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Circadian clocks in the digestive system

Abstract

Many molecular, physiological and behavioural processes display distinct 24-hour rhythms that are directed by the circadian system. The master clock, located in the suprachiasmatic nucleus region of the hypothalamus, is synchronized or entrained by the light–dark cycle and, in turn, synchronizes clocks present in peripheral tissues and organs. Other environmental cues, most importantly feeding time, also synchronize peripheral clocks. In this way, the circadian system can prepare the body for predictable environmental changes such as the availability of nutrients during the normal feeding period. This Review summarizes existing knowledge about the diurnal regulation of gastrointestinal processes by circadian clocks present in the digestive tract and its accessory organs. The circadian control of gastrointestinal digestion, motility, hormones and barrier function as well as of the gut microbiota are discussed. An overview is given of the interplay between different circadian clocks in the digestive system that regulate glucose homeostasis and lipid and bile acid metabolism. Additionally, the bidirectional interaction between the master clock and peripheral clocks in the digestive system, encompassing different entraining factors, is described. Finally, the possible behavioural adjustments or pharmacological strategies for the prevention and treatment of the adverse effects of chronodisruption are outlined.

Key points

  • The circadian system controls diurnal rhythms in gastrointestinal digestion, absorption, motility, hormones, barrier function and the gut microbiota.

  • Human studies disentangling the influence of behavioural cycles (for example, feeding–fasting or activity–sleep) and of the endogenous clock are sparse.

  • Feeding time is the most important synchronizer of peripheral clocks; gut hormones, most notably insulin and IGF1, are essential to communicate feeding time phase information to peripheral clocks.

  • Time-restricted eating, timed exercise and chronobiotics — agents that alter the phase, amplitude or period of the circadian time system — hold promise for preventing or treating chronodisruption and its associated diseases.

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Fig. 1: Diurnal processes in the digestive system and acrophases of gut hormone and leptin levels.
Fig. 2: Circadian regulation of glucose homeostasis.
Fig. 3: Circadian regulation of bile acid production.
Fig. 4: Overview of brain clocks that ensure the circadian control of food intake.
Fig. 5: Hormones that potentially feedback phase information to the circadian system.

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Glossary

Diurnal rhythms

Any biological rhythm that shows an oscillation of about 24 hours.

Free-running period

The duration of the circadian period in the absence of external time cues.

Peripheral clocks

All circadian clocks present in tissues or organs outside of the suprachiasmatic nucleus.

Zeitgeber

An external cue that entrains or synchronizes an organism’s circadian clock.

Chronodisruption

Chronic disruption of circadian rhythms by misalignment between the light–dark cycle and the behavioural cycle resulting in adverse health effects; examples are rotating shift work and frequent flying across different time zones.

Circadian rhythms

Biological rhythms that show an endogenous, entrainable oscillation of about 24 hours that remains over a range of physiological temperatures.

Dark-phase feeding period

Mice are nocturnal animals so they consume most of their food at night.

E-box

Enhancer box, DNA motifs with the consensus sequence CANNTG that appear in a broad variety of promotors and enhancers and serve as protein binding sites; E-boxes can be bound by proteins such as the CLOCK–BMAL1 heterodimer to initiate transcription.

Ileal brake

A primary inhibitory feedback mechanism that is initiated when nutrients arrive in the ileum to promote nutrient digestion and absorption; it inhibits gastric emptying, intestinal transit, food intake, gastric acid secretion, exocrine pancreatic secretion and gallbladder emptying but stimulates postprandial absorption of fluids and electrolytes.

Constant routine protocol

A method used in human circadian rhythm research to study endogenous circadian rhythms in the absence of external cues. Individuals are kept in constant conditions for at least 24 hours under constant temperature, dim light, semi-recumbent posture and awake. Food intake is evenly distributed throughout the protocol.

Chronobiotics

Compounds that can affect the phase, amplitude and/or period of a circadian rhythm.

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Segers, A., Depoortere, I. Circadian clocks in the digestive system. Nat Rev Gastroenterol Hepatol 18, 239–251 (2021). https://doi.org/10.1038/s41575-020-00401-5

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