Trends in Food Science & Technology 95 (2020) 173–182

Contents lists available at ScienceDirect

Trends in Food Science & Technology

journal homepage: www.elsevier.com/locate/tifs

Naturally-derived chronobiotics in chrononutrition T

a b a,∗
Elisa Dufoo-Hurtado , Abraham Wall-Medrano , Rocio Campos-Vega
a
Programa de Posgrado en Alimentos del Centro de la República (PROPAC), Research and Graduate Studies in Food Science, School of Chemistry, Universidad Autónoma
de Querétaro, 76010, Santiago de Querétaro, Qro, Mexico
b
Instituto de Ciencias Biomedicas, Departamento de Ciencias de la Salud, Universidad Autonoma de Ciudad Juarez, Anillo Envolvente del Pronaf y Estocolmo s/n, CP
32310, Ciudad Juarez, Chihuahua, Mexico

A R T I C LE I N FO A B S T R A C T

Keywords: Background: The circadian clock is an evolved autonomous timekeeping system that aligns body functions to the
Chronobiology solar course, by anticipating/coordinating the required metabolic activities; such internal clock responds to
Chrononutrition several exogenous stimuli (Zeitgebers) able to synchronize the endogenous rhythm. A disrupted circadian rhythm
Bioactive compounds leads to several neurodegenerative and metabolic illness such as obesity, diabetes, and psychiatric disorders.
Health
Scope and approach: Circadian rhythm disorders have no current medical treatment, but chrononutrition has
Diseases
emerged as an important tool to enhance metabolic and nutritional health in sleep disorders. This review
highlights the effects of meal timing, food types, nutrients and several bioactive xenobiotic compounds
(chronobiotics) on circadian clocks. The potential application of diet therapies is discussed particularly to deal
with certain metabolic disorders related to circadian misalignment.
Key findings and conclusions: The desynchronization of circadian rhythms negatively influences health ne-
cessitating the development of molecular modulators of circadian rhythms including food components, meal
timing, or different diet types that can help correct circadian disorders attenuating the burden of chronic dis-
eases. However, there is limited research on the chronobiotic effect of specific foods/compounds in clinical trials.
Animal studies evaluating the chronobiological response, resulting from the ingestion of a particular food, are
also limited; most available studies (in vitro and animal models) report the effect of a single nutrient (e.g.,
caffeine, palmitate, among others) which is difficult to translate to real-life situations. This review offers the
perspective of a chronobiotic-based approach, identifying targets for health improvement, which are current
lifestyle-associated issues.

1. Introduction
Every 24 h, the earth rotates once around its axis, exposing live
organisms to predictable fluctuations of light and temperature. To op-
timally adjust their behavior, metabolism, and physiology living or-
ganisms developed an internal system called “circadian clock”. This
clock has evolved as an autonomous timekeeping system that aligns
behavioral patterns (including food intake) to daytime/nighttime and
supports the body functions by anticipating and coordinating the re-
quired metabolic programs. The brain is the master organ controlling
circadian rhythmicity by responding to environmental light and dark-
ness cues called Zeitgebers (Reinke & Asher, 2019).
Each body cell is equipped with its circadian clock (a.k.a. oscillator)
to achieve the timely homeostasis of the entire organism. This master
clock confers rhythmicity by controlling rate-limiting steps in the cell's
daily metabolic program (Kiehn, Koch, Walter, Brod, & Oster, 2017;
Reinke & Asher, 2019). Circadian rhythms, cycles with a recurrent
periodicity also respond to Zeitgebers (Herzog, 2007), and are re-
sponsible for controlling different physiological processes such as sleep
& wake cycles, body temperature, cardiovascular activity, hunger/ap-
petite, endocrine hormone secretion, and renal function (Zee, Attarian,
& Videnovic, 2013).
Disruption of the circadian clock by external (e.g. night shift-work
or jet-lag) or internal desynchronization (e.g. nyctalopia, aging), ne-
gatively affects rest-to-activity cycles, leading to various health pro-
blems including individual psychiatric and metabolic disorders such as
obesity, diabetes, hyperglycemia, and cancer (Pfeffer, Korf, & Wicht,
2018; Zee, Attarian, & Videnovic, 2013). For example, transient timing
changes such as summer time changes are associated with increased
risk of acute myocardial infarction (Tarquini, Carbone, Martinez, &
Mazzoccoli, 2019). The physiologic disruption of circadian rhythms
may also accelerate lung tumorigenesis (Papagiannakopoulos et al.,

∗
Corresponding author.
E-mail addresses: elisadufoo@msn.com (E. Dufoo-Hurtado), awall@uacj.mx (A. Wall-Medrano), chio_cve@yahoo.com.mx (R. Campos-Vega).

https://doi.org/10.1016/j.tifs.2019.11.020
Received 29 July 2019; Received in revised form 18 September 2019; Accepted 21 November 2019
Available online 23 November 2019
0924-2244/ © 2019 Elsevier Ltd. All rights reserved.
E. Dufoo-Hurtado, et al. Trends in Food Science & Technology 95 (2020) 173–182

