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Endocrine, Metabolic & Immune Disorders - Drug Targets, 2015, 15, 000-000
Mediterranean Diet
The Moli-sani Study
and
Low-grade
Subclinical
1
Inflammation:
Marialaura Bonaccio*, Chiara Cerletti, Licia Iacoviello and Giovanni de Gaetano
Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo NEUROMED, Pozzilli (IS),
Italy
Abstract: Low-grade chronic inflammation is an underlying pathophysiological mechanism linking risk factors and/or
metabolic disorders to increased risk of chronic degenerative disease. A meat-based pattern, as the Western type diet, is
positively linked to higher levels of some important biomarkers of inflammation, such as C-reactive protein (CRP),
interleukin-6 and fibrinogen. Conversely, a Mediterranean-like eating behavior is associated with lower degree of these
biomarkers thus suggesting an anti-inflammatory action of its main food components. This chapter goes through the most
important investigations addressing the relationship between dietary habits and subclinical inflammation. Attention was
focussed on the findings from the Moli-sani study: this is a large prospective cohort study that recruited 24,325 men
and women from the general population of the Molise Region, a Southern Italian area, with the aim of investigating
genetic and environmental risk/protection factors for cardiovascular and tumor disease. For the first time, the Moli-sani
study carefully investigated the Mediterranean diet as an environmental determinant of both platelet and white blood cell
counts, starting from the hypothesis that a diet rich in healthy compounds could favorably influence the production and/or
the clearance of these two cellular biomarkers of low-grade inflammation. Additionally, evidence from this large Italian
cohort showed that a Mediterranean-like diet was closely associated with relatively lower values of glucose, lipids, CRP,
blood pressure and 10-year cardiovascular risk, while the consumption of healthy foods with high rather than low content in
antioxidant vitamins and phytochemicals was associated with lower blood pressure and CRP plasma levels at least in men.
Keywords: Antioxidants, biomarkers of inflammation, cardiovascular disease, cancer, low-grade inflammation, mediterranean diet.
BIOMARKERS
OF
INFLAMMATION
CHRONIC
LOW-GRADE
Low-grade inflammation is a condition not yet
uniformely defined: several biomarkers and different levels
of their increase have been reported to be associated with a
condition of low-grade inflammation [1]. Here a low-grade
inflammation is intended as a subclinical condition (systemic
or local, often chronic) characterized by increased levels of
plasmatic and/or cellular biomarkers of inflammation (e.g.
C-reactive protein, platelet or leukocyte counts) without any
apparent clinical sign. In the absence of an acute
inflammatory condition (e.g. CRP <10 mg/L or WBC <=10
x109/L), a low-grade inflammation may reflect different
degrees of variance within the normal range of each specific
biomarker.
A low-grade inflammation has also been defined as an
underlying pathophysiological mechanism linking risk
factors or metabolic disorders (as oxidative stress, obesity,
diabetes, dyslipidemia, etc.) to an increased risk of chronic
degenerative disease [1]. C-reactive protein is the beststudied marker of subclinical inflammation [2] but several
other inflammatory biomarkers have been associated with
*Address correspondence to this author at the Department of Epidemiology
and Prevention, IRCCS Istituto Neurologico Mediterraneo NEUROMED,
Pozzilli (IS), Italy, Via dell'Elettronica, 86077 POZZILLI (IS), Italy;
Tel: +39.0865.929.653; Fax: +39.0865.927.575;
E-mail: marialaura.bonaccio@moli-sani.org
1871-5303/15 $58.00+.00
low-grade inflammation. Increased levels of interleukins,
fibrinogen and the adhesion molecules E-selectin, intercellular
adhesion molecule-1 (ICAM-1), and vascular adhesion
protein-1 (VCAM-1), have been shown to be directly
associated and to predict type-2 diabetes, cardiovascular
disease and cancer; conversely, levels of anti-inflammatory
biomarkers, such as adiponectin, have been associated with
the reduction of cardiovascular disease, type-2 diabetes, and
obesity-related cancer [1].
