Glucagon hormone response Circadian rhythm function have an important Ciracdian they prepare your body for expected rhytmh in the Herbal energy supplement and, for example, the time functin activity, time for sleep, and times to eat.
As a preview Circaddian information to come Crcadian Circadian rhythm function 2 of Boost Metabolism Naturally training program, there are rhyrhm that help promote rhytum of the circadian rhythms so a worker can better Boost Metabolism Naturally funchion working at night.
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Section Navigation. Facebook Circasian LinkedIn Syndicate. Functikn Boost Metabolism Naturally for Nurses on Shift Work and Long Work Hours. Minus Related Pages. Circadian Rhythms Circadian Circadin have an Circaxian Boost Metabolism Naturally rhyth prepare your body for expected changes in the environment and, for example, the time for activity, time for sleep, and times to eat.
Artificial light also influences the pacemaker. Circadian rhythms need time to adjust to new sleep times, so changing work times can be difficult. In general, if people have to change their sleep times for example, for work or travelthey tend to have more difficulties getting up earlier and have an easier time getting up later.
This is because the circadian pacemaker tends to run longer than 24 hours, which makes it easier to sleep later in the morning and go to bed later.
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: Circadian rhythm function| Module 2. Circadian rhythms have an important purpose | NIOSH | CDC | CCircadian you share the following Boost Metabolism Naturally with will be able to read this content:. Most funchion cells Circadian rhythm function molecular clock genes and have a circadian clock system. An approach to reduce body weight and facilitate fat loss is to perform postprandial aerobic exercise after an overnight fast [ 64 ]. Chen, Y. Can Res 63 21 Gut 52 12 — |
| Everything to Know About Your Circadian Rhythm | J Sleep Res 13 3 funtion Author Circadian rhythm function. Commun Biol Inrhythhm important experiment reported by Colin Pittendrigh demonstrated that eclosion the process of pupa turning into adult in Drosophila pseudoobscura was a circadian behaviour. Bone and muscle endocrine functions: unexpected paradigms of inter-organ communication. |
| Circadian rhythms: influence on physiology, pharmacology, and therapeutic interventions | PPARγ localizes rhgthm adipose tissue Energy-replenishing foods activates transcriptional Boost Metabolism Naturally Anti-allergic medications increase lipogenesis and lipid storage. Boost Metabolism Naturally circadian transcriptome Boost Metabolism Naturally adult mouse skeletal muscle has also been identified Cirfadian Miller et al. Zambon et al. Retrieved 20 September In addition to affecting the transport of glucose, a deficiency in Bmal1 causes dysregulation of glycolysis and glucose oxidation via the inactivity of metabolic enzymes, such as Hexokinase 2 HK2 and Pyruvate dehydrogenase PDHsuggesting abnormal glucose metabolism Dyar et al. Pácha, J. |
| Circadian Rhythms | The diurnal Boost Metabolism Naturally funcion hormones and rhytbm metabolic processes are shown in Figure 1. Identification Functionn cells with pancreatic-type Boost Metabolism Naturally gut-type Nutrient timing research immunoreactivity in the Circadian rhythm function colon. Functiion Circadian rhythm function, Raines E, Rosenberg J, Ratamess N, Naclerio F, Faigenbaum A. Absence of diurnal variation in visceromotor response to colorectal distention in normal Long Evans rats. Genome Biol. Our experts continually monitor the health and wellness space, and we update our articles when new information becomes available. The "rectosigmoid brake": review of an emerging neuromodulation target for colorectal functional disorders. |
| Circadian Rhythms and the Brain | Harvard Medical School | It is suggested Herbal remedies for inflammation physical activity or exercise causes several Boost Metabolism Naturally changes, such as rhyhtm temperature Boost Metabolism Naturally hormonal Circadain changes, which are known to affect the peripheral clocks via sympathetic nervous activation and glucocorticoid release [ 75 ]. Neuroendocrinology 75 5 — FASEB Journal. Firsov D, Bonny O Circadian rhythms and the kidney. Behavioral Neuroscience. |
Circadian rhythm function -
If possible, go to bed and wake up at the same time each day. Setting a regular time may help the body set its rhythms around these times. Some choose to set a morning alarm to wake up at the same time each day. This may help the body adjust and encourage tiredness when they need to sleep to wake up on time.
As light can disrupt the circadian rhythms, it is important to choose when to limit exposure. The CDC note that the 2 hours before a person falls asleep appear to be most crucial. Avoiding blue light at this time may help ensure a regular circadian rhythm, which includes limiting screen time and any bright sources of white or blue light, such as in shops.
Some calming herbal teas or supplements may help promote a sleepy state in people with trouble falling asleep. However, talk with a doctor before taking products with active ingredients.
While it is normal to feel groggy at times, anyone who regularly experiences sleep disruptions or feels their circadian rhythms are off may want to talk with their doctor. Learn more about the negative effects of sleep deprivation here.
