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Diurnal Rhythms of Digestion and Metabolism
Circadian rhythms regulate processes such as digestion and metabolism. In the proper rhythm, gastric emptying, thermogenesis, and motility rates reach their peak in the morning. During the active phase of the day, bile acids and nutrient transporters are regulated and more active, as is energy metabolism. Conversely, detoxification becomes more active during the rest phase.
Several factors involved in regulating metabolism have a close relationship with the core clock:
- AMP-activated protein kinase (AMPK): a signal of low cellular energy and one of the most important sensors of nutrient status
- Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α): regulates energy metabolism
- Peroxisome proliferator-activated receptor alpha (PPARα): regulates genes involved in glucose and lipid metabolism
- Nuclear receptor subfamily 1 group D member 1 (REV-ERBα): involved in the differentiation of adipocytes
- RAR-related orphan receptor alpha (RORα): regulates metabolism via lipid and glucose homeostasis
- Sirtuin 1 (SIRT1): a histone deacetylase that helps to signal transcription and stability of genes if dependent upon NAD+
- CLOCK-BMAL1: regulates lipid, glucose, and amino acid metabolism
- Period circadian regulator 2 (PER2): controls lipid metabolism
For example, CLOCK-BMAL1 and omega-3 fatty acids activate some nuclear receptors involved in energy homeostasis, including PPARs. Glycogen synthase functions during the active period, and glycogen phosphorylase functions during the resting period. This means that polymorphisms and other variants in specific genes related to circadian rhythms are associated with obesity and metabolic disease, some of which are affected by certain diets, such as higher carbohydrate or fat intake.
A high-fat meal raises triglycerides in the blood more at night than the same meal consumed earlier in the day. This is likely due, in part, to important adipokines, including leptin and adiponectin, that also have diurnal rhythms.
Daytime rhythms and processes:
– Adiponectin production
– Decreased synthesis of cholesterol
– Glycolytic metabolism
– Increased synthesis of bile acids and glycogen
– Increased uptake of fatty acids
– Lipogenesis
– Secretion of insulin
Nighttime rhythms and processes:
– Biogenesis of mitochondria
– Catabolism of lipid
– Gluconeogenesis and glycogenolysis
– Leptin and glucagon secretion
– Oxidative metabolism
Gut Dysbiosis, Melatonin, and Diurnal Oscillations
It is not just the human cells in the body that have a daily rhythm; the gut impacts—and is impacted by—circadian rhythms. Examples of this have been observed in jet lag, wherein disruption of the circadian rhythm results in gut dysbiosis. Additionally, gut microbiota composition changes when diurnal rhythms are disrupted, which may influence and be affected by different eating times.
An older mouse model study found diurnal changes in 60 percent of the microbial composition, including Bacteroidales, Clostridiales, and Lactobacillales. There were higher numbers during the resting phase compared to the active phase. The diurnal fluctuations match the microbial functions that the microbiota perform. For example, during the active phase, the microbiota performing energy harvest, cell growth, and DNA repair are heightened. At the same time, bacteria involved in detoxification see a greater abundance during the resting phase. However, a functional circadian clock is required for these rhythms to occur. In this study, food intake, feeding times, and sleep disturbances impacted the diurnal patterns of the microbiome, potentially leading to altered microbiota rhythms and gut dysbiosis. Because these factors drive microbiota oscillations, this may explain the connection between gut dysbiosis and metabolic diseases.
Another factor is melatonin, which exists in the gut at levels about 400 times the levels in the pineal gland in the brain. While melatonin is often associated with sleep due to its increased secretion with exposure to darkness, it also has antioxidant, immune function, anti-inflammatory, and neuroprotective properties. Additionally, melatonin helps to regulate the diurnal rhythms of some intestinal bacteria. In an older study, colonies of a specific commensal bacterium, Enterobacter aerogenes, grew faster and experienced increased swarming and motility when exposed to melatonin in a dose-dependent relationship. The most significant response matched the levels of melatonin typically found in the human gut. This finding suggests that the microbiome might synchronize with the human host through melatonin.
Other researchers reported that melatonin supplementation may improve dysbiosis through modulation of the circadian clock. This study aimed to understand if the beneficial effects of probiotics in patients with irritable bowel syndrome (IBS) were due to melatonin. The randomized, double-blind, placebo-controlled trial gave one group of IBS patients a particular probiotic, VSL#3, while the control group had a placebo. The male-treated patients experienced a significant increase in their morning melatonin levels after taking VSL#3 (5.43 pg/ml increased to 9.74 pg/ml), but females and the combined group did not have any significant changes. This increase in melatonin levels correlated with increased contentment with bowel habits. The group with a normal circadian rhythm pre-treatment also experienced an increase in morning melatonin and increased contentment with bowel habits. Thus, the researchers postulated that the efficacy of the probiotics came from the impact on melatonin metabolism and secretion. Newer studies support these findings, especially in individuals with inflammatory bowel diseases. Melatonin supplementation improves microbiota diversity, increases ratios of commensal-to-pathogenic bacteria, and reduces inflammation.
Circadian rhythms might also impact the severity of an allergic response to food. In an older study in an ovalbumin food allergy mouse model, the severity of symptoms (diarrhea and weight loss) was higher in the group that was exposed in the late light period rather than the late dark period. The light period group had a higher absorption of the allergen and a higher intestinal permeability. Timing and type of food also impact the microbial makeup and circadian rhythms.
