Key words
adenosine receptors - caffeine - chlorogenic acid - coffee - cardiovascular system
- diabetes - IBD - liver
Abbreviations
ALT:
alanine aminotransferase
CD:
Crohnʼs disease
CHI3L1:
chitinase 3-like protein 1
CTGF:
connective tissue growth factor
CVD:
cardiovascular disease
CXCL13:
small cytokine belonging the CXC family
CYP1A2:
member of the cytochrome P450 oxidase system
DSS:
dextran sulfate sodium
GABA:
gamma-aminobutyric acid
GLUT 4:
glucose transporter type 4
GLP 1:
glucagon-like peptide 1
IBD:
inflammatory bowel disease
IL10:
interleukin 10
NAT2:
N-acetyltransferase 2
NF-κB:
nuclear factor kappa-light-chain-enhancer of activated B cells
NHANES:
National Health and Nutrition Examination Survey
TCBQ:
tetrachlorobenzoquinone
TNF-α
:
tumor necrosis factor-α
TLR4:
toll-like receptor 4
UC:
ulcerative colitis
WNT10B:
member of the WNT gene family
Introduction
In 2016/17, the production of roar coffee amounted to about 151.62 million 60 kg bags
[1], and it is estimated that 2.25 billion cups of coffee are consumed each day worldwide
[2]. Coffee is served internationally and most countries have developed its own preferences
about how to prepare and present it.
The history of coffee goes at least as far back as the 10th century, with a number
of legends surrounding its use. The native (undomesticated) origin of coffee is thought
to have been Ethiopia. The earliest substantiated evidence of either coffee drinking
or knowledge of the coffee tree is from the 15th century, in the Sufi monasteries
of Yemen. By the 16th century, it had reached the rest of the Middle East, South India,
Persia, Turkey, and Northern Africa. Coffee then spread to the Balkans, Italy, and
the rest of Europe, to Indonesia and then to America [3]. Although coffee was introduced in Europe only a few hundred years ago, consumption
of this beverage now occupies a significant place in our national cultures.
Coffee is taken as a brewed beverage that is prepared from the roasted seeds of a
bush of the genus Coffea. The coffee beans are contained in berries that, once matured, are processed and
dried. The two main species are Coffea Arabica (coffee Arabica) and Coffea canephora (coffee Rustica). They have a large production history and an important role both
in the global market and researches [4].
The high consumption of coffee may have a substantial effect on public health. Therefore,
it is no wonder that coffee stimulates the interest of researchers and clinicians.
In PubMed in May 2017, the term “Coffee” resulted in 12 583 hits including 998 reviews
and 1666 clinical trials. Nevertheless, the impact of coffee intake on chronic diseases
has been a matter of debate in the last two decades, with some conflicting results
due the retrospective nature of most of the studies, although coffee has progressively
moved to a less negative position due to its better-known pharmacology. The novel
approaches in epidemiological data and experimental researches suggest that consumption
of coffee is associated with a reduced risk of several chronic and degenerative diseases.
This paper reviews the most significant protective actions of coffee on the cardiovascular
system, liver diseases, and diabetes as well as gastrointestinal disorders, especially
IBD. Clinical and experimental studies are discussed and, if possible, the role of
caffeine and polyphenols is presented.
Bioactive Components in Coffee
Bioactive Components in Coffee
Coffee includes a complex mixture of compounds. The particular profile of compounds
depends on coffee variety, roasting, and processing. Caffeine has been perhaps the
most widely known compound and is the most investigated component of coffee. When
green coffee beans are roasted under high temperatures, chemical reactions between
amino acids and carbohydrates, known as Maillard reactions, create a number of unique
components. Additionally, coffee is abundant in polyphenols like chlorogenic acids.