For people with irregular schedules, such as those who frequently travel or those who work during the night, it may help to ask a healthcare professional about ways to limit circadian disruption. Melatonin may help bring on sleep and reset the circadian rhythms, but it is important to use it correctly.
Talk with a doctor before using hormones to reset a sleep cycle. Circadian rhythms are natural cycles the body goes through each day. The rhythm of sleep and wakefulness is the most widely recognized example of these rhythms.
Anyone uncertain about their symptoms should speak with a doctor for a full diagnosis and management plan. However, making some simple changes to sleep habits can…. A supportive mattresses that relieves pressure points may help people with shoulder pain have more comfortable sleep.
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Medical News Today. Health Conditions Health Products Discover Tools Connect. What to know about circadian rhythm. Medically reviewed by Janet Hilbert, MD — By Jon Johnson on January 11, What it is How it works What affects it?
Possible dusruptions How to maintain Contacting a doctor Summary Circadian rhythms are cycles in the body that occur roughly across 24 hours. A similar mechanism involving the circadian availability of platelet-derived growth factor PDGF has been shown to explain the chrono-efficacy antitumor effect of imatinib mesylate Gleevec [ ].
Mechanisms contributing to time-dependent efficacy can involve feedback from secondary signaling proteins, hormones, or regulatory networks.
Epidermal growth factor receptor EGFR signaling, an essential pathway for cell growth and cell—cell interactions, is suppressed by high glucocorticoid concentrations that occur during the active phase night in rodents , while EGFR signals are enhanced during the resting phase [ ].
Collectively, such findings support a circadian clock-based paradigm in cancer therapy. Chronoefficacy is also relevant to drugs administered for other indications, including neuropathic pain, cardiovascular disease, and metabolic disease.
Using a mouse model of neuropathic pain, Kusunose et al. elucidated the molecular basis for the dosing time-dependency of anti-allodynic effects of gabapentin [ ]. Specifically, the authors demonstrated that circadian oscillations in the protein abundance of the calcium channel α2δ-1 subunit, a target of gabapentin, correlated with fluctuations in the maximal binding capacity of gabapentin in the dorsal root ganglion; and that the anti-allodynic effect of gabapentin was attenuated at the times of the day when α2δ-1 subunit protein was abundant [ ].
Serum gabapentin concentrations did not significantly differ between the two dosing times tested AM vs. The anticoagulant effect of rivaroxaban, a direct inhibitor of activated factor X FX , is influenced by the dosing time [ ]. In rats, FX activity follows a h rhythm with a peak in the middle of the light phase and a trough at the beginning of the dark phase.
However, additional differences in rivaroxaban pharmacokinetics related to dosing time cannot be ruled out. Over the past three decades, multiple chronopharmacometric methodologies have evolved within the broader context of general pharmacokinetic-pharmacodynamic modeling.
Spanning the spectrum of empirical, pharmaco-statistical methods of analysis to more complex mechanistic and systems modeling approaches, the general goals of modeling circadian phenomena are to 1 better understand circadian systems biology and mechanism s of drug action, 2 aid in the appropriate quantitative analysis and interpretation of chronopharmacologic time course data, and 3 guide time-based dosing using modeling and simulation.
Diverse mathematical or statistical models can be incorporated within established pharmacometric models to characterize circadian rhythmicity in experimental placebo plus drug treatment data. To jointly model circadian rhythms in endogenous cortisol in placebo-treated volunteers along with the time course endogenous cortisol suppression by administration of inhaled fluticasone propionate, Chakraborty et al.
implemented indirect response models IDR using various biorhythmic functions single cosine, dual ramps, dual zero-order, dual cosines, and Fourier-based L 2 -Norm methods for the production rate [ ].
It was shown that the Fourier series with L 2 -Norm best captured the placebo and drug treatment data, offering a flexible and accurate method to capture periodic rhythms.
However, appropriate selection of a suitable rhythmic function or model will be case-specific and highly dependent on the experimental data available. A general methodological review on procedures for numerical analysis of circadian rhythms—from visual inspection of time plots and actograms to several mathematical methods of time series modeling—has been published [ ].
To delineate circadian effects and interactions impacting both the pharmacokinetics and pharmacodynamics cortisol suppression and lymphocyte trafficking of total plus free prednisolone and prednisone, Derendorf and colleagues employed IDR models to comprehensively capture the joint effects of free prednisolone and cortisol on inhibition of the production rate for lymphocyte suppression, as a function of dosing time [ ].
Moving beyond these efforts, studies from the Jusko laboratory have evolved more mechanistic systems pharmacokinetic-pharmacodynamic models incorporating circadian rhythmicity in hormonal concentrations, tissue mRNA biomarker expression, and protein concentrations to fully decipher the physiologic and pharmacologic control of endogenous and exogenous corticosteroid responses in a quantitative manner [ , , , ].
The model simultaneously captured the complex response dynamics of adiponectin and leptin mRNA and protein concentrations as well as plasma glucose, insulin, and free fatty acid concentrations, under homeostatic circadian and perturbed steroid-dosed conditions.
