Abstract
The gastrointestinal tract displays biologic rhythms in basal gastric acid output, epithelial cell proliferation, gastrointestinal motility, and appetite regulation. Furthermore, the development of gastrointestinal complications after administration of aspirin and after chemo- and radiotherapy for metastatic colon cancer depends on the time of administration. Biologic rhythms are driven by so-called clock genes. Thus, it is conceivable that subsets of genes in the gastrointestinal tract are under clock gene control as well. The purpose of this article is to discuss basic concepts in the studies of biologic rhythms, to review examples of biologic rhythms in the gastrointestinal tract, and to discuss examples of gastrointestinal diseases in which alterations in biologic rhythms may play a pathogenetic role.
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References and Recommended Reading
Brown SA, Schibler U: The ins and outs of circadian timekeeping. Curr Opin Genet Dev 1999, 9:588–594.
Sehgal A: Introduction to circadian rhythms: general concepts. In Molecular Biology of Circadian Rhythms. Edited by Sehgal A. Hoboken, NJ: Wiley-Liss; 2004:3–29.
Albrecht U, Eichele G: The mammalian circadian clock. Curr Opin Genet Dev 2003, 13:271–277.
Jin X, Shearman LP, Weaver DR et al.: A molecular mechanism regulating rhythmic output from the suprachiasmatic circadian clock. Cell 1999, 96:57–68
Honma S, Ikeda M, Abe H et al.: Circadian oscillation of BMAL1, a partner of a mammalian clock gene Clock, in rat suprachiasmatic nucleus. Biochem Biophys Res Commun 1998, 250:83–87
Preitner N, Damiola F, Lopez-Molina L, et al.: The orphan nuclear receptor REV-ERB alpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 2002, 110:251–260
Takumi T, Matsubara C, Shigeyoshi Y, et al.: New mammalian period gene predominantly expressed in the suprachiasmatic nucleus. Genes Cells 1998, 3:167–176.
Lopez-Molina L, Conquet F, Dubois-Dauphin M, Schibler U: The DBP gene is expressed according to a circadian rhythm in the suprachiasmatic nucleus and influences circadian behavior. EMBO J 1997, 16:6762–6771.
Zylka MJ, Shearman LP, Weaver DR et al.: Three period homologs in mammals: differential light responses in the suprachiasmatic circadian clock and oscillating transcripts outside of brain. Neuron 1998, 20:1103–1110.
Lavery DJ, Schibler U. Circadian transcription of the cholesterol 7 alpha hydroxylase gene may involve the liverenriched bZIP protein DBP. Genes Dev 1993, 7:1871–1884
Lavery DJ, Lopez-Molina L, Margueron R, et al.: Circadian expression of the steroid 15 alpha-hydroxylase (Cyp2a4) and coumarin 7-hydroxylase (Cyp2a5) genes in mouse liver is regulated by the PAR leucine zipper transcription factor DBP. Mol Cell Biol 1999, 19:6488–6499.
Bubenik GA: Gastrointestinal melatonin: localization, function, and clinical relevance. Dig Dis Sci 2002, 47:2336–2348.
Motilva V, Cabeza J, Alarcon de la Lastra C: New issues about melatonin and its effects on the digestive system. Curr Pharm Des 2001, 7:909–931.
Hardeland R, Poeggeler B: Non-vertebrate melatonin. J Pineal Res 2003; 34:233–241.
Scheving LA: Biological clocks and the digestive system. Gastroenterology 2000, 119:536–549.
Scheving LE, Burns ER, Pauly JE, et al.: Circadian variation in cell division of the mouse alimentary tract, bone marrow and corneal epithelium. Anat Rec 1978, 91:479–486.
Pardini L, Kaeffer B, Trubuil A, et al.: Human intestinal circadian clock: expression of clock genes in colonocytes lining the crypt. Chronobiol Int 2005; 22:951–961.
Levi F: Chronotherapeutics: the relevance of timing in cancer therapy. Cancer Causes Control 2006, 17:611–621.
Levi F: From circadian rhythms to cancer chronotherapeutics. Chronobiol Int 2002, 19:1–19.
Levi F, Zidani R, Misset JL: Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. International Organization for Cancer Chronotherapy. Lancet 1997, 350:681–686.
Haus E: Chronobiology of the mammalian response to ionizing radiation. Potential applications in oncology. Chronobiol Int 2002, 19:77–100.
Ijiri K, Potten CS: The circadian rhythm for the number and sensitivity of radiation-induced apoptosis in the crypts of mouse small intestine. Int J Radiat Biol 1990, 58:165–175.
Bjarnason GA, Jordan R: Rhythms in human gastrointestinal mucosa and skin. Chronobiol Int 2002, 19:129–140.
Moore JG, Englert E Jr: Circadian rhythm of gastric acid secretion in man. Nature 1970, 226:1261–1262.
Moore JG: Circadian dynamics of gastric acid secretion and pharmacodynamics of H2 receptor blockade. Ann N Y Acad Sci. 1991, 618:150–158.
Sozzi M, Valentini M, Poletti M et al.: Nocturnal gastric acidity pattern in gastro-oesophageal reflux disease with or without oesophagitis. Ital J Gastroenterol 1995, 27:413–418.
Zentilin P, Dulbecco P, Bilardi C, et al.: Circadian pattern of intragastric acidity in patients with non-erosive reflux disease (NERD). Aliment Pharmacol Ther 2003, 17:353–359.