Abbreviations GLUT3 Glucose transporter 3

GSPE Grape seed polyphenol extract
5-HIAA 5-Hydroxyindoleacetic acid IBD Inflammatory bowel diseases
ALT Alanine transaminase IBS Irritable bowel syndrome
aMT6s 6-Sulfatoxymelatonin MDD Major depressive disorders
AST Aspartate transaminase NCCD Non-communicable chronic diseases
BLT Bright light therapy NOB Nobiletin
BMAL1 Brain and muscle aryl hydrocarbon PER Period
CA Chicoric acid PPAR-γ Peroxisome proliferator-activated receptor gamma
CCGs Clock-controlled genes REV-ERB Nuclear receptor
CLOCK Circadian locomotor output cycle ROR Retinoic acid receptor-related orphan receptors
Cpt2 Carnitine palmitoyl transferase 2 SAD Seasonal affective disorders
CRY Cryptochrome SCF Spent coffee fiber
EGCG Epigallocatechin-3-gallate SCFAs Short-chain fatty acids
FAA Food anticipatory activity SCN Suprachiasmatic nucleus
FFA Free fatty acids Sglt1 Sodium-glucose cotransporter 1
FW Fresh weight TP Tea polyphenols
GLUT1 Glucose transporter 1 Trp Tryptophan
GLUT2 Glucose transporter 2

2016) by affecting its initiation-progression- metastasis continuum
(Masri & Sassone-Corsi, 2018). Furthermore, experimental and clinical
studies have consistently demonstrated that altering of circadian
rhythms may enhance the development and progression of digestive
pathologies, such as irritable bowel syndrome (IBS), and inflammatory
bowel diseases (IBD), a fact linked to dysmotility or changes in mi-
crobiota composition (Codoñer-Franch & Gombert, 2018). Conse-
quently, research has focused on chrono-therapeutic approaches, as an
additive, and noninvasive treatment aid to deal with several illnesses;
for example, bright light therapy (BLT), wake therapy, and sleep phase
are used in the treatment of adult depression (Kirschbaum-Lesch,
Holtmann, & Legenbauer, 2019).
The first part of this narrative review (Siddaway, Wood, & Hedges,
2019) relates to the metabolomics regulation of peripheral circadian
clocks and their synchronization. The second part deals with evidence
on the effects of specific nutrients/xenobiotics, all of them known as
naturally-derived chronobiotics, in the chrononutrition area, and their
relation with normal and abnormal metabolism and non-communicable
chronic diseases (NCCD) such as cancer, liver diseases and insulin re-
sistance.
2. Method
In selecting the search strategy and classification of the information
included herein, the recommendations of Siddaway et al. (2019) were
followed. Briefly, to ensure ‘state of the art’ scientific communications
in the field of ‘chrononutrition’ and ‘chronobiotics’, a cursory search of
articles' titles or abstracts (tiab) using these exact searching terms or
their associated Medical Subject Heading (MeSH; https://meshb-prev.
nlm.nih.gov/search) codes [circadian rhythm (MeSH D002940), circa-
dian clock (D057906), biological clock (D001683), nutritional physio-
logical phenomena (D009747), diet/food/nutrition (D000066888)]
was carried out in four open-access search engines (Scopus, Web of
Science, Google scholar, PubMed) from 1975 to 2019. Only papers in
English were considered from original observations from in vitro, in vivo,
and human clinical studies.
The first manuscript with ‘chrononutrition’ in its title was published
in 2007 and 34 to 40 scientific communications on this matter were
published from 2007 to June 2019, although only fifteen papers pub-
lished original observations (Table 1); the term “chronobiotics” appear
in the scientific literature since 1967 and its binary combination with
other terms using ‘and’ as Boolean operator, reduced even more the
amount of articles; particularly, when using ‘food’ or ‘nu-
trient’ + ‘chronobiotics’, thirteen articles were identified (each), within
which it was possible to identify theophylline (present in black tea) and
caffeine (present in coffee) as the most common ‘natural’ chronobiotics,
from 1975 onwards. Lastly, ‘chrononutrition’ or ‘chronobiotics’ linked
to ‘gastrointestinal microbiome’ (MeSH ID, D000069196), ‘biological
clock’ (D001683), ‘metabolic diseases’ (D008659) or ‘chronic diseases’
(D002908) provided further evidence as to the role of specific nutri-
tional regimens, supplements and mealtime as synchronizers of biolo-
gical clocks, as it will be discussed in detail in the following paragraphs.
3. History of the study of biological rhythms
Biological rhythms in plants and animals date from 5000 B.C.
Hippocrates (1955, century IV B.C.) described the relation between
biological rhythmicity, seasonality, time of day, and age with the in-
cidence of some diseases (Fig. 1). In this era, Androsthenes of Thasos
also described the cyclical opening of the tamarind plant (Bretzl, 1903);
however, Sanctorius was the first to design a “chronobiology labora-
tory” in 1657 and use an “autorhytmometric method” in 1711
(Reinberg & Smolensky, 1983). Surprisingly, the oldest review on
“Chronobiology” indexed on Scopus, indicates that the study of
rhythms dates from 1920, with some early biological models doc-
umenting oscillating circuits based on natural and purely mathema-
tical/statistical data (Halberg, 1969). Furthermore, in 1790 and 1797
preliminary statements on our natural 24 h scale-chronology were ex-
pressed by Seguin and Lavoisier, and Hufeland respectively, while the
concept of “desynchronization” dates from 1958 (Halberg, 1960), and
that the term “chronobiotic” appeared only in 1967 (Recchioni, 1967).
“Quiadon”, a 3-alkyl pyrazolyl piperazine, was one of the first com-
pounds used as chronobiotic and evaluated in a natural laboratory for
human circadian rhythm (Simpson, Bellamy, Bohlen, & Halberg, 1973).
The knowledge of food effects on biological rhythms dates back to
Charles Chossat in 1832, who demonstrated that the circadian rhythm
of the cloacal temperature of food and water deprived pigeons, per-
sisted with large amplitude even until death, as a base of “chrononu-
trition” (Reinberg & Smolensky, 1983). However, Halberg is considered
the father of modern chronobiology after proposing the term “circa-
dian” from the Latin circa (“around” or “approximately”) and diēm
(“day”). Aschoff and Pittendrigh developed the basic (parametric and
non-parametric, respectively) models to explain the cornerstone of
circadian rhythms and are considered the fathers of chronobiology
(Aschoff, 1960; Halberg, Halberg, Barnum, & Bittner, 1959;
Pittendrigh, 1960). More recently, the 2017 Nobel prize in Physiology/
Medicine went to the discovery of the molecular mechanisms control-
ling circadian rhythms (nobelprize.org) (Fig. 1). Considering that rising