A fatty meal may represent an acute in vivo challenge
that induces a low-grade inflammatory reaction. In a group
of subjects at different degree of cardiovascular risk, the
post-prandial condition, characterized by acutely elevated
levels of triglyceride-rich lipoproteins, was accompanied by
significant changes in haematological parameters: increased
white blood cell counts, in particular granulocytes, increased
platelet count and decreased mean platelet volume [3, 4].
The changes were statistically significant, although in a
small range of differences, and were accompanied by the
cell surface expression of activation markers and
myeloperoxidase degranulation within granulocytes. The
post-prandial state, a physiological phenomenon that may
occur several times a day, could lead to a complex series of
events (including endotoxemia) that may initiate and develop
atherothrombosis.
The occurrence of similar predictive biomarkers in
conditions and diseases being apparently different for their
pathogenesis, such as vascular diseases and cancer, together
© 2015 Bentham Science Publishers
2 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2015, Vol. 15, No. 1
Bonaccio et al.
with additional pharmacological and epidemiological
evidence, supports the hypothesis of a common soil underlying
the pathogenetic mechanisms involved [5].
frequency questionnaire [17, 18] was administered to all
subjects, allowing analyses of diet and dietary components
association with different biomarkers and incidence of
diseases at follow-up.
MEDITERRANEAN DIET AND
CHRONIC INFLAMMATION
One of the very first findings from this large communitybased study was the relationship between different dietary
patterns and well-known markers of inflammation or risk
factors [19]. The so-called a posteriori approach was used in
this type of analysis, a data-driven way which basically
allows to put together a list of specific food groups in a way
reflecting the actual dietary habits of the study population.
This approach differs from the a priori scores which are
more oriented to test whether the eating behavior of people
does reflect a pre-defined ideal way of eating.
LOW
GRADE
The relationship between low-grade inflammation and
dietary habits has been investigated by either single nutrient
or food approaches but recent evidence suggests that the diet
as a whole is more effective in accounting for the beneficial
health outcomes documented [6].
Epidemiological studies support the evidence of an
association between dietary patterns and biomarkers of
inflammation, as summarized in the recent systematic review
by Barbaresko and coworkers [1].
A meat-based pattern, as the Western type diet, is
positively linked to higher levels of some important
biomarkers of inflammation, such as CRP, interleukin-6 and
fibrinogen. Conversely, a Mediterranean-like eating behavior
is associated with lower degree of these biomarkers thus
suggesting an anti-inflammatory action of its main food
components.
The traditional Mediterranean diet (MD) was originally
defined by the American scientist Ancel Keys who firstly
described the dietary behavior of the Mediterranean people
living in Southern Italy whose consumption of some
particular foods was more frequent as compared to other
populations [7]. Moreover, the number of cardiovascular
deaths within that Mediterranean population was much lower
than that recorded in the United States [8] and vital statistical
data were confirmatory, e.g., Italian CHD death rates for
middle-aged men in 1960 being less than half that for
U.S. men [9]. These facts led Keys to reason for a possible
link between dietary behavior and risk of coronary heart
disease.
The MD is characterized by a wide consumption of plant
foods, cereals, legumes, fish, nuts, olive oil as the main fat
sources and moderate wine consumption [10, 11].
Since Keys’ first investigation, a large body of evidence
has linked the MD to reduced risk of major chronic diseases,
such as cardiovascular and cerebrovascular disease, tumours
and neurodegenerative disease [12]. The beneficial effects of
MD on health have been basically ascribed to its high
content of antioxidants, fibre, monounsaturated and
polyunsaturated fatty acids (PUFA) [13]. In particular,
antioxidants and polyphenols have been shown to exert a
positive role against ischemic vascular disease mainly due to
their anti-inflammatory properties [14, 15].
PEOPLE
EAT
FOODS
NOT
NUTRIENTS:
MEDITERRANEAN DIET AS A WHOLE
Moli-sani is a prospective cohort study which has
recruited 24,325 men and women from the general
population of the Molise Region, a Southern Italian area,
with the aim of investigating genetic and environmental
risk/protection factors for cardiovascular and tumor diseases
[16]. In this study, the Italian version of the EPIC food
In the study by Centritto et al. [19], the following three
dietary patterns generated by principal component analysis
(PCA) were identified.