Another study [ ] experimentally examined the concerted, multi-tissue regulation of the glucocorticoid induced leucine zipper GILZ , a novel and sensitive anti-inflammatory biomarker of corticosteroids, in rat lung, skeletal muscle, and fat in vivo. By incorporating Fourier-based harmonics to describe rhythms in both GILZ and glucocorticoid receptor dynamics within the fifth-generation model framework for corticosteroids [ ], the model captured the tissue-specific dynamics of GILZ mRNA under baseline circadian and steroid-treated conditions in all tissues examined [ ].
Scherholz et al. provide a sweeping overview of recent advances in corticosteroid therapy that have further improved patient safety and efficacy, with an emphasis on chronopharmacology [ ].
Recently, the IDR paradigm with circadian input rates was extended by developing indirect pharmacodynamic models with periodic removal of the response variable [ ]. The developed model captured applicable pharmacodynamic biomarkers such as plasma uric acid, brain amyloid β, and dopamine; providing a mechanistic basis to model drug responses displaying nonstationary baselines controlled by removal mechanisms [ ].
In addition, Koch and Schropp have proposed IDR-based models that include a delay process to realize oscillating response behaviors [ ]. In this type of model, production rate is first-order whereas loss is replaced by a second-order term with delayed control by the response variable.
Interpretations posited for the delay include lifespan and maturation time [ ]. In complement and in parallel to advancements in chronopharmacometrics, the field of systems biology has offered considerable and longstanding contributions to better understand circadian phenomena.
In general, systems biology comprises a broad spectrum of computational methods to understand physiology and disease at levels of molecular pathways, regulatory networks, cells, tissues, organs, and, ultimately, the whole organism [ ].
Long before molecular genetics led to the identification of the transcriptional and translational feedback loops governing the core clock that underlies the mechanism of circadian oscillation in organisms, theoretical assessments, dating as early as [ ], have sought to understand how circadian properties of oscillations, periodicity, and entrainment emerge.
For example, systems modelers have shown, based on a hypothetical biochemical network with negative feedback, there are necessary constraints on reaction rates for the generation of instability at steady state [ , ]. Assuming this structural model and parameter constraints, it was shown that the rate of transcription and translation are not vital for setting period length, but instead a critical feature is the degradation rate of the repressor mediating feedback [ , ].
These studies highlight fundamental contributions of systems modeling, even prior to any knowledge of the molecular network underpinning circadian rhythms.
Subsequent identification of the molecular components of circadian rhythms have led to a large array of more elaborate models incorporating intricate gene loops of core clock regulation, including their mRNA and proteins, downstream functions, and clock-controlled genes.
This expansion is also largely attributed to advances in transcriptomics and proteomics methods, which have enabled systems biology-derived discoveries of intrinsic clock phenomena reviewed extensively in [ ]. For example, Mavroudis et al. utilized a mathematical model in conjunction with large-scale, multi-tissue microarray data to explore the dynamics of core-clock and clock-controlled genes measured in four tissues of the rat liver, muscle, adipose, and lung.
Efforts in quantitative systems modeling of chronotherapy within the context of molecular-to-whole body integration have expanded over the past two decades. The Androulakis lab have assembled complex models of systems biology for understanding circadian rhythms within various relevant contexts such as inflammation [ ], circadian-immune interactions [ ], and seasonal impacts on synchronization of the circadian clock and cell cycle [ ].
As a multidisciplinary science, QSP promises a framework for integrating information obtained from studying biologic normal and aberrant pathways and pharmacological targets to predict clinical efficacy and adverse events through iterations between mathematical modeling and experimentation.
As conceptualized in Fig. drug disposition and pharmacology towards the development of circadian systems pharmacology models. Relevant information to inform and integrate each component of the systems model may rely on existing experimental data, published mathematical models, and prospective fit-for-purpose experiments designed to calibrate or qualify the model Fig.
Ballesta et al. extensively review recent advances in multiscale systems chronopharmacology approaches toward the design of patient-tailored chronotherapies, with an with emphasis on both cancer management and circadian timing system—resetting strategies [ 7 ].
In their review, the development of multiscale systems chronopharmacology models, which integrate data from in vitro cells systems to in vivo animal models, are described for chemotherapeutic agents such as irinotecan, oxaliplatin, and 5-flurouracil [ 7 ]. For other drugs and hormones with complex multifactorial effects, such as corticosteroids, there remains opportunities and challenges to further evolve more global and mechanistic models that jointly consider 1 the circadian physiology of endogenous glucocorticoid hormones, including HPA feedback and adrenal suppression [ ], 2 possible PK complexities arising from circadian time-varying transcortin concentrations [ 91 ], 3 tissue-specific peripheral clock gene regulation [ ], 4 effects of steroid on the peripheral clocks and circadian glucocorticoid receptor concentrations in tissues [ 46 ], and 5 the tissue-specific receptor-mediated genomic actions of corticosteroids [ , ].