Larsen KR, Moore JG, Dayton MT: Circadian rhythms of acid and bicarbonate efflux in fasting rat stomach. Am J Physiol 1991, 260:G610-G614.
Barattini P, Larsen KR, Moore JG, et al.: Circadian rhythm of pepsin efflux in the fasting rat stomach. Chronobiol Int 1993, 10:403–409.
Moore JG, Mitchell MD, Larsen KR, et al.: Circadian rhythm in prostacyclin activity in gastric tissue of the fasting rat. Am J Surg 1992, 163:19–22.
Johns CE, Newton JL, Westley BR, et al.: The diurnal rhythm of the cytoprotective human trefoil protein TFF2 is reduced by factors associated with gastric mucosal damage: ageing, Helicobacter pylori infection, and sleep deprivation. Am J Gastroenterol 2005, 100:1491–1497.
Larsen KR, Moore JG, Dayton MT et al.: Circadian rhythm in aspirin (ASA)-induced injury to the stomach of the fasted rat. Dig Dis Sci 1993, 38:1435–1440.
Olson CE, Soll AH, Guth PH.: Circadian variation of susceptibility to gastric mucosal injury by acidified aspirin or absolute ethanol in the rat. Gastroenterology 1986, 91:1192–1197.
Moore JG, Goo RH: Day and night aspirin-induced gastric mucosal damage and protection by ranitidine in man. Chronobiol Int 1987, 4:111–116.
Goo RH, Moore JG, Greenberg E, et al.: Circadian variation in gastric emptying of meals in humans. Gastroenterology 1987, 93:515–518.
Lindberg G, Iwarzon M, Hammarlund B: 24-hour ambulatory electrogastrography in healthy volunteers. Scand J Gastroenterol 1996, 31:658–664.
Rao SS, Sadeghi P, Beaty J, et al.: Ambulatory 24-h colonic manometry in healthy humans. Am J Physiol Gastrointest Liver Physiol 2001, 280:G629-G639.
Furukawa Y, Cook IJ, Panagopoulos V, et al.: Relationship between sleep patterns and human colonic motor patterns. Gastroenterology 1994, 107(5):1372–81
Auwerda JJA, Bac DJ, Schouten WR: Circadian rhythm of rectal motor complexes. Dis Colon Rectum 2001, 44:1328–1332.
Rao SS, Sadeghi P, Beaty J, et al.: Ambulatory 24-hour colonic manometry in slow-transit constipation. Am J Gastroenterol 2004, 99:2405–2416.
Shemerovskii KA: Circadian rhythm of rectal reactivity in individuals with regular and irregular bowel evacuation function. Bull Exp Biol Med 2002, 134:565–567.
Lu WZ, Gwee KA, Moochhalla S, et al.: Melatonin improves bowel symptoms in female patients with irritable bowel syndrome: a double-blind placebo-controlled study. Aliment Pharmacol Ther 2005, 22:927–934. This interesting study reports improvement of IBS symptoms following treatment with melatonin. In addition to elucidating the poorly understood mechanistic effects of melatonin on gastrointestinal symptoms, this study also raises the question of whether symptoms encountered in IBS reflect abnormal circadian physiology.
Kalra SP, Kalra PS: NPY and cohorts in regulating appetite, obesity and metabolic syndrome: beneficial effects of gene therapy. Neuropeptides 2004, 38:201–211.
Turek FW, Joshu C, Kohsaka A, et al.: Obesity and metabolic syndrome in circadian Clock mutant mice. Science 2005, 308:1043–1045. This study demonstrates that clock mutant mice are hyperphagic and obese and that they suffer from the metabolic syndrome. These findings have implications for the role of the circadian clock in the pathogenesis of obesity.
Knutsson A: Health disorders of shift workers. Occup Med 2003, 53:103–108.
Vener KJ, Szabo S, Moore JG: The effect of shift work on gastrointestinal (GI) function: a review. Chronobiologia 1989, 16:421–439.
Costa G: The impact of shift and nightwork on health. Appl Ergon 1996, 27:9–16.
Caruso CC, Lusk SL, Gillespie BW: Relationship of work schedules to gastrointestinal diagnoses, symptoms, and medication use in auto factory workers. Am J Ind Med 2004, 46:586–958.
Griefahn B, Kunemund C, Golka K, et al.: Melatonin synthesis: a possible indicator of intolerance to shiftwork. Am J Ind Med 2002, 42:427–436.
Cassone VM, Stephan FK: Central and peripheral regulation of feeding and nutrition by the mammalian circadian clock: implications for nutrition during manned space flight. Nutrition 2002, 18:814–819.
Scott JR, Hellmich HL, Hoogerwerf WA: Circadian expression of clock genes in the murine colon. Gastroenterology 2005, 128(Suppl 2):A1500.
Hoogerwerf WA, Scott JR, Savidge TC, Hellmich H: Timed feeding alters clock gene expression in the murine stomach and colon. Gastroenterology 2006, 130(Suppl 2):A456.
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Hoogerwerf, W.A. Biologic clocks and the gut. Curr Gastroenterol Rep 8, 353–359 (2006). https://doi.org/10.1007/s11894-006-0019-3
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DOI: https://doi.org/10.1007/s11894-006-0019-3