82.

    Vrieze, A. et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 143, 913–916 (2012).

  83. 83.

    Kootte, R. S. et al. Improvement of insulin sensitivity after lean donor feces in metabolic syndrome is driven by baseline intestinal microbiota composition. Cell Metab. 26, 611–619 (2017).

  84. 84.

    Fujisaka, S. et al. Antibiotic effects on gut microbiota and metabolism are host dependent. J. Clin. Invest. 126, 4430–4443 (2016).

    Google Scholar 

  85. 85.

    Janssen, A. W. & Kersten, S. The role of the gut microbiota in metabolic health. FASEB J. 29, 3111–3123 (2015).

    CAS  Google Scholar 

  86. 86.

    Zhang, X. et al. Human gut microbiota changes reveal the progression of glucose intolerance. PLoS ONE 8, e71108 (2013).

    CAS  Google Scholar 

  87. 87.

    Yassour, M. et al. Sub-clinical detection of gut microbial biomarkers of obesity and type 2 diabetes. Genome Med. 8, 17 (2016).

    Google Scholar 

  88. 88.

    Li, J. et al. Gut microbiota dysbiosis contributes to the development of hypertension. Microbiome 5, 14 (2017).

    Google Scholar 

  89. 89.

    Depommier, C. et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nat. Med. 25, 1096–1103 (2019).

    CAS  Google Scholar 

  90. 90.

    Plovier, H. et al. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat. Med. 23, 107–113 (2017).

    CAS  Google Scholar 

  91. 91.

    Voigt, R. M. et al. Circadian disorganization alters intestinal microbiota. PLoS ONE 9, e97500 (2014).

    Google Scholar 

  92. 92.

    Rosselot, A. E., Hong, C. I. & Moore, S. R. Rhythm and bugs: circadian clocks, gut microbiota, and enteric infections. Curr. Opin. Gastroenterol. 32, 7–11 (2016).

    Google Scholar 

  93. 93.

    Voigt, R. M., Forsyth, C. B. & Keshavarzian, A. Circadian disruption: potential implications in inflammatory and metabolic diseases associated with alcohol. Alcohol Res. Curr. Rev. 35, 87–96 (2013).

    Google Scholar 

  94. 94.

    Voigt, R. M. et al. The circadian clock mutation promotes intestinal dysbiosis. Alcohol. Clin. Exp. Res. 40, 335–347 (2016).

    CAS  Google Scholar 

  95. 95.

    Ramanan, D. & Cadwell, K. Intrinsic defense mechanisms of the intestinal epithelium. Cell Host Microbe 19, 434–441 (2016).

    CAS  Google Scholar 

  96. 96.

    Henao-Mejia, J. et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179–185 (2012).

    CAS  Google Scholar 

  97. 97.

    Purohit, J. S. et al. The effects of NOD activation on adipocyte differentiation. Obesity 21, 737–747 (2013).

    Google Scholar 

  98. 98.

    Tremaroli, V. & Backhed, F. Functional interactions between the gut microbiota and host metabolism. Nature 489, 242–249 (2012).

    CAS  Google Scholar 

  99. 99.

    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).

    CAS  Google Scholar 

  100. 100.

    Rogero, M. M. & Calder, P. C. Obesity, inflammation, toll-like receptor 4 and fatty acids. Nutrients 10, 432 (2018).

    Google Scholar 

  101. 101.

    Semlali, A. et al. Expression and polymorphism of toll-like receptor 4 and effect on NF-κB mediated inflammation in colon cancer patients. PLoS ONE 11, e0146333 (2016).

    Google Scholar 

  102. 102.

    Himes, R. W. & Smith, C. W. Tlr2 is critical for diet-induced metabolic syndrome in a murine model. FASEB J. 24, 731–739 (2010).

    CAS  Google Scholar 

  103. 103.

    Kim, F. et al. Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. Circ. Res. 100, 1589–1596 (2007).

    CAS  Google Scholar 

  104. 104.

    Saberi, M. et al. Hematopoietic cell-specific deletion of toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice. Cell Metab. 10, 419–429 (2009).

    CAS  Google Scholar 

  105. 105.

    Vijay-Kumar, M. et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328, 228–231 (2010).

