Circadian rhythms: a regulator of gastrointestinal health and dysfunction

Abstract

Circadian rhythms regulate much of gastrointestinal physiology including cell proliferation, motility, digestion, absorption, and electrolyte balance. Disruption of circadian rhythms can have adverse consequences including the promotion of and/or exacerbation of a wide variety of gastrointestinal disorders and diseases. Areas covered: In this review, we evaluate some of the many gastrointestinal functions that are regulated by circadian rhythms and how dysregulation of these functions may contribute to disease. This review also discusses some common gastrointestinal disorders that are known to be influenced by circadian rhythms as well as speculation about the mechanisms by which circadian rhythm disruption promotes dysfunction and disease pathogenesis. We discuss how knowledge of circadian rhythms and the advent of chrono-nutrition, chrono-pharmacology, and chrono-therapeutics might influence clinical practice. Expert opinion: As our knowledge of circadian biology increases, it may be possible to incorporate strategies that take advantage of circadian rhythms and chronotherapy to prevent and/or treat disease.

Keywords: Circadian rhythm; chronotype; circadian rhythm disruption; clock genes; diurnal fluctuation; gastrointestinal disease; gastrointestinal tract; intestine; shift work; social jet lag.

Fig 1

The molecular circadian clock. CLOCK and BMAL are transcription factors that dimerize and initiate transcription of genes containing an E-Box in the promoter, these genes are called ‘clock-controlled genes.’ There are a large number of clock-controlled genes, but depicted are those that are critical for the molecular circadian clock. Following transcription and translation, PER and CRY dimerize and are translocated into the nucleus where they repress CLOCK-BMAL-mediated transcription, essentially repressing their own transcription. A secondary loop consists of transcription and translation of REVERBα and RORα the respectively inhibit and promote transcription of BMAL. CLOCK = circadian locomotor output cycles kaput, BMAL = aryl-hydrocarbon receptor nuclear translocatorlike 1 (ARNT1, also called BMAL1/2), PER = Period (Per1, Per2, Per3), CRY = Cryptochrome (Cry1, Cry2), RORα = retinoic acid-related orphan receptor, REV-ERBα = reverse transcript of erythroblastosis gene.

Fig 2

Entrainment of central and peripheral circadian clocks. Light entering the eye is a primary factor entraining central circadian rhythms in the suprachiasmatic nucleus in the brain (known as the master pacemaker). The central circadian clock sets rhythms in peripheral tissues using a variety of methods including fluctuations in temperature, hormone production, and behaviorally via activities such as rest/activity, sleep/wake, and fasting/feeding. Circadian rhythms in the intestine can also be influenced by time of eating independent of input from the central circadian clock.

Fig 3

Circadian regulation of gastrointestinal function and dysfunction. Circadian homeostasis is the consequence of consistent patterns of sleep/wake and eating and avoidance of eating late. Circadian homeostasis permits optimal gastrointestinal function. Conversely circadian misalignment including irregular schedules and late night eating promote disease and dysfunction in the gastrointestinal tract.