Rhythm of digestion: Keeping time in the gastrointestinal tract
1. The best characterized mammalian circadian rhythms follow a light-entrained central master pacemaker in the suprachiasmatic nucleus and are associated with fluctuations in the activities of clock genes, including Clock, Bmal1, Per and Cry, the products of which bind to sequences in the promoters of effector genes. This is the central clock.
2. In the present review, we discuss evidence for an independent, but interacting, gut-associated circadian clock, the peripheral clock, which is entrained by food.
3. Disruption of circadian rhythms is associated with a wide range of pathologies, most prominently metabolism linked, but the effects of disruption of circadian rhythms on the digestive system are less well studied, although also likely to lead to functional consequences. There are clues suggestive of links between gastrointestinal disorders related to inflammation, cancer and motility and disruption of peripheral rhythms. Research aimed at understanding these links is still in its infancy.
4. We also discuss practical aspects of the presence of circadian rhythms in gastrointestinal tissues for researchers related to experimental design, data interpretation and the choice of animal models.
5. There is currently sufficient evidence to suggest that circadian rhythms are important to gut function, metabolism and mucosal defence and that further investigation will uncover connections between disordered rhythms and gastrointestinal malfunction.
Available from: Katarzyna Kirsz
- "Recent research has shown that the circadian rhythm and expression of clock genes are modified by diet, allowing us to conclude that the secretion of ghrelin is closely connected with the circadian rhythm and metabolic processes . Patients with sleep disorders have been found to display increases in both ghrelin and hunger. "
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ABSTRACT: The gut hormone and neuropeptide ghrelin was initially identified in the periphery as a compound released in the bloodstream in response to a negative energetic status. In the central nervous system (CNS), ghrelin mainly acts on the hypothalamus and the limbic system, with its best-known biological role being the regulation of appetitive functions. Recent research has shown that ghrelin is not an indispensable factor in the regulation of food intake. However, it plays a key role in the metabolic changes of lipids, mainly those involving hypothalamic NOS, AMPK, CaMKK2, CPT1 and UCP2 proteins. Ghrelin participates in the regulation of memory processes and the feeling of pleasure resulting from eating, both of which are metabolism-dependent and may be essential for the successful achievement of adaptive appetitive behavior. Ghrelin exerts its biological effect through a complicated network of neuroendocrine links, including the melanocortin and endocannabinoid systems. The activity of ghrelin is connected with circadian and annual fluctuations, which depend on seasons and food availability.
Available from: Garth Swanson
- "Indeed, our recent study (Preuss et al., 2008) demonstrating that chronic disruption of the central circadian clock in mice can lead to an increased vulnerability of the intestine to chemically (DSS)-induced colitis (a model where intestinal hyperpermeability is the primary pathogenic mechanism) strongly suggests that circadian clock machinery at the level of the brain-gut axis and/or in the intestine plays a pivotal role in the regulation of intestinal permeability in physiological and pathological states. As recently noted in a review on circadian rhythms and the GI tract, while there are clues suggestive of links between gastrointestinal disorders and peripheral circadian rhythms, " … understanding these links is still in its infancy " (Bron and Furness, 2009). "
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ABSTRACT: Several studies have indicated that endotoxemia is the required co-factor for alcoholic steatohepatitis (ASH) that is seen in only about 30% of alcoholics. Recent studies have shown that gut leakiness that occurs in a subset of alcoholics is the primary cause of endotoxemia in ASH. The reasons for this differential susceptibility are not known. Since disruption of circadian rhythms occurs in some alcoholics and circadian genes control the expression of several genes that are involved in regulation of intestinal permeability, we hypothesized that alcohol induces intestinal hyperpermeability by stimulating expression of circadian clock gene proteins in the intestinal epithelial cells.
We used Caco-2 monolayers grown on culture inserts as an in vitro model of intestinal permeability and performed Western blotting, permeability, and siRNA inhibition studies to examine the role of Clock and Per2 circadian genes in alcohol-induced hyperpermeability. We also measured PER2 protein levels in intestinal mucosa of alcohol-fed rats with intestinal hyperpermeability.
Alcohol, as low as 0.2%, induced time dependent increases in both Caco-2 cell monolayer permeability and in CLOCK and PER2 proteins. SiRNA specific inhibition of either Clock or Per2 significantly inhibited alcohol-induced monolayer hyperpermeability. Alcohol-fed rats with increased total gut permeability, assessed by urinary sucralose, also had significantly higher levels of PER2 protein in their duodenum and proximal colon than control rats.
Our studies: (i) demonstrate a novel mechanism for alcohol-induced intestinal hyperpermeability through stimulation of intestinal circadian clock gene expression, and (ii) provide direct evidence for a central role of circadian genes in regulation of intestinal permeability.
Available from: Alon Y Avidan
- "There has been a recent explosion of research in the field of food-entrainable oscillations, which are important for proper metabolism and also in synchronizing rest and activity rhythms.83 Clock genes cycle robustly throughout the liver and the entire GI tract, and there is a normal circadian variation in gut motility that needs to be tightly regulated to maintain the sequential contraction of smooth muscle to push food and nutrients through the gut.84,85 Peripheral clocks also show a hierarchical control in the circadian system, suggesting that there is some plasticity in control of synchronization at different levels of the body.86 "
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ABSTRACT: The circadian system regulates the cyclical occurrence of wakefulness and sleep through a series of oscillatory networks that comprise two different theoretical processes. The suprachiasmatic nucleus (SCN) of the hypothalamus contains the master oscillatory network necessary for coordinating these daily rhythms, and in addition to its ability to robustly generate rhythms, it can also synchronize to environmental light cues. During jet lag, abrupt shifts in the environmental light–dark cycle temporarily desynchronize the SCN and downstream oscillatory networks from each other, resulting in increased sleepiness and impaired daytime functioning. Polysomnographic data show that not only does jet lag result in changes of sleep–wake timing, but also in different aspects of sleep architecture. This type of circadian misalignment can further lead to a cluster of symptoms including major metabolic, cardiovascular, psychiatric, and neurological impairments. There are a number of treatment options for jet lag involving bright light exposure, melatonin, and use of hypnotics, but their efficacy greatly depends on their time of use, the length of time in the new time zone, and the specific circadian disturbance involved. The aim of this review is to provide mechanistic links between the fields of sleep and circadian rhythms to understand the biological basis of jet lag and to apply this information to clinical management strategies.
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