A “Mediterranean-type” pattern was characterized by
high combined intake of olive oil, vegetables, legumes,
soups, fruits and fish, and was basically comparable to what
is commonly defined as a MD-style.
A second pattern was the “Western-type” characterized
instead by high consumption of pasta with tomato sauce, red
meat, animal fats and alcohol and was somehow considered
as an Italian version of the Western-type diet most popular in
Western countries.
An “Eggs and Sweets” pattern presented positive
loadings of eggs, processed meat, margarines, butter, sugar
and sweets.
These three dietary models were then analysed in relation
to a wide panel of well recognized markers of inflammation
and to a series of risk factors for major chronic diseases.
The Mediterranean-type eating behavior was closely
associated with relatively lower values of glucose, lipids, Creactive protein, blood pressure and cardiovascular risk.
Conversely, subjects adhering most to the Western-type
pattern showed higher glucose, lipids, C-reactive protein and
cardiovascular risk score, whereas the Eggs and Sweet type
had significantly higher levels of C-reactive protein.
Similar findings from the ATTICA study [20] reveal that
levels of some crucial markers of inflammation and
coagulation were significantly lower in healthy adults
reporting higher adherence to the MD. The group sticking
the most to this pattern reported lower levels of CRP, IL-6,
homocysteine and fibrinogen and lower white blood cell
count as compared with those in the lowest adherence group.
Possible mechanisms underlying the beneficial effects
deriving from following a Mediterranean-like diet have been
ascribed to the high antioxidant content of the foods typical
of this eating behavior.
The protective role of antioxidant compounds, included
in a healthy dietary pattern such as the Mediterranean diet,
on blood pressure levels and hypertension has been
established in epidemiological studies and clinical trials [21,
22]. For instance, vegetarians, whose antioxidant vitamins
and phytochemicals consumption is particularly high, tend to
have lower blood pressure than non- vegetarians [23].
Mediterranean Diet and Low-grade Subclinical Inflammation
Endocrine, Metabolic & Immune Disorders - Drug Targets, 2015, Vol. 15, No. 1
A study considered within the Moli-sani cohort provides
further support to the role played by dietary antioxidants
[24]. In a total of 6,879 women and 6,892 men from the
cohort, the consumption of healthy foods with high rather
than low content in antioxidant vitamins and phytochemicals
was associated with lower blood pressure and CRP plasma
levels in men, whereas these associations were not apparent
in women. In men, an increase in the food antioxidant
content, which represents an increased consumption of
high antioxidant content with respect to low antioxidant
content foods, was associated with a decrease in systolic and
diastolic blood pressure and CRP levels [24]. The possible
greater protective role of healthy foods with high as
compared with low antioxidant content foods on hypertension
and inflammation stresses the importance of studying healthy
foods according to their content in antioxidant vitamins and
phytochemicals, in primary prevention of cardiovascular
disease [24].
INTERVENTION STUDIES WITH MEDITERRANEAN
DIET
The relationship between diet and inflammatory markers
has also been investigated in intervention studies. In a small
trial performed on Swedish subjects, Ambring and
colleagues [25] tested whether a Mediterranean-inspired diet
provided to healthy subjects would affect either the
inflammatory process, endothelial indexes such as
vasoregulation and vascular endothelial growth factor
(VEGF) or serum phospholipid fatty acid composition. A
total of 22 subjects (10 women) received a Mediterraneaninspired diet or an ordinary Swedish diet for 4 weeks in a
crossover way. The Mediterranean-inspired diet was able to
reduce the number of leukocytes and platelets by 10% and
15%, respectively, and VEGF levels by about 15%. Neither
C-reactive protein nor IL-6 concentrations were changed
significantly and this has been ascribed to a relatively low
degree of vascular inflammation in these healthy subjects
[25]. Consistently, in a similar intervention study in patients
with metabolic syndrome and higher CRP concentrations,
the Mediterranean diet improved endothelial dysfunction
and reduced markers of vascular inflammation [26]. The
observed positive outcomes were attributed to the higher
concentrations of n-3 fatty acids, which promote a favorable
composition of phospholipids and are largely present in
seafood and nuts.