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Table 1
Results of scientific articles in the chrononutrition field obtained with the app “Web of science.”
Topic Focus Food, nutrients, diet or feeding Related disease Reference
schedule

Neurosciences
Nutrition and dietetics
Night and day tryptophan enriched milk formula improves sleep/wake rhythms Infant milk formula Infant sleep disorders Aparicio et al. (2007)
Trp enriched cereal intake facilitates sleep Cereal Infant sleep disorders Cubero et al. (2009)
Day/night infant milk formula helps consolidate sleep/wake rhythms Infant milk formula Sleep disorders Cubero et al. (2007)
FED is seasonally associated with sleep quality; it is higher in winter, resulting in Food energy density Sleep disorders Stelmach-Mardas et al. (2017)
lower sleep quality
Reducing the evening meal load potentially improves children and adolescent Protein Obesity and weight control Mathias et al. (2017)
health
Night administration of L- serine and bright light in the morning is useful to treat Amino acids Circadian disturbances Yasuo et al. (2017)
circadian misalignment
Time restricted food favorably changes dietary intakes and reduces adiposity Restricted food Metabolic disorders and Antoni et al. (2018)
adiposity

175
Cell biology
Geriatrics gerontology
Physiology
Endocrinology metabolism
Biochemistry molecular biology
Adolescents with diurnal eating patterns have higher BMI and waist circumference Meal timing Obesity Palla and Almoosawi (2019)
Maternal chrononutrition during pregnancy is important for the circadian system Maternal eating behavior – Canaple, Gréchez-Cassiau, Delaunay, Dkhissi-
entrainment of the offspring Benyahya, and Samarut (2018)
Trp enriched cereal intake improves sleep disorders, anxiety and depression Cereal Mood disorders Bravo et al. (2013)
symptoms
Delayed meal times shift the phase of circadian rhythm Late mealtimes – Yoshizaki et al. (2013a)
Scheduling meals earlier regulate the circadian phase of the cardiac autonomous Early feeding schedule – Yoshizaki et al. (2013b)
nervous system and decrease fasting serum lipids
Sleep disturbance and circadian rhythms may be associate with the risk of obesity Various Obesity Broussard and Van Cauter (2016)
Food factors and nutrients can modulate the circadian clock Type of diet and phyto- Various Oike (2017)
chemicals
Morning administration of fish oil exerts hypolipidemic activity Fish oil Liver diseases and Oishi et al. (2018)
hyperlipidemia

Trp: Tryptophan; FED: Food energy density; BMI: Body mass index.
Trends in Food Science & Technology 95 (2020) 173–182
E. Dufoo-Hurtado, et al. Trends in Food Science & Technology 95 (2020) 173–182

Fig. 1. Timeline of chronobiology history and the appearance of chrononutrition as a science. (With the information of Hippocrates, 1955; Later, Seguin and
Lavoisier 1790; Chossat 1832; Halberg et al., 1959; Pittendrigh, 1960; Wurtman et al., 1968; Aschoff 1969; Rosenthal, 1975; nobelprize.org).