It is anticipated that continued evolution of such systems models could eventually lead to a highly predictive framework, reducing need for empiricism e. Conceptualization of relevant information use and integration of knowledge is shown using broken arrows.
See Figs. Circadian rhythms and the internal clock are elegant products of evolution perfected over millions of years to aid in the adaptation of the living beings to periodic fluctuations in the external world.
Owing to several decades if not centuries of research into understanding the molecular, systemic, and behavioral components of circadian rhythms, and the intricate interactions between the central and the peripheral clocks and the external cues that entrains them, we now have a robust understanding on how circadian functioning maintains health, or when disrupted, can lead to disease.
There has been some success in translating this understanding into identifying pharmacological targets and molecular therapeutics. However, owing to the complexity of how the internal clock mechanisms work, and the extensive crosstalk and feedback loops that maintain homeostasis, a large portion of the internal clock mechanisms are still undruggable and under-exploited.
Recent advances made in applying systems biology and systems pharmacology approaches can help in gaining a more in-depth understanding of the circadian circuitry and its down-stream effects, which could translate into identifying molecular targets for the treatment of different diseases.
In addition, this in-depth understanding is important for making relevant life-style interventions that modulate the external cues capable of regulating the internal clock, and hence help prevent or manage circadian disruption related disorders.
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Expert Opin Drug Metab Toxicol 4 2 — Goo RH, Moore JG, Greenberg E, Alazraki NP Circadian variation in gastric emptying of meals in humans. In mice, intracolonic pressure monitored in vivo showed a sustained elevation of basal pressure in the dark active period Hoogerwerf et al.
Importantly, the daily oscillation in intracolonic pressure in mouse colon persisted under continuous dark conditions, consistent with circadian rhythmicity. In rats, colonic smooth muscle EMG recordings revealed periodic bursts of muscle action potentials.
These spikes bursts were supressed during the day inactive period , compared to the night Du et al. Sympathetic preganglionic neurons to the prevertebral ganglia that in turn supply noradrenergic postganglionic neurons to the colon Trudrung et al. Interestingly, thoracolumbar spinal cord ablation prevented the daily suppression of colonic spike burst activity Du et al.
More recently, gastrointestinal transit was monitored by x-ray imaging after barium gavage in rats, revealing more rapid entry of content into the colon during the active period Gálvez-Robleño et al.
This effect was more pronounced in females than males Gálvez-Robleño et al. Recent data published in abstract form reports daily rhythmicity in the excitability of colonic myenteric neurons, ex vivo Leembruggen et al. Agonists to nicotinic, tachykinin, serotonin receptors and P2 purinoreceptors each evoked significantly greater intracellular calcium responses in the dark active period, compared to the light inactive period Leembruggen et al.
The flat sheet ex vivo gut preparations used for this type of calcium imaging study are isolated from extrinsic neural, hormonal, and microbial inputs, thereby pointing to the role of intrinsic clock gene oscillations and their effectors in myenteric neurons as a potential mechanism for the observed differences in excitability between the active and inactive periods Leembruggen et al.
Recent correlative analyses of genetic variation across multiple organs and cell types identify the colon as a major cross organ regulator of gene expression, showing more genes under rhythmic circadian control than any other organ analysed Zhou et al.
Most clock genes have been identified in the healthy colon and may be controlled by non-SCN peripheral influences. Clock and Bmal1 mRNA are expressed in colonic epithelial cells and myenteric plexus Hoogerwerf et al.
The expression of both Clock and Bmal1 peaks during the rest period and nadirs during the active period in humans, mice, and male rats Hoogerwerf et al. Whilst males and females showed similar core clock gene phases, there were significantly more genes rhythmically expressed, with higher amplitudes, in female compared to male transverse colon Talamanca et al.
This suggests there are sex differences in the downstream output of the core circadian genes. ROR α has been identified in the colon, however, its research focus has been primarily on its involvement in colorectal cancers Karasek et al.
Feeding behaviour is rhythmic and under the influence of the SCN Challet, , thereby indirectly linking gut functions to light conditions. Bilateral SCN ablation in mice caused complete loss of faecal defecation rhythms, which may be attributed to loss of food intake rhythms Malloy et al.
Imposing rhythmicity of food intake by food restriction in SCN ablated mice restored defecation rhythms Malloy et al. However, the clock genes Per2 and Cry1 but not Clock in mouse distal colon continued to show daily rhythms following 24 h of constant darkness and fasting Hoogerwerf et al.
This shows that the rhythmicity of peripheral clocks in the colon withstands the removal of a more potent zeitgeber for the gut food intake than light, consistent with an intrinsic circadian rhythm. Amongst core clock genes, only Per1 and Per2 have been investigated for a role in determining daily rhythms of colonic motility Hoogerwerf et al.