Recent studies turned attention to subclinical inflammation
in adolescents, with particular regard to obese kids for whom
the adipose tissue represents a favorable condition for a lowgrade inflammation to occur [27]. In 12- to 17-year old
Spanish girls’ measures of adiposity (BMI and waist to hip
ratio) were significant predictors of plasma levels of markers
of inflammation such as leptin and hs-CRP [28] whereas
concentrations of adiponectin were positively linked to a
Mediterranean dietary pattern.
Although, the observed relationship was mainly mediated
by fat mass (BMI) and body fat distribution (WtHR), the diet
may modulate the association between adiposity and
subclinical inflammation. The relatively poor accounting of
diet may be ascribed to the fact that the association between
nutrients and inflammation has been usually investigated
3
within populations affected by disease or at high risk of
certain diseases. Studies in healthy adults are scarce and just
lately this research question has been addressed in largescale populations of healthy adolescents. Indeed, this study is
of importance since is one of the first addressing the
relationship between subclinical inflammation and diet in
adolescent healthy subjects.
INSIDE THE MEDITERRANEAN DIET: ANY ROLE
OF SINGLE FOODS FROM THE PYRAMID?
Although MD should be considered as a whole, a “single
food approach” was often used to test possible associations
with low-grade inflammation, in apparently healthy
individuals or in subjects at different cardiovascular risk. In
these studies, beside the traditional Mediterranean dietary
components, other polyphenol and flavonoid-rich foods (and
beverages) such as cocoa, coffee and tea have been
investigated. Coffee, tea and chocolate seem to exert their
optimal favorable effects on cardiovascular risk profile
following a regular and moderate consumption, while
healthy outcomes vanish at large consumption [29].
A study by Di Giuseppe et al. [30] has shown the
beneficial properties of intake of dark chocolate against lowgrade inflammation, defined as high plasma levels of CRP. A
J-shaped relationship between dark chocolate consumption
and serum CRP was observed: consumers of up to 1 serving
(20 g) of dark chocolate every 3 days had serum CRP
concentrations significantly lower than either nonconsumers or higher consumers.
Another food item that has attracted great scientific
interest is red wine, a rich source of antioxidant and antiinflammatory polyphenols. In a prospective randomized
crossover study by Estruch and coworkers [31], the different
effects of red wine and polyphenol-free gin consumption
were compared. Forty healthy men consumed 30 g of ethanol
per day as either wine or gin for 28 days. Both wine and gin
showed anti-inflammatory effects by reducing plasma
fibrinogen and IL-1alpha levels. However, wine had the
additional effect of decreasing hs-CRP (-21%), VCAM-1
(-17%) and ICAM-1 (-9%), as well as monocyte and
endothelial adhesion molecules.
In another study, regular wine consumption was able to
prevent acute toxicity in patients undergoing radiotherapy
after conservative surgery for breast carcinoma. The daily
amount of alcohol intake influenced the incidence of skin
toxicity, with an incidence of 38.4% in patients with no wine
intake, 31.8% in patients drinking half a glass per day,
13.6% in patients drinking one glass per day, and 35.0% in
patients drinking two glasses per day [32].
RECENT INSIGHTS FROM THE MOLI-SANI
STUDY: MEDITERRANEAN DIET, WHITE BLOOD
CELL AND PLATELET COUNTS
A direct association between white blood cell count and
increased morbidity and mortality for ischemic vascular
disease has been observed for more than half a century [33].
From numerous epidemiological studies and meta-analyses
the risk of coronary heart disease, and of different end-
4 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2015, Vol. 15, No. 1
Bonaccio et al.
points, was significantly greater in subjects with higher
WBC count than in those with lower WBC count (all values
being within the normal range) [34].
trends across the categories of coronary risk after
adjustments (for age, gender, race, BMI, and various comorbidities).
The Baltimore longitudinal study investigated the secular
trend in WBC count and its relationship with mortality
between 1958 and 2002: a downward trend, independent of
age, gender, race, smoking, BMI, physical activity, was
linearly associated with cardiovascular mortality and nonlinearly with all-cause mortality; participants with > 6,000
WBC/µL had higher mortality than those with 3,500-6,000
cells/uL [35].