evidence supports their link with health/disease status, the chrononu-
trition field has a remarkable translational, clinical, and therapeutic
potential on the regulation of the circadian rhythm through diet pat-
terns & bioactive compounds.
Dietary tryptophan (Trp) has been suggested as a synchronizer
(entrainment) of the circadian rhythm with external environmental
factors called Zeitgeber (Wurtman, Shoemaker, & Larin, 1968). This was
further supported and confirmed, establishing thereby the science
foundation of chrononutrition (Rosenthal, 1975).
Chrononutrition implies that nutrients or meal timing per se posi-
tively or negatively affect the circadian clock system (and vice versa) in
health (Aparecida & Mota, 2019); chronobiology is a relatively new
field investigating the relationship between food and the circadian
rhythm. Chrononutrition has been proposed as a tool for adapting
macro/micronutrient diet composition or meal timing to people's cir-
cadian rhythm, to affect whole-body physiology and metabolism (Dollet
& Zierath, 2019) and to improve overall health. Moreover, dietary ha-
bits are influenced by the circadian rhythm including eating time, and
irregularity, inconsistency, and food frequency or meal occasions (Pot,
2018). However, chrononutrition as the main topic for research in-
vestigation has been scarcely reported with only 40 published papers
indexed in “Scopus” from 2007 to 2018 (Fig. 1) and 15 indexed in ‘WEB
of science’ since 1980, almost half of them reported in the last five years
(Table 1, excluding reviews, conference presentations, and duplicate
documents).
4. Regulation of the master and peripheral clocks
Circadian rhythms are generated endogenously and regulated by a
master or central clock located in the suprachiasmatic nucleus (SCN), in
the anterior hypothalamus of mammals. The SCN contains approxi-
mately 15–20,000 neurons which have the remarkable feature of os-
cillating with a 24 h based rhythm. However, they do not function in
isolation from their surroundings; instead, they are entrained by ex-
ternal cues. Light has been described as the most potent synchronizer in
humans, allowing us to anticipate the natural temporal environmental
variations. The eye signals the status of the environmental light-dark to
the master clock via the neuro-anatomical pathway called “re-
tinohypothalamic tract”. Specialized extra-ocular photoreceptors on the
retina participate in this communication with the local clock organi-
zation of the peripheral tissues through multiple pathways involving
neuronal and hormonal functions (Duffy & Wright, 2005; King &
Takahashi, 2000). SCN primarily functions like an “orchestra director”
for the peripheral clocks present in all other tissues and cells in the
body, whose synchronization is essential to ensure temporally co-
ordinated physiology. These regulations express genes, and corre-
sponding physiological activities repeat in every cycle through mole-
cular control in every single cell of the system (Asher & Sassone-Corsi,
2015).
Studies in numerous organisms have shown that circadian rhythms
are controlled at the cellular level through a central set of highly con-
served genes called “clock” (Fig. 2). At the molecular level, two tran-
scription factors are known, CLOCK (Circadian locomotor output cycle),
and BMAL1 (Brain and muscle aryl hydrocarbon receptor nuclear
translocator); they heterodimerize and drive the transcription of many
clock-controlled genes (CCGs) by binding to E-box sites within their
promoters. CLOCK and BMAL1 also control the transcription of their
repressors, period (PER) and cryptochrome (CRY) family members,
generating a tightly self-regulated feedback loop. During the day (in
response to light) CLOCK interacts with BMAL1 to activate Per and Cry

Fig. 2. Molecular regulation of circadian clocks, its entrainment by different zeitgebers, and its impact on human physiological activities (With information of
Damiola et al., 2000; Zee et al., 2013; Oosterman et al., 2014; Tahara & Shibata, 2014; Reschke et al., 2018).