The main chlorogenic acid in coffee is 5-caffeoylquinic acid, although other caffeoylquinic,
feruloylquinic, and di-caffeoylquinic acids are present in significant quantities
[5]. Phenolic metabolites of chlorogenic acids have been studied for potential bioefficacy,
and controversy still remains as the results are not entirely clear [6], [7]. Only a few studies have investigated the bioavailability of coffee phenolic and
chlorogenic acids due to the complex metabolic pathways in humans [8], [9]. Chlorogenic acids may be transformed into phenolic acids (caffeic, ferulic, and
isoferulic moieties) and, subsequently, into colonic metabolites (dihydrocaffeic and
dihydroferulic acids). With extensive conjugation at the level of the intestine and
the liver, many different metabolites (aglycone, sulfate, glucuronide, and methyl)
could then be identified from a single cup of coffee. Lactones, diterpenes, including
cafestol and kahweol, niacin, and the vitamin B3 precursor trigonellin are also present
in coffee ([Fig. 1]). Cafestol and kahweol found in coffee oil have shown antioxidant activity in cell
models and mice models that involved triggering the upregulation of key antioxidant
enzymes [10], [11]. On the other hand, the two diterpenes are the main cholesterol-rising compounds
in coffee. They are retained in part by paper filters, but are preserved when coffee
is directly prepared by boiling the ground beans [12]. Moreover, coffee is rich in vitamin B3, magnesium, and potassium.
Fig. 1 Chemical structures of adenosine and major biologically active compounds in coffee.
Pharmacokinetics and Mode of Action of Caffeine
Pharmacokinetics and Mode of Action of Caffeine
Caffeine is the most widely consumed behaviorally active substance in the world. It
is present in a number of dietary sources, i.e., tea, coffee, cocoa beverages, and
chocolate bars as well as soft and energy drinks ([Table 1]). Caffeine was first extracted from cocoa beans into its purest form, a white powder,
in the 1820s by the German Scientist Friedrich Ferdinand Runge. Caffeine is contained
in more than sixty plants, which is a remarkable number, thus it has been hypothesized
that caffeine was originally a minor nutrient, not essential for the plant, but extremely
useful as a pesticide. In fact, caffeine is toxic for several insects and animals,
especially herbivores. Through caffeine the plant may defend itself and have a better
chance of survival. In this view, caffeine can be considered as a “co-evolutionary
protecting agent” [13]. The amount of this natural alkaloid in coffee is influenced by the method of coffee
preparation, and amounts between 65 to 120 mg of caffeine have been reported to be
contained in a normal cup of coffee, whereas Arabica coffee normally contains less
caffeine than the Robusta variety [14]. Soft drinks typically contain about 30 to 60 mg of caffeine per serving. By contrast,
energy drinks contain as much as 80 mg of caffeine per serving ([Table 1]). The caffeine in these drinks either originates from the ingredients used or is
an additive derived from the product of decaffeination or from chemical synthesis
[15], [16].
Table 1 Caffeine content chart (according to data from [16]).
|
Item
|
mg of caffeine
|
|
Typical
|
Range*
|
|
*Due to brewing method, plant variety, brand, formulation etc.
|
|
Coffee (240 ml)
|
Brewed, drip method
|
85
|
65 – 120
|
|
Instant
|
75
|
60 – 85
|
|
Decaffeinated
|
3
|
2 – 4
|
|
Espresso (30 ml)
|
40
|
30 – 50
|
|
Teas (240 ml)
|
Brewed, major U. S. brands
|
40
|
20 – 90
|
|
Brewed, imported brands
|
60
|
25 – 110
|
|
Instant
|
28
|
24 – 31
|
|
Iced
|
25
|
9 – 50
|
|
Soft drinks (e.g. Cola 360 ml serving)
|
40
|
30 – 60
|
|
Energy drinks (250 ml serving)
|
80
|
50 – 160
|
|
Cocoa beverage (240 ml)
|
6
|
3 – 32
|
|
Chocolate milk beverage (250 ml serving)
|
5
|
2 – 7
|
|
Solid Milk chocolate (30 ml serving)
|
6
|
1 – 15
|
|
Solid Dark chocolate, semi-sweet (30 ml serving)
|
20
|
5 – 35
|
|
Bakerʼs chocolate (30 ml serving)
|
26
|
26
|
|
Chocolate flavored syrup (30 ml serving)
|
4
|
4
|
Caffeine is completely absorbed by the stomach and small intestine within 45 min of
oral ingestion. The hydrophobic properties of caffeine allow its passage through all
biological membranes and the peak plasma concentration is reached within 15 – 20 min
after oral ingestion in humans [15]. Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system,
specifically the CYP1A2 enzyme into three primary metabolites: paraxanthine (84%),
theobromine (12%), and theophylline (4%) [17]. Another enzyme involved in caffeine clearance is the NAT2, whose function is to
catalyze the transformation of a broad range of xenobiotics [18]. This enzyme has previously been studied with relation to the risk of Parkinsonsʼs
disease and in gene-environment interaction studies [19], but with mixed results.