Patients undergoing percutaneous coronary interventions
in the higher tertile of platelet count measured at baseline
reported a small but significant increase in the risk of 30-day
mortality, in respect to patients in the lowest tertile.
However, the 30-day incidence of major adverse cardiac
events did not differ significantly according to tertiles of
platelet count [43].
A high WBC count also predicts greater risk of
reinfarction and of in-hospital death after coronary bypass
graft [36].
In the Lyon Diet Heart Study, a secondary prevention
trial, the number of leukocytes was shown to be linked to
cardiovascular disease risk [37].
Also in conditions of leukocytosis as in patients with
polycytemia vera, WBC count was directly associated with
major thrombotic risk, with hazard ratios of 1.71 (1.10-2.65)
and 2.84 (1.25-6.46) for risk of thrombosis and myocardial
infarction, respectively, in subjects with leukocyte count
>15x 109/L vs. <10x 109/L [38].
The predictive value of WBC count is plausible as these
cells make a major contribution to the rheologic properties of
blood, alter adhesive properties under stress, including the
stress of ischemia, enhancing their rheologic importance,
participate in endothelial injury, both acutely and
chronically, by adhering to endothelium and damaging it
with toxic oxygen compounds and proteolytic enzymes,
interact with platelets, contributing to their activation and
release of bioactive compounds.
It will therefore be interesting to verify in future
studies whether conditions that modify the leukocyte
number, may also affect other markers of low grade chronic
inflammation.
At variance with leukocyte count, a very scarce
epidemiological evidence is available on platelet count and
risk of vascular disease, although inhibition of platelet
function activation is effective in preventing secondary
cardiovascular events [39].
Platelet count has been associated with vascular and nonvascular death, including cancer [39, 40]. More recently, precancer platelet count was found to be significantly associated
with risk of symptomatic venous thromboembolism in cancer
patients, but not in cancer-free subjects leading to speculate
that platelet count and platelet-leukocyte interactions may
have a role in the pathogenesis of cancer-related venous
thromboembolism [41].
Park et al. [42] in a large representative sample of the
United States population, identified a positive, independent,
and dose-dependent relation between systemic inflammatory
markers and the degree of estimated 10-year risk for
coronary artery disease, categorized according to the
Framingham risk score. Besides inflammatory markers
already identified (CRP, fibrinogen, homocysteine and
leukocytes), platelet levels showed significantly positive
In the Moli-sani study, white blood cell count has
been shown to be one of the main determinants of platelet
count variability, together with CRP and D-dimer levels,
independent of age and sex [44].
Starting from this original observation and from the
recognized role of platelets in inflammation, researchers
from the Moli-sani study carefully investigated the association
of a Mediterranean diet with platelet or white blood cell
counts based on the hypothesis that a diet rich in healthy
compounds could favourably influence these two cellular
biomarkers of low-grade inflammation in subjects without
any overt chronic or hematological disease [45].
Platelet and WBC ranges were set according to normal
values recently established for the Italian population [46];
this means that low or high platelet or WBC categories did
not indicate any pathological value (Table 1).
Results clearly showed that a better adherence to a
Mediterranean dietary pattern was significantly associated
with reduced WBC and platelet counts, independently of
other known inflammatory markers such as CRP (Fig. 1).
Moreover, subjects reporting a higher adherence to this
eating pattern revealed reduced odds of being in the highest
platelet count group compared to those with lower
adherence. Similarly, maximum adherence to MD was also
linked to greater chances of having low WBC count. The
associations observed between diet and the levels of these
two inflammatory cells were partially explained by the high
content of both antioxidants and fiber typical of a
Mediterranean-style behavior. The findings are in line with
the results, already mentioned, of an intervention study
showing that a MD eating pattern was directly linked to a
lowering in some markers of inflammation, including
platelets and WBC [23].
The favorable accounting of antioxidants is strictly
related to reducing oxidative stress, an important
intermediate mechanism of disease. This issue has been
addressed in a well- controlled study of twins aimed at
investigating the association of the Mediterranean diet and
oxidative stress in which an established plasma marker of
oxidative stress, namely the ratio of reduced to oxidized
glutathione (GSH/GSSG), was considered. The association
between the Mediterranean diet and the decreased oxidative
stress was robust and not confounded by genetic or shared
environmental factors and represents a plausible mechanism
linking the Mediterranean diet to reduced cardiovascular
disease risk [47].
