Design of polyphenol-rich diets in clinical trials: A systematic review

Food Research International 149 (2021) 110655

Available online 20 August 2021

(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Review

Luis Condezo-Hoyos

, Christina Gazi

, Jara P

erez-Jim

enez

Department of Metabolism and Nutrition, Institute of Food Science, Technology and Nutrition (ICTAN-CSIC), Madrid, Spain

Universidad Nacional Agraria la Molina, Facultad de Industrias Alimentarias, Innovative Technology, Food and Health Research Group, La Molina, Lima, Perú

ARTICLE INFO

Keywords:

Polyphenols

Clinical trial

Systematic review

Healthy diet

ABSTRACT

Most randomized clinical trials of polyphenols focus on individual foods. Nevertheless, due to their presence in

many foods and in order to reect a real situation, clinical trials based on polyphenol-rich diets are particularly

important. This systematic review explores the characteristics of the polyphenol-rich diets used in intervention

studies. The bibliography search for English-language scientic papers was performed in the Elsevier Scopus

Database and PUBMED in March 2020, and focused on intervention studies with whole polyphenol-rich diets,

establishing several exclusion criteria. In studies fullling the requirements, information on the design of the

polyphenol-rich diet and associated polyphenol intake was extracted and compared. A total of 5 studies were

selected. Among them, substantial differences were found in the design of the polyphenol-rich diets, regarding

specic instructions and concerning the foods provided. Similarly, although a median daily polyphenol intake of

2,564 mg/day (17,945 mg/week) was obtained from the studies, which corresponds to a nutritional dose, intake

values varied widely both for total polyphenols (the difference between studies reached threefold), and for in-

dividual polyphenol intake (for hydroxycinnamic acids, a tenfold difference was found between percentile 25

and percentile 75 values). These differences made the comparison of results difcult and may affected the

observed health effects. Thus, despite the relevance of studying polyphenol-rich diets as a whole, this systematic

review found substantial differences between the studies performed, making direct comparisons difcult.

1. Introduction

Polyphenols constitute a large group of plant secondary metabolites

widely distributed throughout the plant kingdom (Rodriguez-Mateos

et al., 2014). They exhibit several biological activities, for instance

functioning as antioxidants (Morvaridzadeh et al., 2020a) and anti-

inammatory compounds (Morvaridzadeh et al., 2020b). Cumulative

scientic evidence, including the results of mechanistic experiments,

assessments of metabolic fate, clinical trials and observational studies,

has shown that these compounds play a promising role in the modula-

tion of several non-communicable chronic diseases, particularly car-

diometabolic diseases (Serino & Salazar, 2018; Martini et al., 2019), as

well as certain kinds of cancer (Bondonno et al., 2019), neurodegener-

ative processes (Squillaro et al., 2018) and specic diseases such as

polycystic ovarian syndrome (Heshmati et al., 2020).

However, research on polyphenols has sometimes apparently been

contradictory as demonstrated, for instance, in two systematic reviews

of the role of grapes (one of the fruits with the highest polyphenol

content) in the regulation of metabolic syndrome (Akaberi & Hossein-

zadeh, 2016; Woerdeman et al., 2017). It has been suggested that con-

sistency in several aspects when designing and performing nutritional

clinical trials would eliminate some of these discrepancies; for instance,

clearly dening clinical endpoints when translating preclinical studies

on polyphenols into clinical trials (Nú

nez-S

anchez et al., 2015). In the

same way, some studies have suggested certain criteria for reporting

results of inter-individual variability in the response to bioactive dietary

compounds, a highly relevant aspect in the eld of polyphenols (Nikolic

et al., 2019), as well as for study design and analytical determinations in

studies on the biological effects of bioactive compounds, including

polyphenols, on gene expression (Pokimica & García-Conesa, 2018).

Also, the importance of systematically measuring microbiota variations

in clinical trials with polyphenols has been addressed (Marino et al.,

2020). Overall, the increasing interest in recommendations on how

polyphenol studies should be conducted or reported shows the relevance

of study design and how it is an aspect that deserves specic attention.