The half-life time of caffeine varies widely among individuals depending on such factors
as age, liver function, pregnancy, some concurrent medications, and the level of enzymes
in the liver needed for caffeine metabolism. In healthy adults, caffeineʼs half-life
time is approximately 3 – 4 h. In women taking oral contraceptives, this is increased
to 5 – 10 h [20] and in pregnant women the half-life time is roughly 9 – 11 h [21]. In infants and young children, it may be longer than in adults [15].
The principal mode of action of caffeine at doses in normal human consumption is as
an antagonist of adenosine receptors. Adenosine receptors have been cloned, namely,
A1, A2A, A2B, and A3. A1 and A3 receptors preferentially couple to Gi proteins and
inhibit adenylate cyclase, while A2A and A2B couple to Gs and stimulate production
of cyclic AMP (cAMP) [21]. These receptors are widely expressed in the human body and have been implicated
in several biological functions, both physiological and pathological. These include
cardiac rhythm and circulation, lipolysis, renal blood flow, immune function, sleep
regulation, and angiogenesis as well as inflammatory diseases, ischemia-reperfusion,
and neurodegenerative disorders [22]. The caffeine molecule is structurally similar to adenosine and is able to potently
block adenosine effects on A2A and A1 receptor subtypes already at the low concentration
achieved after a single cup of coffee. Twenty times higher concentrations are required
to inhibit cyclic nucleotide breakdown via inhibition of phosphodiestarases. To block
GABAA receptors 40 times higher and to mobilize intracellular calcium stores via activation
of ryanodine receptors, 100 times higher concentrations are needed [23]. These high concentrations of caffeine are unlikely to be reached in human by normal
use of coffee [15]. For children and young adults, the primary sources of caffeine are soft drinks
and teas, while for adults aged 25 and older, it is mostly derived from coffee. Interestingly,
people in Asia mainly drink tea instead coffee.
Effects of Coffee on the cardiovascular System
Effects of Coffee on the cardiovascular System
Considerable controversy exists regarding the association between coffee consumption
and CVD risk. The relationship between coffee consumption and the risk of coronary
heart disease was first studied in the 1960s, given that the prevalence of coffee
drinking and CVD were both high in Western countries [24]. Since 2000, the association between coffee consumption and other CVD outcomes such
as stroke, heart failure, and total CVD mortality has also been more frequently studied
and summarized in meta-analyses [25], [26], [27]. These meta-analyses did not support an association between coffee consumption and
a higher CVD risk, but the shape of the association remains uncertain. Interestingly,
a meta-analysis published in 2014 [28] concluded that moderate coffee consumption (3 – 5 cups/day) was associated with
a lower CVD risk, and heavy coffee consumption (≥ 6 cups/day) was neither associated
with a higher nor a lower risk of CVD. A further meta-analysis [29] has also showed that heavy coffee consumption was not associated with risk of CVD
mortality. In contrast, the cohort study by Liu et al. [30] found that 4 cups per day of coffee consumption was associated with increased mortality,
but the association was only significant for participants under 55 years of age. The
results from this study contradict those from other meta-analyses and the majority
of studies in the literature. Possible reasons for the discrepancy may be a relatively
small size, lack of updated dietary assessment, and subgroup analysis in Liuʼs study.
In addition, coffee brewing methods were not assessed in the included studies.