Diet, Mealtimes, and Circadian Rhythm Disruption
Composition and timing of meals can have a significant impact on circadian rhythm and human health. When certain foods and mealtimes fall outside of the body’s circadian rhythm, the master clock and peripheral clocks may become imbalanced. When imbalance occurs, individuals may experience glucose dysregulation, reduced insulin sensitivity, increased blood pressure, increased inflammation, increased calorie consumption, and decreased energy expenditure.
Dietary patterns have been shown to affect the circadian rhythm. For example, a high-fat diet might interrupt the feeding and fasting cycles, cause a weakened rhythm, change circadian gene expression, and increase inflammation. In an older study, a high-fat diet stopped the normal oscillation of NAD+ in a mouse model. Amino acids, including lysine, did not change their oscillation patterns, while there was amplification in coenzyme A, which is involved in beta-oxidation and the synthesis of fatty acids. It also caused a phase shift. However, these changes were reversible through changing the diet. Another mouse study found that time-restricted feeding mitigates some negative metabolic changes that occur with eating ad libitum, even on the same high-fat diet.
High-protein diets may alter circadian rhythm by affecting liver lipid metabolism and the expression of clock genes. If high-protein and high-carbohydrate meals are eaten later at night, the expression of PER2 and REV-ERBα increases. These factors usually peak during daytime hours.
Meal timing is also a known disruptor of circadian rhythm and may affect metabolic function. Studies show that late-night eating increases the risk of developing metabolic diseases, including obesity and type 2 diabetes, due to increased ghrelin and decreased leptin, which causes an increase in appetite and further heightens the risk of developing metabolic diseases. In an older observational study, participants who ate lunch after 3 p.m. (i.e., “late eaters”) were twice as likely to have a reduced weight loss response to bariatric surgery, regardless of the meal composition. A randomized crossover trial on 30 overweight/obese persons compared morning-loaded versus evening-loaded weight loss diets. While both diets resulted in similar weight loss, morning-loaded diets contributed to less hunger. Ultimately, researchers found that the behavior of morning-loaded calories may help with weight loss compliance and suppression of appetite. Feeding times, especially unusual routines around eating (i.e., erratic eating patterns),can also lead to a shift of the peripheral circadian genes, which could disrupt the clock balance. This means that meal timing may be important in circadian rhythm synchronization.
Certain nutrients also impact the circadian rhythm. For example, adenosine, retinoic acid, and caffeine can shift circadian rhythms, and thiamin deficiency might lead to a disruption. Additionally, alcohol alters the natural rhythms through changes in hormone secretion, body temperature, and the ability to sleep. High-salt and high-fat diets decrease the amplitude of normal circadian rhythms. An older study found oscillations in vitamin D, calcium, and the calcium-phosphorus ratio. In this study, newly-diagnosed diabetic patients and healthy controls had higher levels of vitamin D at noon, and lowest levels at 6 a.m. Calcium rhythms were later in diabetic patients compared to controls. Alternations in the rhythms of these nutrients may be related to the pathogenesis of type 2 diabetes mellitus.
Another study indicated that supplementation with melatonin-rich tart cherry juice may improve sleep quality. In this older double-blind, placebo-controlled study, 20 subjects drank two servings of either tart cherry juice concentrate or a placebo for a week, served within 30 minutes of waking and before their evening meal. Those who consumed the cherry juice had a significantly higher melatonin level (P < 0.05) and a significant increase in sleep efficiency, total sleep time, and time in bed. The timing of the melatonin circadian rhythm was unchanged, but there was a higher mesor (i.e., an analysis that shows a rhythm-adjusted mean) and amplitude. Although the researchers found that cherry juice did not regulate the circadian rhythms in the healthy population, they postulated that it might help others. Newer research confirms this theory by suggesting improved sleep time and efficiency with consistent cherry juice ingestion. However, the direct mechanism of action requires more research.
Proanthocyanidins, which are one of the biggest classes of polyphenols, have the potential to regulate the peripheral components of circadian rhythms. Polyphenols are found in various plant foods, including fruits, cocoa, nuts, vegetables, red wine, and tea. In an animal study, both healthy and obese rats were given chow supplemented with different doses of grape seed proanthocyanidin extract (GSPE). The rats given GSPE had an increased expression of two important circadian genes in the liver, CLOCK and Per2, in a dose-dependent fashion. The researchers reported that these modulations in the main and periphery circadian genes occurred in the obese rats as well, demonstrating that the polyphenols were able to counteract disruption in the rhythm that occurs with obesity. Newer research also shows the beneficial effects of polyphenols, including flavonoids, tannins, and phenolic acids, on circadian rhythm processes. This is another reason why eating a colorful diet rich in various phytochemicals is so important.
In addition to generally maintaining a functional circadian rhythm, consider the impact of enzymes, digestion and absorption, and metabolism when deciding mealtimes and meal composition. Before making any changes in the diet, supplementation, and lifestyle, talk to a doctor, nutritionist, dietitian, or another healthcare team member. Personal options should be based on individual circumstances, conditions, medications, and health needs.