176
E. Dufoo-Hurtado, et al.
transcription; the increase in these genes transcription results in accu-
mulation of the circadian repressors PER and CRY which hetero-
dimerize, translocate to the nucleus and inhibit CLOCK/BMAL1 medi-
ated transcription. During the night (in response to the decrease/
absence of light) the PER/CRY repressor complex degrades, and the
cycle begins again; this complex is also regulated by its degradation in
the cytoplasm by casein kinase 1 phosphorylation. In a secondary
feedback cycle, REV-ERB (Nuclear receptor) and ROR (Retinoic acid
receptor-related orphan receptors) participate in regulating BMAL1
expression (Fig. 2) (Reschke et al., 2018; Zee et al., 2013).
Furthermore, peripheral clocks are entrained by various factors,
feeding/fasting being the most important (Oosterman, Kalsbeek, la
Fleur, & Belsham, 2014); food intake, appetite, digestion, and meta-
bolism exhibit circadian patterns that are regulated by rhythmically
expressed genes in different tissues. However, food intake serves as a
regulator of the circadian clock, particularly of the peripheral clocks in
some tissues like liver and intestine (Fig. 2) (Damiola et al., 2000;
Tahara & Shibata, 2014). The food anticipatory activity (FAA) is an
example of this regulation responsible for inducing characteristic of
anticipatory rhythms or feeding by gene expression, enzyme secretion,
and metabolic hormones release necessary for digestion; it is attributed
to the food-entrainable oscillator located outside the SCN (Shibata,
Hiaro, & Tahara, 2010). This necessitatesthe study of foods ability to
modulate circadian rhythms through synchronization of peripheral
clocks, located in different tissues, analyzing meal timing, food type,
food components, and their effects on circadian clocks.
5. Food as synchronizers of peripheral clocks
British adults with more irregular food consumption, especially
during breakfast and between meals, showed increased cardiometabolic
risk, as well as a higher risk of obesity and metabolic syndrome, despite
consuming less energy (Pot, Hardy, & Stephen, 2014). However, the
study did not evaluate the relationship of diet characteristics (mealtime
and food consumption) and the circadian rhythm suggested as de-
terminants of the circadian rhythm synchronization that can directly
influence metabolic and hormone processes. Daily distribution of food,
particularly protein intake can potentially improve adolescent and
children health (Mathias, Almoosawi, & Karagounis, 2017). Dietary fish
oil improves plasma and liver concentrations of triglycerides and cho-
lesterol, exerting a hypolipidemic activity depending on the time of
Fig. 3. The interplay between circadian clock, nutrition, and metabolism. (With information of Froy, 2007; Kohsaka et al., 2007; Oishi et al., 2009; Oike et al., 2010;
Leone et al., 2015; Oike, 2017; Tahara et al., 2018).
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Trends in Food Science & Technology 95 (2020) 173–182
consumption, better when consumed at breakfast than at dinner (Oishi
et al., 2018).
Furthermore, specific nutritional diets such as high-fat, ketogenic
and high-salt diets affect circadian oscillators, suggesting that food
quality is also a factor in the entrainment of circadian clocks (Fig. 3). A
high-fat diet in mice leads to changes in the period of the locomotor
activity rhythm and alterations in the expression and cycling of cano-
nical circadian clock genes, nuclear receptors that regulate clock tran-
scription factors, and clock-controlled genes involved in fuel utilization
in the hypothalamus, liver, and adipose tissue (Kohsaka et al., 2007).
Ketogenic diet, used for weight loss disrupts the circadian clock (phase-
advanced) and increases hypofibrinolytic risk by inducing expression of
plasminogen activator inhibitor-1 (Oishi et al., 2009). High salt diet
advances the phase of clock gene expression by about 3 h in the liver,
kidney, and lung, without altering circadian feeding, drinking, and lo-
comotor rhythms in mice. This diet also increases mRNA expression of
sodium–glucose cotransporter 1 (Sglt1) and glucose transporter 2
(Glut2) in the jejunum, responsible for the increase in glucose absorp-
tion in the small intestine, indispensable to other nutrients absorption
and indirectly controlling the entrainment of peripheral circadian
clocks (Oike, Nagai, Fukushima, Ishida, & Kobori, 2010). In animals,
high-protein, lowcarbohydrate chow advanced expression rhythms of
clock genes in multiple organs of mice and enhanced Bmal1 and Cry2
expression (Oishi, Uchida, & Itoh, 2012). In humans, changing from
higher carbohydrate and lower fat to isoenergetic diets delays the
amplitude of cortisol rhythms and alters Per gene expression rhythm in
monocytes (Pivovarova et al., 2015).
On the other hand, evidence suggests that the time of eating is es-
sential to maintain the synchrony on circadian rhythms in the central
clock and peripherals affecting energy metabolism (Yoshizaki et al.,
2013a; 2013b). For example, British adolescents, (11 and 18 years old)
with early main meals and highest energy intake during the night
showed higher body mass index and circumference (Palla & Almoosawi,
2019). A pilot study demonstrated that time-limited food intervention
leads to reduced adiposity, and favorable changes in dietary intakes of
free-living subjects (Antoni, Robertson, Robertson, & Johnston, 2018).
However, further research is needed to determine the best time to eat
food or type of diet to improve their health impact.
Interestingly, one of the main goals of chrononutrition is to establish
a well-regulated smart meal, called the “Smart Nutri Style,” considering
the way people eat or the meal style used, selecting the best for health
E. Dufoo-Hurtado, et al.
(Oda, 2015). In fact, the principles of chrononutrition have already
been demonstrated to improve human weight loss and are likely to
benefit the health of individuals with metabolic disease, as well as of
the general population (Johnston, Ordovás, Scheer, & Turek, 2016).
6. Influence of nutrients on circadian rhythms and clock gene
expression in different tissues
Single nutrients such as sodium, amino acids, caffeine, cinnamic
acid, nobiletin, palmitate, theophylline, thiamine, ethanol, and retinoic
acid can reset or phase-shift circadian rhythms according to in vitro or
animal studies (Fig. 3) (Froy, 2007; Oike, 2017). For instance, glucose
can activate circadian gene expression of Per1, Per2, and Bmal1 sug-
gesting a role in the synchronization of central and peripheral clocks
(Oosterman et al., 2014). Amino acids have also been reported as cir-
cadian regulator; for example, L-serine night treatment improves cir-