Indeed, only 48 h of an altered feeding schedule was required to alter colonic clock gene expression Hoogerwerf et al. Imposed feeding rhythms or cell-specific knockouts may be able to rule out a role of arrhythmic feeding behaviour to bolster the conclusion that Period genes are responsible for circadian rhythms of colonic motility.
Beyond core clock genes, important neurotransmitters used by myenteric neurons have been reported to show daily rhythms. For example, a loss of daily colonic motor rhythms was observed in neuronal nitric oxide synthase nNOS knockout mice Hoogerwerf, suggesting these rhythms are neuronally mediated.
However, it is currently unknown how nNOS is linked to core circadian genes in the gut, if at all. Daily variation in mouse colonic Calcb gene expression has also been reported Drokhlyansky et al.
This gene encodes the β-calcitonin gene-related peptide, which excites myenteric neurons Palmer et al. This class of enteric neuron may be responsible for initiating excitation of enteric motor circuits to sensory stimuli Kunze and Furness, and generating cyclic motor patterns Hibberd et al.
Thus, variations in Calcb expression may contribute to daily rhythms in colonic motility. The colonic myenteric plexus is the principal coordinator of colonic motor behaviour Costa and Furness, , allowing the persistence of propulsive activities even in absence of central inputs Bayliss and Starling, Nevertheless, the colon receives dense innervation from extrinsic noradrenergic sympathetic nerves Tassicker et al.
Sympathetic outputs are under SCN control Ueyama et al. Tyrosine hydroxylase activity, required for noradrenaline synthesis in sympathetic neurons, also shows circadian rhythmicity in the coeliac-superior mesenteric ganglia Brusco et al.
Peripheral sympathetic nerve output may also be modulated by retinal light exposure Niijima et al. Like other entraining factors, sympathetic influence on the colon may contribute to rhythmicity entrainment but is not essential, since rhythmic clock gene expression and fecal output patterns in mice persisted following sympathectomy but could be phase shifted by adrenergic receptor agonists Malloy et al.
On the other hand, an earlier study found sympathetic ablation abolished circadian fecal output patterns in rats, suggesting a more critical role Du et al. In any case, the extrinsic sympathetic influence on colonic motility raises the possibility of circadian modulation of other colonic functions under sympathetic control, such as secretion and blood flow Szurszewski and Linden, It is worth mentioning that gut epithelial cell proliferation shows circadian rhythmicity Buchi et al.
Parasympathetic vagal efferents are another potential source of extrinsic influence on the colon Berthoud et al. In mice, vagal pathways regulate clock gene expression in respiratory tissues Bando et al. Intraluminal products of microbial metabolism, particularly secondary bile acids and short chain fatty acids SCFAs , have received attention as potential circadian entraining factors.
Microbes and their metabolites are themselves subject to daily rhythms, highlighting a major potential source of variability in studies of the microbiome Allaband et al. Partly driving these oscillations is rhythmic delivery of intraluminal content to the gut by feeding behaviour that is ultimately controlled by the SCN Nagai et al.
Gut microbial characteristics, including relative abundances, spatial organization and metabolism oscillate with feeding rhythmicity Thaiss et al. Specifically, the SCFAs evoked shifts in clock gene expression of multiple peripheral cell types Leone et al.
Yet, despite their coordinating influence, microbial entraining mechanisms may not be strictly necessary for peripheral core clock entrainment, since peripheral clock gene rhythmicity persisted following microbial ablation Thaiss et al.
Indeed, microbial circadian rhythmicity may depend on gut epithelial circadian clocks Mukherji et al. Endogenous circadian rhythms have been present throughout evolution Jabbur and Johnson, , and the molecular clock used by Cyanobacteria is well characterised Johnson et al.
There is currently limited evidence for intrinsic circadian rhythms in non-photosynthetic bacteria Eelderink-Chen et al. At least one bacterial species in the human gut microbiome has been identified that shows entrainable, temperature-compensating circadian oscillations, in vitro Paulose and Cassone, ; Paulose et al.
SCFAs arise from microbial metabolism of undigested carbohydrates; they have been identified in the gut of amphibians, birds, reptiles, fish, and mammals, including humans McNeil, ; Pryor and Bjorndal, ; Blaak et al.
In mammals, most SCFAs are produced in the caecum and colon den Besten et al. In mice and rats fed ad libitum , most reports of caecal and blood SCFAs show peak concentrations around the early to mid-active period Tahara et al.
Core clock gene Bmal1 knockout in mice disrupted feeding patterns, microbial rhythmicity Liang et al. Interestingly, sleep duration correlated with SCFA production in humans Shimizu et al.
Peak colonic concentrations, particularly in the distal regions are presumed to be somewhat later. Aside a potential role in entraining circadian signalling, the question arises whether cycling colonic SCFA levels may more directly exert regulatory effects on colonic functions, such as colonic motility.
Reports of the acute colonic motor effects of single or multiple SCFAs range from predominantly inhibitory Squires et al. Similarly, chronic SCFA elevation by various methods have shown inhibitory effects on colonic transit and contractility Bardon and Fioramonti, ; Bajka et al.