The question remains whether mechanisms lower the risk of CVD. Pharmacological studies
have confirmed that A1 receptor activation has a number of effects in the cardiovascular
system, including a reduction in heart rate and atrial contractility, and the attenuation
of the stimulatory actions of catecholamines on the heart, and the A2A receptors are
involved in vasodilation in the aorta and coronary artery [31]. The blockade of these receptors by caffeine can contribute to the protective effect
of coffee in CVD. Apart from caffeine, further studies suggested the involvement of
other components confirmed by results from studies with unfiltered and paper-filtered
coffee [32] or caffeinated and decaffeinated coffee [33]. Chlorogenic acids and their metabolites, for example, attenuate oxidative stress
(reactive oxygen species), which leads to the benefit of blood pressure reduction
through improved endothelial function and nitric oxide bioavailability in the arterial
vasculature [34]. It is concluded that the available evidence, although limited, allows for stating
that there is no clinical basis for associating moderate coffee intake with an increased
risk of cardiovascular diseases, including stroke [35]. Not only caffeine but also other components of coffee may contribute to the cardiovascular
effects.
Coffee and Type 2 Diabetes
Coffee and Type 2 Diabetes
Coffee has recently received scientific attention as a current epidemiologic, and
in vivo studies have revealed its health benefits against metabolic disorders, especially
type 2 diabetes [36]. An inverse correlation has been confirmed in most but not all studies. Therefore,
an updated systematic review and a dose-response meta-analysis of all available data
on the correlation of both caffeinated and decaffeinated coffee consumption with the
risk of type 2 diabetes have been published in 2014 by Ding et al. [37]. The systematic review and meta-analysis based on 1 109 272 study participants and
45 335 cases of type 2 diabetes demonstrate a robust inverse correlation between coffee
consumption and the risk of diabetes. Compared with no coffee consumption, 6 cups/day
of coffee was associated with a 33% lower risk of type 2 diabetes. The correlation
was consistent for men and women [37]. By contrast, a multiethnic cohort study [38] suggested that the protective effect of coffee intake was stronger for women (34%
lower diabetes risk) than for men (14% lower diabetes risk). The discrepancy may be
due to the coffee intake assessment through self-reported dietary questionnaires.
Misclassification, therefore, cannot be excluded. A further aim of Dingʼs systematic
review [37] was to compare the effects of caffeinated and decaffeinated coffee consumption and
the risk of type 2 diabetes. Decaffeinated coffee consumption was associated with
the same level of protection as seen for caffeinated coffee and therefore confirmed
previous findings of the European Prospective Investigation into Cancer and Nutrition
(EPIC)-Germany study [39], which reported a 23% lower incidence for caffeinated and a 30% lower risk for decaffeinated
intake of ≥ 4 cups/day. It remains unclear, however, by which mechanism(s) the diabetes-preventive
effect is brought about. There is evidence for both increased insulin secretory responsiveness
and increased insulin sensitivity [40]. Coffee appears to act primarily, if not exclusively, through postprandial, as opposed
to fasting, glucose homeostasis [41].
Studies observed a protective effect of decaffeinated coffee pointing to a relevant
role of constituents other than caffeine, such as polyphenols, which are a major source
of antioxidants in the Westernized diet [42], [43]. As seen in knockout mice (Lepr/db), chlorogenic acid inhibited gluconeogenesis by affecting expression and activity
of enzyme glucose-6-phosatase. Moreover, it improved skeletal muscle glucose uptake
by increasing expression and translocation of GLUT 4. A 2.5-fold increase in glucose
transport was described as an additive action with insulin [44]. Polyphenols in coffee stimulate GLP 1, which is a major intestinal hormone that
activates glucose-induced insulin secretion from β-cells [45]. Prolonged activation of the GLP-1 signal has been shown to attenuate diabetes in
animals and human subjects. This hypothesis has been confirmed by studies suggesting
that polyphenols in coffee bean extract may bring an additive effect in decreasing
body weight gain and increasing insulin sensitivity [46]. These beneficial effects are possibly due to the downregulation of genes associated
with WNT10B- and galanin-mediated adipogenesis and the TLR4-mediated proinflammatory
pathway as well as stimulation of GLUT4 translocation to the plasma membrane in white
adipose tissue of mice [47]. So far, coffee has consistently been inversely associated with type 2 diabetes,
and polyphenols, among other bioactive compounds, are the best candidates to be responsible
for the beneficial actions.