cadian disturbances through a light phase reset in mice and humans
(Yasuo et al., 2017). The consumption of tryptophan enriched-cereal
increases melatonin and serotonin urinary metabolites (5-HIAA and
aMT6s, respectively). This rise in aMT6s result in improved sleep
parameters in elderly subjects due to increased sleep time, immobile
time, wake bouts, among other parameters related to sleep quality.
Furthermore, 5-HIAA increase attenuates mood disorders (Bravo et al.,
2013). Fiber also affects the circadian rhythms, for instance, spent
coffee fiber (SCF) consumption changes eveningness to morningness
chronotypes and even increases plasmatic melatonin levels after 21
days’ consumption of SCF fortified biscuit (Oseguera-Castro et al.,
2019).
Metabolism and circadian rhythms are tightly interlocked since
metabolic signals react to the circadian rhythm through modulation of
circadian gene expression and behavior (Fig. 2) (Green, Takahashi, &
Bass, 2008). In fact, the consumption of phenolic compounds plays a
vital role in improving the synchronization of gene expression from the
clock system in different tissues in animal models with unadjusted
circadian rhythm (Qi et al., 2017; Ribas-Latre et al., 2015b, 2015a).
Moreover, the supplementation of commercial green tea polyphenols
(TP), through drinking water, can reverse the daily oscillations trig-
gered by constant darkness in mice (eight weeks), simulating the
shiftwork disruption in humans (Shi, Ansari, McGuinness, Wasserman,
Fig. 4. Potential effects of bioactive compounds as chronobiotics in different diseases. (With information of Garrido et al., 2010; Sun et al., 2015; Bahavani et al.,
2016; He at al. 2016; Mi et al., 2017; Qi et al., 2017; Schinozaki et al., 2017; Sur & Panda, 2017; Guo et al., 2018).
178
Trends in Food Science & Technology 95 (2020) 173–182
& Johnson, 2013). TP therefore possesses chronobiological properties
that modulate the altered expression or rhythmicity of circadian clock
genes (Bmal1, Per1, and Cry2) in the hypothalamus (Qi et al., 2017).
However, it is important to evaluate natural TP since it can interact
with other components, altering the reported effect.
Pro-anthocyanidins present in grape seed polyphenol extract (GSPE)
can modulate peripherical clocks by synchronizing the expression of
clock-core genes (Clock and Bmal1), and clock-controlled genes (Per,
Rorα, and Rev-erb) in some peripheral tissues like liver (Ribas-Latre
et al., 2015a; 2015c). These effects can also be linked to resveratrol, one
of grape seed components able to adjust the circadian rhythms in ani-
mals (Loureiro et al., 2017). However, since the GSPE effects depend on
their administration time, the expression of clock genes may also be
entrained by the frequency, daytime meals and diet composition.
7. Gut microbiota and peripheral clocks
Microbiome plays an essential role in regulating many physiological
processes including digestion of food components, host metabolism,
immune system, epithelial homeostasis, host behavior, and cognitive
function (Mukherji, Kobiita, Ye, & Chambon, 2013). Interestingly, gut
microbiota also influences the circadian clock, displaying circadian
oscillations, characterized by day-night changes in composition or
function of the intestinal microbiome, and its interaction with the host
can also affect circadian clock activity in different tissues (Leone et al.,
2015; Mukherji, Kobiita, Ye, & Chambon, 2013; Murakami et al., 2016).
The microbiota circadian cycle patterns are controlled by food intake,
diet type, and its composition (Leone et al., 2015; Thaiss, Levy, &
Elinav, 2015; Zarrinpar, Chaix, Yooseph, & Panda, 2014). As a result,
oscillations are produced in key metabolic mediators which are in-
tegrated into the host circadian rhythm, maintaining their metabolic
homeostasis (Fig. 3) (Leone et al., 2015).
Leone et al. (2015) reported the impact of a high-fat diet in two
types of animal models (conventional and germ-free) and their re-
lationship with the circadian function of the liver. Germ-free animals
fed low or high-fat diet exhibit markedly impaired central and hepatic
circadian clock gene expression and no weight gain compared with
their counterpart. For example, the levels and the oscillatory behaviors
of Bmal1, Clock, and Cry1 genes, is suppressed in the livers and brains of
E. Dufoo-Hurtado, et al.
germ-free mice. These results show that gut microbiota has an impact
on clock gene expression in more distal organs such as the liver, but the
mechanisms remain unclear.
Furthermore, circadian disruptions such as altered sleep cycles, in-
terruption or altered sleep quality (jet lag, shift work or apnea) cause
dysbiosis in the host microbiome, which is critical for metabolic
homeostasis, promoting obesity and other metabolic syndrome mani-
festations (Parkar, Kalsbeek, & Cheeseman, 2019).
Microbiota-produced metabolites such as short-chain fatty acids
(SCFAs) can change with host diet and may affect circadian rhythms,
highlighting the link between nutrition and physiology (Leone et al.,
2015; Tahara et al., 2018). Acetate, butyrate, and propionate, produced
by dietary fiber fermentation, exhibit rhythmic fluctuations, and are
absorbed in the bloodstream to be distributed to the whole body. Bu-
tyric acid significantly affects clock component (Bmal1 and Per2) ex-
pressions by shifting their phase, suggesting that not only food com-
ponents but even derived-metabolites can potentiate clock oscillations
(Fig. 3) (Leone et al., 2015). The oral administration of mixed SCFAs or
a single administration of each for three days changed phase s in the
peripheral clocks with stimulation timing dependency. Likewise, fiber-
containing diets (cellobiose) facilitate SCFAs production and the en-
trainment of peripheral clocks, suggesting that prebiotics can be used to
treat misalignment (Tahara et al., 2018). In a recent human trial con-
sumption of spent coffee fiber (SCF) produced a shift in microbiota
composition (Oseguera-Castro et al., 2019). Taking into account the
relationship between the microbiome and circadian rhythm, this type of
fiber can decrease dysbiosis caused by chronodisruption.
These evidences suggest that clock gene expression is vital in per-
ipheral clock systems such as liver and gut because this organ in-
corporates metabolism and energy production with food consumption,
affecting numerous physiological processes including glucose, lipid,
and cholesterol metabolism.
8. Effect of bioactive compounds on metabolism and chronic
degenerative diseases
8.1. Sleep efficiency
Sleep loss has recently been recognized as a public health concern
increasingly prevalent in our society. A third of the United States po-
pulation obtains insufficient regular sleep, with adverse health con-