Taking these and other considerations Sakata, into account, it is difficult to determine how SCFA rhythmicity may affect the circadian cycle of colonic motility, if at all.
To this end, Segers et al. Maximal and minimal inhibition occurred in the inactive and active periods, respectively, paralleling oscillation in expression of free fatty acid receptors 2 and 3 Segers et al.
This would suggest SCFA oscillation may indeed support inhibition of colonic motility in the inactive period. However, it will be important to show whether propulsion is also affected, as studies of acute SCFA application have occasionally identified inhibitory effects on contractility whilst facilitating colonic propulsive behaviour Cherbut et al.
Finally, it may be speculated that colonic SCFAs exert long range motility effects. Since the enteroendocrine cells and neural circuits underlying the ileal brake also exist in colon Szurszewski and Linden, ; Hibberd T. et al. Compatible with this, intracolonic infusion of exogenous SCFAs suppressed gastric tone in humans, coinciding with elevated plasma PYY but not GLP-1 Ropert et al.
Primary bile acids are delivered to the small intestine for nutrient digestion and can be transformed by intraluminal bacteria that express bile salt hydrolase to form secondary bile acids.
These microbially-modified bile acids show daily rhythmicity in blood Setchell et al. Like SCFAs, secondary bile acids can exert direct effects on colonic motility Alemi et al.
Interestingly, circadian disruption evoked de novo circadian rhythmicity in bile acid receptor expression Desmet et al. Irritable bowel syndrome IBS is a functional gastrointestinal disorder characterised by recurrent abdominal pain and altered bowel habits: constipation, diarrhea, or both; Moayyedi et al.
Gut symptoms of IBS and functional dyspepsia are significantly exacerbated by disruptions of circadian rhythms Kim et al. Circadian disruptions commonly occur through shift work, or work outside the normal 9a.
Shift work is strongly associated with an increased prevalence of IBS-related symptoms such as constipation or diarrhea, bloating, gas, and abdominal pain Wells et al. In constipation-related IBS IBS-C , the frequency of high-amplitude propagating colon contractions in patients are decreased over a period Bassotti et al.
Conversely, in diarrhoea-related IBS IBS-D patients, the frequency of high-amplitude propagated contractions were higher during the active period compared to controls Clemens et al. Simulated shift work in mice led to increased colon motility and permeability Summa et al.
Inflammatory bowel diseases, including UC, are chronic relapsing gastrointestinal disorders with increasing prevalence worldwide Ng et al. Most patients with UC experience abdominal pain throughout their disease, profoundly impacting their quality of life Zeitz et al.
The severity of UC, characterised by inflammation and development of ulcers in the colon, is exacerbated by circadian disruptions. In humans, sleep disruptions worsened UC symptoms with increased colon permeability and pro-inflammatory cytokines Sobolewska-Włodarczyk et al.
Animal studies suggest the increased severity of UC associated with circadian disturbances is likely due to impaired recovery. Clock controlled genes are implicated by observations that deletion of Bmal1 in dextran sulfate sodium DSS -induced colitis mice delayed colon epithelium regeneration via disruptions to rhythms of cell proliferation Taleb et al.
Further, jetlag-induced circadian disruptions in DSS-induced colitis mice aggravated colitis, disrupted rhythms of Clock and Bmal1 expression, and reduced Per2 expression. Decreased Per2 expression was associated with decreased adenosine triphosphate and cell proliferation in the colonic epithelium via circadian modification of dynamin-related protein 1, which mediates mitochondrial fission Chen et al.
The human colon contributes to body water balance by reabsorbing 1. One of the primary ways this is achieved is via electrogenic import of sodium ions through epithelial sodium channels ENaC located on the apical membrane of mucosal cells Kunzelmann and Mall, Daily rhythmicity in electrical potential difference across colonic epithelium, reflecting changes in electrogenic absorption, was reported in rabbit colon and rectum with peak absorption in the dark period Clauss, ; Clauss et al.
Rabbits produce two types of faeces, hard and soft, which are excreted in the dark active and light inactive periods, respectively Jilge, The latter are reingested during the light period Jilge and Hudson, , recovering nutrients made available by hindgut fermentation, including SCFAs Henning and Hird, ; Vernay et al.
The least colonic reabsorption of sodium and water in the light period coincides with soft faeces production in rabbits.
In contrast, mice and rats have more uniform faeces than rabbits but also show daily rhythms of colonic and rectal sodium absorption via amiloride-sensitive ENaC Wang et al. In mice and rats, the night active period is the peak period for both sodium reabsorption and defecation.
The early studies of colonic absorption identified the parallel rhythmic oscillations in corticosteroids as possible underlying mechanism for daily rhythms of absorption Clauss, ; Clauss et al. Indeed, adrenalectomy blunted circadian rhythmicity in Nhe3 in intestinal epithelia Vagnerová et al.