The already mentioned changes in platelet and white
blood cell counts induced by a standardized fatty meal [4]
Mediterranean Diet and Low-grade Subclinical Inflammation
Table 1.
Endocrine, Metabolic & Immune Disorders - Drug Targets, 2015, Vol. 15, No. 1
5
Mean values of biomarkers of low-grade inflammation in a healthy Moli-sani population (n= 14,586) according to
categories of adherence to the Mediterranean diet as measured by the Italian Mediterranean index.
Adherence to the Mediterranean diet
C-reactive protein (mg/L)
9
Platelets (x 10 /L)
White blood cells (x 109/L)
9
Neutrophil/lymphocyte ratio (x 10 /L)
Low
Low-medium
Medium-high
High
1.41 (1.36-1.46)
1.35 (1.30-1.39)
1.36 (1.33-1.40)
1.33 (1.29-1.38)
252.0 (62.4)
252.1 (64.4)
249.0 (62.0)
246.8 (59.9)
6.33 (1.72)
6.31 (1.97)
6.18 (1.55)
6.15 (1.56)
2.11 (1.48)
2.05 (0.83)
2.00 (0.78)
1.98 (0.75)
Values are reported as means± standard deviation and are controlled for age and sex. C-reactive protein is reported as geometric means with corresponding 95% confidence intervals.
All p values<0.05 (Elaborated from data reported in reference 45).
Fig. (1). Each line (vertical axes) indicates mean platelet or leukocyte counts, respectively. Categories of adherence to the Mediterranean diet
as measured by the Mediterranean diet score are reported in the horizontal axis. There was an inverse relationship between adherence to this
eating pattern and the number of both platelets and white blood cells (Elaborated from data reported in reference 45).
were in the ranges of the cell count variations observed in
concomitance with different degrees of adhesion to the
Mediterranean diet. Whether the Mediterranean diet could
modulate the consequences of the oxidative stress, due to an
occasional fatty meal intake, remains to be established by
appropriate studies. It was recently observed that orange
juice consumption by healthy subjects during a fatty
meal reduces the postprandial low-grade inflammatory
response [48] by blunting the leukocyte count increase
and myeloperoxidase release occurring after a fatty meal
ingestion. This is suggestive and encouraging towards
possible mechanism(s) explaining the beneficial effects of
the Mediterranean diet and its prevention or modulation of
the low-grade inflammation status, present in subjects at
different degree of cardiovascular risk.
CONCLUSIONS
Studies conducted so far have shown that different diets
are strictly linked to different degrees of low-grade
inflammation. Dietary behaviors may act by modulating the
levels of several inflammatory markers, from the most wellknown such as C-reactive protein, interleukin-6 or leukocytes,
to the newest one as the platelet count.
There is an ample consensus on the favorable effect
of a Mediterranean-type eating, rich in antioxidants, fiber
and healthy fats, on reducing these inflammatory biomarkers.
At variance, Western-like or meat-based diets provided
detrimental health-outcomes possibly due to their direct link
to increased low-grade chronic inflammation. As mentioned
above, future prospective studies should shed light on
6 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2015, Vol. 15, No. 1
whether dietary patterns may yield positive changes in
biomarkers of inflammation over time.
[15]
CONFLICT OF INTEREST DISCLOSURES
None of the authors has a personal or financial conflict of
interest.
ACKNOWLEDGEMENTS
The enrolment phase of the Moli-sani Project was
performed at the Research Laboratories, Catholic University,
Campobasso, Italy and was supported by unrestricted
research grants from Pfizer Foundation (Rome, Italy) and the
Italian Ministry of University and Research (MIUR, Rome,
Italy)–Programma Triennale di Ricerca, Decreto no.1588.
Pfizer Foundation and MIUR had no role in study design,
collection, analysis, and interpretation of data and in the
writing of this review. All Authors were and are independent
from funders. The MOLI-SANI research group thanks IL
Laboratory (Milano) for their generous supply of instruments
and reagents.
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