sequences including metabolic and mental disorders affecting human
physiology and behavior (Liu, 2016). Sleep loss has also been associated
with deficits in attention, cognition, metabolism, hormonal balance,
mood, and cardiovascular function (Aguirre, 2016).
The intake of Jerte Valley cherries produces beneficial effects on
sleep-wake rhythms by increasing 6-sulfatoxymelatonin (aMT6), and
total antioxidant capacity in urine and circulating melatonin levels, and
can be a potential nutraceutical tool to counteract oxidation (Fig. 4).
The increase in urinary total antioxidant capacity is presumably due to
the antioxidant role of the amino acid Trp, the neurotransmitter ser-
otonin, and the indole melatonin (Garrido et al., 2010). Cherries
(Prunus avium L.) contains 0.01–20 ng phyto-melatonin per gram of
fresh weight (FW), depending on cultivar. For example, Pico Limón and
Pico Colorado varieties contain the lowest phyto-melatonin (0.01 ng
and 0.05 ng, respectively), and Burlat variety the highest phyto-mela-
tonin (0.22 ng) level, which may explain improved sleep parameters in
varieties with higher phyto-melatonin contents (Garrido et al., 2010;
Meng et al., 2017). However, information is inadequate on cherry
polyphenols and phyto-melatonin modulation of circadian rhythms and
its regulation in improving sleep quality.
Melatonin is considered an internal sleep facilitator that also dis-
plays a circadian expression. The highest melatonin levels are found at
night because absence of light stimulates its synthesis and excretion and
is responsible for improving sleep quality (Alonso-Vale et al., 2008). In
fact, increase in dietary melatonin levels, through a Trp enriched diet
179
Trends in Food Science & Technology 95 (2020) 173–182
improves sleep in babies and older adults (Bravo et al., 2018).
In addition, the chronobiological changes in the normal components
of the diet can improve infantile development of sleep/wake rhythms.
For instance, day/night infant formula milks designed according to the
principles of chrononutrition help to consolidate the sleep/wake
rhythm in bottle-fed infants (Cubero et al., 2007). The administration of
tryptophan enriched milk during night-time improves sleep parameters,
associated with an increased use of serotonin to melatonin synthesis in
infants (Aparicio et al., 2007). Similar results are obtained with the
inclusion at supper of cereals enriched with tryptophan, adenosine-5′-
phosphate, and uridine-5′-phosphate (Cubero et al., 2009).
8.2. Insulin resistance
Insulin resistance is characterized by its reduced ability to stimulate
glucose use by muscles and adipose tissue and to suppress hepatic
glucose production and output. This condition contributes to the de-
velopment of several health problems, including type 2 diabetes,
polycystic ovary disease, dyslipidemia, hypertension, cardiovascular
disease, sleep apnea, certain types of cancers, and obesity (Matthaei,
Stumvoll, Kellerer, & Haring, 2000).
Many hormones that modulate insulin secretion, glucose home-
ostasis, and feeding are regulated cyclically by the circadian rhythm.
Also, evidence suggests an association between short sleep duration and
the risk of obesity and diabetes (Buxton et al., 2012). A study (Qi et al.,
2017) revealed that TP can alleviate insulin resistance provoked by
circadian misalignment; elevated TP treatment decreases mRNA levels
of predominant glucose transporters in the brain (GLUT1 and GLUT3)
caused by constant darkness (Fig. 4). Epigallocatechin-3-gallate (EGCG)
is the major catechin found in green tea and has been demonstrated to
possess some health benefits. The supplementation with commercial
EGCG may be a strategy to combat circadian misalignment, since EGCC
improved glucose homeostasis and alleviated insulin resistance in a
mice model caused by high-fat and high-fructose diets, that is similar to
some modern human diets (Fig. 4) (Mi et al., 2017).
8.3. Body weight and obesity
Obesity occurs when the energy income (food) is higher than the
energy expenditure (physical activity) during a sufficiently long period;
this imbalance is influenced by an interaction of genetic and behavioral
factors as well as physical and social environment. Overweight and
obesity are important global public health challenge given its size,
growth and also its significant impact in increasing the risk in the de-
velopment of chronic diseases, premature mortality and social health
cost (Davila-Torres, Gonzalez-Izquierdo & Barrera-Cruz, 2015). Evi-
dence suggests that circadian alterations such as social jet lag, shift
work, sleep/wake schedules and lack of sleep contribute to obesity
development; in this context the chrononutrition field is of vital im-
portance (Broussard & Van Cauter, 2016; Laermans & Depoortere,
2016).
The administration of resveratrol reduces body weight of mice fed a
high-fat diet, by restoring the circadian rhythm of plasmatic leptin and
insulin levels (Sun et al., 2015). EGCG prevented and reversed adiposity
associated with regulating the plasma lipid status. Besides, TP and
EGCG increased PPAR-γ (Peroxisome Proliferator-Activated Receptor
Gamma) and decreased Cpt2 (Carnitine Palmitoyl Transferase 2) ex-
pressions, maintaining lipid homeostasis (Mi et al., 2017; Qi et al.,
2017). Thus, green tea polyphenols can serve as a strategy to combat
obesity and metabolic syndrome (Fig. 4).
8.4. Liver diseases
The liver is one of the most important organs as it is responsible for
controlling different energy metabolic processes. A clock dysfunction
on the peripheral liver clock speeds up the development of liver
E. Dufoo-Hurtado, et al.
diseases such as fatty liver diseases, cirrhosis, hepatitis, and cancer
while disrupting clock function (Tahara & Shibata, 2016).
Chicoric acid (CA), a caffeic acid-ester polyphenol, was ignored for a
long time until recent studies demonstrated its potential health benefits
through the consumption of CA containing foods. This compound has
been reported in many plants and foods, including lettuce, basil, and
chicory (Lee & Scagel, 2013). In an in vitro culture model of human
hepatic cancer cells (HepG2) misaligned through the administration of
free fatty acids (FFA), CA improved lipid droplets formation, mi-
tochondria function, and redox status imbalance by circadian modula-
tion that regulates fatty acid synthesis and β-oxidation-dependent of
Bmal1 (Fig. 4) (Guo et al., 2018). Thus, foods with high CA content can
serve as natural circadian clock modulators in the liver and a potential
therapeutic tool against non-alcoholic liver diseases.
Melatonin is a hormone produced from tryptophan in the pineal
gland of humans, but it is also found in microorganisms and plants,