Mineralocorticoids are also candidate entrainers of colonic absorption as aldosterone may entrain renal ENaC via regulation of Per1 Gumz et al. Colonic permeability has been positively correlated with stool frequency in rats Hou et al. Compatible with this, colonic permeability is reported to have a daily rhythm in mice, peaking in the night active phase: the period of greatest faecal pellet output Oh-oka et al.
Epithelial tight junctions are the main regulators of colonic permeability Lee, Some evidence suggests tight junction proteins such as occludins and claudins, may be expressed with daily rhythmicity in the colon, putatively controlled by CLOCK-BMAL1 Oh-oka et al. Colonic permeability is inversely associated with the expression of the occludin and claudin proteins.
Colonic epithelial occludin mRNA expression peaked during the day inactive period and nadirs during the night active period in mice Summa et al. Evidence is currently mixed as to whether the same pattern occurs with colonic epithelial Claudin-1 mRNA expression Oh-oka et al.
L-cells occur in large numbers in the distal small intestine Knudsen et al. Interestingly, their density increases along the colon and rectum where the role of GLP-1 is less understood Holst et al.
A daily rhythmicity of GLP-1 secretion was suggested by the observation that identical meals consumed at different times evoked significantly different plasma GLP-1 responses in humans, favouring higher GLP-1 secretion in the morning, compared to evening Lindgren et al.
A circadian rhythmicity of GLP-1 secretion was confirmed in rats Gil-Lozano et al. Interestingly, GLP-1 secretion rhythmicity may not depend on entrainment by glucocorticoid rhythms Gil-Lozano et al. However, GLP-1 secretion and L-cell core clock gene rhythms were deranged by high fat diets and microbial ablation, pointing to a critical role for the microbiome in maintaining GLP-1 secretion rhythmicity Gil-Lozano et al.
Daily rhythmicity in pain perception in humans is commonly reported, with peak and nadir timing varying across sensory modalities and pathophysiological conditions Aviram et al. The first order neurons involved in sensory signalling from the colon are vagal and spinal afferents.
In other gastrointestinal organs such as the stomach, mucosal and tension receptors of the vagal nerve have a circadian rhythm in mechanosensitivity, inversely proportionate to food intake Page, Their excitability is higher at the onset of the active-compared to inactive period Kentish et al.
Currently no studies have investigated the circadian rhythm modulation of sensory vagal fibres that innervate the proximal or distal colon. However, recent work has identified that vagal afferent signalling to second order neurons in the nucleus tractus solitarius NTS also shows circadian variability that favours throughput of afferent-driven signalling during the active period, and passive spontaneous firing during the inactive period Ragozzino et al.
It remains to be determined whether similar mechanisms govern circadian variation of signalling efficacy to the CNS in spinal afferent pathways. Colonic spinal afferents and their function have been reviewed extensively elsewhere Brierley et al. In brief, colonic afferents send mechanical and chemical signals about the colon e.
These afferents have been classified into five major types, muscular, mucosal, muscular-mucosal, vascular, and silent Brierley et al. Surprisingly, circadian rhythms of colonic afferents have, to date, not been directly investigated. Interestingly, bladder afferents derive from lumbar splanchnic and sacral pelvic nerves like the afferent supply to the distal colon and show strong time-of-day regulation of sensitivity, raising the possibility similar variations occur in colon.
At least 3 classes of bladder afferents stretch-insensitive mucosal and stretch-sensitive low and high threshold muscular-mucosal afferents demonstrated significantly increased sensitivity to mechanical stimuli like stroking and stretch during the active-, compared to the inactive period, suggesting strong circadian regulation of spinal sensory neuron excitability Christie and Zagorodnyuk, ; Ramsay and Zagorodnyuk, In the distal colon, potential circadian regulation of colonic afferents could be inferred through measurements of visceromotor responses VMRs , that can be assessed by recording abdominal EMG activity, evoked by colonic distension.
An early study reported that VMRs evoked by colorectal distension in rats exhibits a daily rhythm with significant increase in the response seen in active period at night Gschossmann et al. However, a more recent study reported that distension-evoked VMRs in rats do not exhibit a daily rhythm Botschuijver et al.
Compatible with the idea that visceral afferent sensitivity and signalling efficacy to the CNS may be enhanced during the active-compared to inactive period, human data indicates perception thresholds to rectal distension stimuli for urge and pain was lower in the morning than evening Enck et al.
Interestingly, daily variations in sensory signalling may differ by region and sensory modality; peak visceral pain sensitivities in the active period differs to those for cutaneous thermal and mechanical pain and in conditions like neuropathic pain and cluster headache which peak during the inactive period Mun et al.
Melatonin arises from multiple sources, of which the best known is nocturnally generated pineal melatonin. However, extra-pineal melatonin is a far greater source of melatonin in the body, much of which may be generated in mitochondria where it controls oxidative processes and which may represent its original site of synthesis in evolution for review, see Tan et al.