Coffee and Liver Diseases
Coffee and Liver Diseases
There is increasing evidence in favor of protective effects of coffee consumption
in the development and progression of liver disease due to various causes. The clinical
evidence of benefit of coffee consumption in hepatitis B and C, as well as nonalcoholic
fatty liver disease and alcoholic liver disease, has been reviewed by Wadhawan and
Anand in 2016 [48] and for hepatic fibrosis and cirrhosis by Liu et al. in 2015 [49]. The two meta-analyses clearly indicated that coffee intake of more than 2 cups
per day in patients with preexisting liver disease is associated with a lower incidence
of fibrosis and cirrhosis, lower hepatocellular and carcinoma rates, as well as decreased
mortality. In favor of this protection, two recent population-based studies, the NHANES
I and III [50], [51], [52], have reported that higher coffee consumption (> 2 cups per day) was associated
with a lower risk of elevated ALT levels by 44% and a lower risk of chronic liver
disease compared to non-coffee drinkers. Additionally, a recent large cohort study
[53] of 330 patients with alcoholic and non-alcoholic cirrhosis showed a strong inverse
relationship between coffee drinking (> 4 cups per day) and elevated serum enzyme
levels, especially in those who drank large quantities of alcohol. Moreover, coffee
consumption decreased liver stiffness, which may indicate less fibrosis and inflammation
in patients with nonalcoholic fatty liver disease, and hepatitis C and B virus infection
[54]. Although coffee consumption has been associated with a reduced frequency of liver
disease, it is unclear whether the effect is from caffeine or other components. The
beneficial effects of caffeine against liver fibrosis have been demonstrated by several
studies using standard rodent models of experimental liver fibrosis. In almost every
study, ingestion of coffee/caffeine blocked toxin-induced liver fibrosis/cirrhosis
[55]. In particular, in experimental models of fibrosis, caffeine was shown to inhibit
hepatic stellate cell activation by blocking A2A receptors, and emerging evidence
indicates that caffeine might also favorably impact angiogenesis and hepatic hemodynamics.
Successively, Gressner et al. [56] have shown that caffeine inhibits TGF-β-induced CTGF expression in hepatocytes. TGF-β levels are reduced by coffee and caffeine administration to rats subjected to chemical-induced
liver fibrosis [52], [57], [58]. On the other hand, Vitaglione et al. [59] reported that consumption of decaffeinated espresso coffee was able to reduce not
only liver steatosis but also inflammation and fibrosis in rats. It is therefore suggested
that caffeine in coffee is not essential and that specific coffee components contribute
to the hepatoprotective effect [37], [60], [61]. Chlorogenic acid possesses a hepatoprotective nature [62]. In a recent study [63] conducted on TCBQ-induced liver damage in mice, the acid pretreatment seems to be
effective in suppressing TCBQ-induced oxidative stress, therefore possessing a hepatoprotective
nature. Additionally, chlorogenic acid reduced liver fibrosis and the expression of
collagen I and III. These rats displayed reduced concentrations of VEGF, TGF-β, and α-smooth muscle actin [64]. The diterpenes cafestol and kahweol may offer protective effects against aflatoxin
B1-induced liver damage in rats and in hepatocyte cultures [58], [65]. Cafestol and kahweol may also induce the synthesis of glutathione, which has a
role in detoxification and the prevention of liver damage. Taken together, a growing
body of literature has consistently shown an inverse relationship between coffee consumption
and liver diseases. However, there are not enough data to make firm conclusions about
the relative importance of caffeine or other components within coffee in the development
and progression of liver disease.