    CAS  Google Scholar 

  106. 106.

    Ahmad, R. et al. Elevated expression of the toll like receptors 2 and 4 in obese individuals: its significance for obesity-induced inflammation. J. Inflamm. 9, 48 (2012).

    CAS  Google Scholar 

  107. 107.

    Masters, S. L. et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nat. Immunol. 11, 897–904 (2010).

    CAS  Google Scholar 

  108. 108.

    Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17, 179–188 (2011).

    CAS  Google Scholar 

  109. 109.

    Byrne, C. S., Chambers, E. S., Morrison, D. J. & Frost, G. The role of short chain fatty acids in appetite regulation and energy homeostasis. Int. J. Obes. 39, 1331–1338 (2015).

    CAS  Google Scholar 

  110. 110.

    Ganapathy, V., Thangaraju, M., Prasad, P. D., Martin, P. M. & Singh, N. Transporters and receptors for short-chain fatty acids as the molecular link between colonic bacteria and the host. Curr. Opin. Pharmacol. 13, 869–874 (2013).

    CAS  Google Scholar 

  111. 111.

    Tan, J. et al. The role of short-chain fatty acids in health and disease. Adv. Immunol. 121, 91–119 (2014).

    CAS  Google Scholar 

  112. 112.

    Frost, G. et al. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat. Commun. 5, 3611 (2014).

    CAS  Google Scholar 

  113. 113.

    Hong, Y. H. et al. Acetate and propionate short chain fatty acids stimulate adipogenesis via GPCR43. Endocrinology 146, 5092–5099 (2005).

    CAS  Google Scholar 

  114. 114.

    Zaibi, M. S. et al. Roles of GPCR41 and GPCR43 in leptin secretory responses of murine adipocytes to short chain fatty acids. FEBS Lett. 584, 2381–2386 (2010).

    CAS  Google Scholar 

  115. 115.

    Teichman, E. M., O’Riordan, K. J., Gahan, C. G. M., Dinan, T. G. & Cryan, J. F. When rhythms meet the blues: circadian interactions with the microbiota-gut-brain axis. Cell Metab. 31, 448–471 (2020).

    CAS  Google Scholar 

  116. 116.

    Gao, Z. et al. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes 58, 1509–1517 (2009).

    CAS  Google Scholar 

  117. 117.

    Bellahcene, M. et al. Male mice that lack the G-protein-coupled receptor GPCR41 have low energy expenditure and increased body fat content. Br. J. Nutr. 109, 1755–1764 (2013).

    CAS  Google Scholar 

  118. 118.

    Kimura, I. et al. The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPCR43. Nat. Commun. 4, 1829 (2013).

    Google Scholar 

  119. 119.

    Yaribeygi, H., Sathyapalan, T. & Sahebkar, A. Molecular mechanisms by which GLP-1 RA and DPP-4i induce insulin sensitivity. Life Sci. 234, 116776 (2019).

    CAS  Google Scholar 

  120. 120.

    Takiishi, T., Fenero, C. I. M. & Camara, N. O. S. Intestinal barrier and gut microbiota: shaping our immune responses throughout life. Tissue Barriers 5, e1373208 (2017).

    Google Scholar 

  121. 121.

    Hotamisligil, G. S. Inflammation, metaflammation and immunometabolic disorders. Nature 542, 177–185 (2017).

    CAS  Google Scholar 

  122. 122.

    Fechner, A., Kiehntopf, M. & Jahreis, G. The formation of short-chain fatty acids is positively associated with the blood lipid-lowering effect of lupin kernel fiber in moderately hypercholesterolemic adults. J. Nutr. 144, 599–607 (2014).

    CAS  Google Scholar 

  123. 123.

    Talati, R., Baker, W. L., Pabilonia, M. S., White, C. M. & Coleman, C. I. The effects of barley-derived soluble fiber on serum lipids. Ann. Fam. Med. 7, 157–163 (2009).

    Google Scholar 

  124. 124.

    Ferrell, J. M. & Chiang, J. Y. Short-term circadian disruption impairs bile acid and lipid homeostasis in mice. Cell. Mol. Gastroenterol. Hepatol. 1, 664–677 (2015).

    Google Scholar 

  125. 125.