called “phyto-melatonin”. There are few data regarding melatonin
concentration in foods, including walnuts, cereals, fruits and vege-
tables, coffee, green tea, animal origin products, among others (Meng
et al., 2017).
Melatonin is essential to preserve and maintain the good function of
the clock system (Touitou, Reinberg, & Touitou, 2017); however, the
amount of physiologically produced melatonin decreases with age and
may be related to the development of pathological conditions linked to
clock disruption. This effect may be improved by administering mela-
tonin through balanced diets, since the consumption of melatonin-
containing foods increases their circulating levels and the total plas-
matic antioxidant potential. Nevertheless, evidence is lacking or in-
adequate on the use of phyto-melatonin, plant-derived or foods con-
taining it, as a chronobiotic.
8.5. Cancer
Modern lifestyle is a factor promoting the desynchronization,
especially in individuals staying awake for extended hours during the
night and with disturbed sleep patterns, as well as shift and night
workers, and individuals exposed to frequent transnational trips (jet
lag) (Reddy, Field, Maywood, & Hastings, 2002). Circadian disruption
is closely associated with homeostasis perturbation and this, in turn, is
involved with cancer development by contributing to cell transforma-
tion, aberrant proliferation, and tumorigenesis; thus, shift work is
probably carcinogenic for humans (Haus & Smolensky, 2013). For ex-
ample, subjects with chronodisruption associated to a short sleep pre-
sent a higher risk in the development of breast and prostate cancers
(He, Anand, Ebell, Vena, & Robb, 2015). Nevertheless, not only altered
sleep patterns are acting as circadian disruptors, but also a late time of
eating episode is associated with increased risk of breast cancer in
woman and prostate cancer in men (Srour et al., 2018).
Moreover, it is also interesting to analyze beyond the nutritional
quality of food intake, the circadian dietary regulation, and how
bioactive components present in food participate in the context of
cancer prevention. Taking this in account, Bhavani, Subramanian, and
Shanmugapriya (2016) showed that vanillic acid administration to rats
with a carcinogen (Methyl-nitro-nitrosoguanidine) disrupted circadian
rhythm. This phenolic acid improved the disturbed circadian rhythm
and mitigated endometrial carcinoma development in the animal
model. The elucidation of the clock system function is a new tool in
developing new target therapies that will be a focus on optimizing in-
dividualized chronotherapy through food consumption and meal timing
(Fig. 4).
Abnormal expression of clock gene Per2 has been suggested to be
vital in carcinogenesis process, since this gene is suppressed in various
types of cancer cells, including breast, prostate, and oral squamous cell
carcinoma. This clock gene can regulate cell cycle genes involved in cell
proliferation, apoptosis, metastasis, invasion, and tumor angiogenesis
(Chen et al., 2005; Hua et al., 2006). Continuous administration of tea,
180
Trends in Food Science & Technology 95 (2020) 173–182
particularly EGCG potentially restricts carcinogenesis in multiple or-
gans at early stages (Sur & Panda, 2017). However, the functional
mechanisms of bioactive compounds and their molecular interaction
with the circadian genes it is not completely understood (Fig. 4).
8.6. Other diseases
Mood disorders are serious diseases that affect a large portion of the
population. The evidence suggests that an interaction exists between
mood disorders, such as major depressive disorders (MDD), bipolar
disorders, and seasonal affective disorders (SAD), with genetic and
environmental disturbances of circadian clocks like shift work.
Treatment of these diseases includes regular sleep, meals, and exercise,
light therapy, wake therapy, and the use of some drugs that act as
antidepressant through an adjustment of the circadian rhythms like
melatonin or nobiletin (Hühne, Welsh, & Landgraf, 2018; McClung,
2013). For example, nobiletin (NOB), a polymethoxy flavone commonly
found in citrus, regulates circadian rhythms by increasing the ampli-
tude of clock gene rhythms in cells. Therefore, foods containing poly-
methoxy flavones like NOB, may have beneficial effects on circadian
rhythm disorders, jet lag, and potentially be useful in mood disorders
treatment (He at al., 2016; Shinozaki et al., 2017). However, there are
no current reports on the function or mode of action of these bioactive
compounds, so it becomes necessary to focus investigation into this
area.
9. Ingenuity/knowledge gap
The desynchronization of the circadian rhythms either in the central
clock or one of the peripheral clocks can be caused by external or in-
ternal cues, adversely impacting various diseases particularly related to
metabolic and neurological problems. This necessitates the develop-
ment of molecular modulators of circadian rhythms, for example food
components such as bioactive compounds, specific feeding schedules or
different diet types. The evidence suggests that bioactive compounds
can correct circadian disorders. However, the dose for each bioactive
compound and the daily intake of foods rich in these compounds must
be evaluated to obtain a positive health effect necessitating in depth
investigation in chrononutrition field to understand molecular me-
chanisms and circadian activities at the macroscopic level.
Some botanicals, for example, valerian and Kava Kava have been
used in Europe for improving sleep, with limited research on the cir-
cadian rhythm regulation (Kim et al., 2018). Food components influ-
encing the circadian clock such as beta-blockers (a compound present in
beans), histamine blockers (antihistamine), and specific insulin-reg-
ulating peptides should also be addressed as potential chronobiotics.
The recent evidence suggests that further discoveries may be in the
offing's in the future, for example, in the area of “chrononu-
traceuticals”, that are nutraceutical compounds modulating biological
rhythms.
Declaration of competing interest
The authors report no conflicts of interest.
Acknowledgements
Author E. Dufoo-Hurtado thanks the Consejo Nacional de Ciencia y
Tecnología (CONACYT-Mexico) for the support of a Ph D. scholarship
(779172). The authors would like to thank Dr. Mario Enrique Rodríguez
García (Universidad Nacional Autónoma de México, Centro de Física
Aplicada y Tecnología Avanzada, México), and Dr. B. Dave Oomah
(Retired; Agriculture and Agri-Food Canada, Summerland, British
Columbia, Canada) for their valuable support to this paper.
E. Dufoo-Hurtado, et al.
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https://www.nobelprize.org/prizes/medicine/2017/press-release/.