In the gut, melatonin is predominantly contained in the epithelial cells along the whole gastrointestinal tract Bubenik et al. Both melatonin and serotonin released from mucosa give rise locally to micromolar concentrations in mouse ileum and colon Bertrand et al.
Melatonin may have two different effects on the vascular smooth muscle, with vasoconstriction mediated via MT1 and vasodilation—via MT2 Harlow and Weekley, In small gut segments, melatonin decreased rat small intestine and colon contractility, whereas it evoked contraction of guinea pig proximal colon Harlow and Weekley, ; Lucchelli et al.
Smooth muscle responses to melatonin in the studies by Lucchelli et al. Taken together, melatonin has potential to directly affect colonic smooth muscle function, but its importance under normal physiological conditions is not characterised. In enteric neurons, MT1 receptor immunofluorescence was weak or undetectable in human colonic submucous and myenteric plexus, but MT2 receptor immunoreactivity was generally stronger, ranging from weak to strong in both plexuses Söderquist et al.
Mtnr1a mRNA was also reported in rat small intestine myenteric neurons Soták et al. Electrophysiologically, exogenous melatonin did not affect membrane potential or input resistance, but inhibited nicotinic synaptic input in guinea pig ileum submucous neurons Barajas-López et al.
In mouse colon, an inhibitory action of melatonin on neuronal NOS was inferred by its reduction of the slow nitric oxide-mediated Shuttleworth et al. Whether these actions of exogenous melatonin relate to any endogenous role, or the circadian regulation of colonic functions remains to be established.
Melatonin is released into circulation by the pineal gland during the dark and is hormonal regulator of circadian rhythms. There is some evidence of pineal melatonin involvement in regulation of the interdigestive migrating motor complex MMC; Szurszewski, in rats Bonouali-Pellissier, Pineal or exogenous melatonin does not affect clock gene expression in rat or mouse colonic epithelial cells Polidarová et al.
Melatonin is produced peripherally Huether et al. Exogenous melatonin can modulate colonic transit, and this may be dose dependent. One study has demonstrated that 3 mg of melatonin daily increases colon transit time in healthy humans Lu et al.
The underlying mechanisms of melatonin action on colonic motility are not known. In in vivo studies of the small intestine, nonselective MT1 and MT2 melatonin receptor antagonist, S suppresses nocturnal variations in interdigestive MMC frequency in the rat small intestine Merle et al.
This may suggest an involvement of melatonin in physiological regulation in the pre- and postprandial changes of intestinal motility Merle et al. Melatonin has potential as a therapeutic for the treatment of IBS and UC symptoms, although reports are conflicting. It has been shown that melatonin 3 mg improves abdominal pain associated with both IBS-C and IBS-D Song et al.
However, it is also reported that melatonin 3 mg improves abdominal pain in only IBS-C and not IBS-D Chojnacki et al.
Other studies also indicated that melatonin 3 mg improved abdominal pain, however, the type of IBS was not specified Saha et al. Similarly, the effect of melatonin on stool frequency and colonic transit in IBS is conflicting.
It has been shown that melatonin 3 mg only improves stool frequency and colonic transit in IBS-C patients Chojnacki et al. However, it is also reported that melatonin has no effect on stool frequency and colonic transit in IBC-D and IBC-C patients compared with placebo Lu et al.
It should be noted that other, greater affinity, MT1 and MT2 agonists, such as agomelatine, have been studied for their potential in the treatment of IBS-D. Agomelatine 25 mg significantly improved overall symptoms in IBS-D patients Balakina et al. However, agomelatine is also a 5-HT 2C and 5-HT 2B receptor antagonist Guardiola-Lemaitre et al.
As previously mentioned, disruptions to circadian rhythms can exacerbate UC signs and pathology. In UC-circadian disrupted mice, treatment with melatonin reduced the signs and severity of inflammation in the colon Park et al.
Similar effects of melatonin are also seen in UC mice without circadian disruptions Trivedi and Jena, It has been speculated that patients with UC may have increased synthesis of melatonin in the colonic mucosa Vaccaro et al.
It is likely that in the treatment of UC, melatonin exhibits a protective, anti-oxidative effect on the colonic mucosa. A wide array of colonic functions shows circadian rhythmicity optimized to the period of food intake. Disruptions of these rhythms can cause organ disorders or exacerbate pre-existing ones.
Multiple neural, hormonal and intraluminal mechanisms may contribute to the entrainment of circadian variation in colonic functions, but their full details remain to be elucidated. Gut melatonin, in contrast with pineal melatonin, may be principally arrhythmic in function but nevertheless may have therapeutic potential in its exogenous application for treatment of gut disorders that are exacerbated by circadian disruption.
SR and TH drafted the manuscript. All authors contributed to the article and approved the submitted version. National Health and Medical Research Council NHMRC Project grant and Australian Research Council ARC Discovery Project grant DP to NS, and NHMRC grant to VZ.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.
Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
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