    Zhai, H. et al. Takeda G protein-coupled receptor 5-mechanistic target of rapamycin complex 1 signaling contributes to the increment of glucagon-like peptide-1 production after Roux-en-Y gastric bypass. EBioMedicine 32, 201–214 (2018).

    Google Scholar 

  126. 126.

    Pathak, P. et al. Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism. Hepatology 68, 1574–1588 (2018).

    CAS  Google Scholar 

  127. 127.

    Chavez-Talavera, O., Tailleux, A., Lefebvre, P. & Staels, B. Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease. Gastroenterology 152, 1679–1694 (2017).

    CAS  Google Scholar 

  128. 128.

    Albaugh, V. L. et al. Role of bile acids and GLP-1 in mediating the metabolic improvements of bariatric surgery. Gastroenterology 156, 1041–1051 (2019).

    CAS  Google Scholar 

  129. 129.

    Tang, G., Zhang, L., Yang, G., Wu, L. & Wang, R. Hydrogen sulfide-induced inhibition of L-type Ca2+ channels and insulin secretion in mouse pancreatic beta cells. Diabetologia 56, 533–541 (2013).

    CAS  Google Scholar 

  130. 130.

    Szabo, C. Roles of hydrogen sulfide in the pathogenesis of diabetes mellitus and its complications. Antioxid. Redox Signal. 17, 68–80 (2012).

    CAS  Google Scholar 

  131. 131.

    Moore, S. R. et al. Robust circadian rhythms in organoid cultures from PERIOD2::LUCIFERASE mouse small intestine. Dis. Model. Mech. 7, 1123–1130 (2014).

    CAS  Google Scholar 

  132. 132.

    Jovel, J. et al. Characterization of the gut microbiome using 16S or shotgun metagenomics. Front. Microbiol. 7, 459 (2016).

    Google Scholar 

  133. 133.

    Heintz-Buschart, A. & Wilmes, P. Human gut microbiome: function matters. Trends Microbiol. 26, 563–574 (2018).

    CAS  Google Scholar 

  134. 134.

    Wang, Y. et al. The intestinal microbiota regulates body composition through NFIL3 and the circadian clock. Science 357, 912–916 (2017).

    CAS  Google Scholar 

  135. 135.

    Nguyen, T. L., Vieira-Silva, S., Liston, A. & Raes, J. How informative is the mouse for human gut microbiota research? Dis. Model. Mech. 8, 1–16 (2015).

    CAS  Google Scholar 

  136. 136.

    Vargason, A. M. & Anselmo, A. C. Clinical translation of microbe-based therapies: current clinical landscape and preclinical outlook. Bioeng. Transl. Med. 3, 124–137 (2018).

    Google Scholar 

  137. 137.

    Baydoun, M. et al. An interphase microfluidic culture system for the study of ex vivo intestinal tissue. Micromachines 11, 150 (2020).

    Google Scholar 

  138. 138.

    Brouwer, A. et al. Light therapy for better mood and insulin sensitivity in patients with major depression and type 2 diabetes: a randomised, double-blind, parallel-arm trial. BMC Psychiatry 15, 169 (2015).

    Google Scholar 

  139. 139.

    Brouwer, A. et al. Effects of light therapy on mood and insulin sensitivity in patients with type 2 diabetes and depression: results from a randomized placebo-controlled trial. Diabetes Care 42, 529–538 (2019).

    CAS  Google Scholar 

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The authors acknowledge the support provided by NIAAA AA025387 and Rush Translational Sciences Consortium/Swim Across America Organization to F.B., NIAAA AA026801 to A.K. and R.M.V., NIAAA AA023417 and AA026801 to A.K, and NIA AG056653 to R.M.V.. The authors are grateful for the support of the Brinson Foundation, Barbara and Larry Field, Ellen and Philip Glass, and Marcia and Silas Keehn.

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The authors contributed equally to all aspects of the article.

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Correspondence to Ali Keshavarzian.

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Nature Reviews Endocrinology thanks J. Cryan and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Bishehsari, F., Voigt, R.M. & Keshavarzian, A. Circadian rhythms and the gut microbiota: from the metabolic syndrome to cancer. Nat Rev Endocrinol 16, 731–739 (2020).

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