Coffee and inflammatory Bowel Disease
Coffee and inflammatory Bowel Disease
Studies to date suggest that there is no association between coffee consumption and
the risk of dyspepsia [66], gastroesophagal reflux disease [67], peptic ulcers [68], gastritis, and stomach cancer [69], [70]. People with IBD are coffee users as well, but the question remains as to whether
coffee consumption is safe for people living with a chronic digestive disease. IBD
consists of two major forms, CD and UC. In a study performed by Ng et al. [71], coffee had a protective effect against UC development. Another report studying
41 836 postmenopausal women for 15 years showed that high coffee consumption is inversely
correlated to the severity of inflammatory diseases [72]. It is well known that the herbal mixture of myrrh, dry extract of chamomile flowers,
and coffee charcoal has anti-inflammatory and antidiarrheal properties. In a randomized,
double-blind, double-dummy study [73], 96 patients with inactive UC were randomized to receive either the herbal preparation
or mesalazine over a 12-month period. There was no significant difference in the relapse
rate between the two groups. No significant differences were also shown in relapse-free
time, endoscopy, and fecal biomarkers. In vitro, the herbal mixture influenced gene expression of activated human macrophages within
the cytokine/chemokine signalling pathway. Particularly, chemokine gene expression
was suppressed. Subsequently, the production of CXCL13 (which controls the organization
of B cells within follicles of lymphoid tissues) and, to a minor extent, cytokine
TNF-α were inhibited, whereas IL10 release from activated macrophages was enhanced by coffee
charcoal extracts [74]. In vivo, mice treated with caffeine (2.5 mM; equivalent to the concentration of caffeine
in 2 – 3 cups of coffee) displayed a delayed response towards DSS-induced colitis,
characterized by lower body weight loss and clinical and histological scores. Bacterial
translocation into other organs and proinflammatory cytokine production were also
reduced in the caffeine-treated mice with DSS-induced colitis. Caffeine treatment
also resulted in the loss of CHI3L1-associated signalling pathway activation [75]. The disease-associated CHI3L1 expression was also observed in colonic tissue samples
obtained from CD and UC patients, but was undetected in normal control individuals
[76].
It is, however, considered that the effects of coffee are not exclusively due to caffeine
but seem to be linked with other specific constituents [77]. Chlorogenic acid displayed a significant anti-inflammatory activity in a well-established
mouse model of experimental colitis, as evidenced by a reduction of the macroscopic
damage score, myeloperoxidase activity, and inhibition of the NF-κB dependent pathway [78]. Apart from these, the inhibition of cyclooxygenase-2, inducible nitric oxide synthase
(iNOS) with the lack of a cytotoxic effect, attenuation of IL-1β and IL-6 along with TNF-α in a dose-dependent manner, and inhibition of NF-κB by chlorogenic acid in a DSS-induced colitis have been reported in a recent study
[79].
Although clinical practice guidelines [80] recommend that people with IBD avoid caffeine, there are more clinical and experimental
evidences indicating a possible prospective effect of coffee and its components to
IBS symptoms or other inflammatory diseases of the gastrointestinal tract.
Summary
To date, there are still many misconceptions about coffee and health that can lead
to confusion about whether coffee consumption can be enjoyed as part of a healthy,
balanced diet. Therefore, the potential effect of coffee on the risk of many diseases
has been studied intensively during the last years, sometimes with contradictory results.
The acknowledgment that coffee and caffeine are not equivalent has increased the interest
in whether other components of coffee might contribute to the protective action in
the human body and, should that be the case, in which sense. In this case, the majority
of research has mainly focused on polyphenols. Nevertheless, there is not enough information
to answer this question.
It is important to note that individual differences exist in responses to coffee.
Some people are more sensitive to the effects than others. Part of such variability
is due to tolerance, but there are indications that it might have a genetic basis
as well [81]. Another interesting fact is that males and females differ in their responses to
caffeine and that these differences may be mediated by changes in circulating steroid
hormones [82]. In most people, moderate coffee consumption of up to 4 cups of coffee per day (around
400 mg caffeine) can be enjoyed as part of a healthy, balanced diet and an active
lifestyle. Lower levels are recommended for pregnant women who are advised to limit
caffeine intake to 200 mg from all sources, as well as in children where the intake
should be reduced because of a lower body weight [83]. Finally, there is a need for well-designed, randomized, controlled trials further
investigating the effect of different doses of coffee or coffee bioactive components
on healthy individuals as well as on patient populations to clarify important points
discussed controversially in the literature.