Another relevant aspect is that many clinical trials with polyphenols

* Corresponding author at: Department of Metabolism and Nutrition, Institute of Food Science, Technology and Nutrition (ICTAN-CSIC), Jos

e Antonio Novais 10,

28040 Madrid, Spain.

E-mail address: [email protected] (J. P

erez-Jim

enez).

Contents lists available at ScienceDirect

Food Research International

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

https://doi.org/10.1016/j.foodres.2021.110655

Received 17 March 2021; Received in revised form 27 July 2021; Accepted 17 August 2021

Food Research International 149 (2021) 110655

have evaluated the effect of supplementation with an individual food

(Akaberi & Hosseinzadeh, 2016; Gianfredi et al., 2018; Woerdeman

et al., 2017). Although such studies are absolutely needed for the

identication of responses to individual foods, at the same time the ef-

fect of the whole diet may not be disregarded. Indeed, it has been

pointed out that the combination of polyphenols from different foods is

precisely what can give rise to biological activities (de Pascual-Teresa &

Clifford, 2017). And a study (Molinar-Toribio et al., 2018) where rats

consuming either a control diet of a high-fat high-sucrose diet were

supplemented with grape seed extract showed that the generation of

microbial-derived metabolites was decreased in the high-fat high-su-

crose group, probably due to a shift in microbial communities. This

might show modied biological activities of a particular polyphenol

supplementation in the context of an unhealthy dietary pattern. For

these reasons, some researchers have chosen to evaluate the effect of a

polyphenol-rich diet (Bozzetto et al., 2015; Noad et al., 2016); they have

shown benecial effects in subjects at high cardiometabolic risk, which

has increased the existing evidence on the biological relevance of

polyphenols. Nevertheless, the issue of heterogeneity in the design also

arises here, for example: What may be considered a polyphenol-rich

diet? Which individual foods are included? In what proportions? How

detailed must the instructions provided to the volunteers be? All these

aspects are relevant when it comes to comparing results, as well as in

order to establish public health recommendations; but to date, they have

not been explored in detail.

For these reasons, we consider it is pertinent to perform a systematic

review of nutritional clinical trials based on polyphenol-rich diets. The

aim of this systematic review is not to address a specic clinical ques-

tion, since the selected studies may have dealt with different physio-

logical situations and focused on varied primary outcomes, but to focus

on the concept of a polyphenol-rich diet itself and how it has been

dened in previous studies (foods, serving sizes and associated poly-

phenol intake), in order to identify the main shared characteristics and

divergences between them and, ultimately, to suggest criteria that will

allow consistency in this kind of study. Therefore, the question we

address here is: “How are polyphenol-rich diets designed in nutrition

clinical trials?” We adopted an established PICOS approach, as dened

below. Quantitative data on polyphenol content in the designed diets

were integrated from the different studies and an overall analysis was

carried out; nevertheless, since these data did not correspond to modi-

cations in a clinical outcome, this not a meta-analysis.

2. Methods

This systematic review was conducted according to PRIMSA guide-

lines; although, as it did not deal with a specic clinical question, some

aspects could not be adopted. The complete PRISMA checklist is pro-

vided as Supplementary Table 1.

2.1. Search strategy and study selection

The bibliographic databases Elsevier Scopus Database and PUBMED

were systematically searched for relevant papers until March 2, 2020.

No other sources were included.

The following PICOS parameters were applied: Participants, adults;

Intervention, treatment with polyphenol-rich diet; Comparison, inter-

vention treatment with low-polyphenol diet; Outcome, since the focus of

the systematic review was the design of the polyphenol-rich diet, no

clinical outcome was predened; Study design, only intervention studies

were selected.

The rst step of the systematic search was performed with the

following keyword combinations “polyphenol*” AND “diet” AND

(“trial” OR “intervention”) AND “human” and the papers returned were

exported to Endnote software (Clarivate Analytics, PA, USA) with

duplicated papers being eliminated. Once in Endnote, the titles of papers

were screened for two inclusion criteria: I) trial OR intervention AND

diet; and II) poly* OR av* OR phe*. After this, the abstracts were

analyzed based on the following inclusion criteria: 1) an original study;

2) conducted in humans; 3) an intervention study, including either

randomized controlled trials (2 arms with and without intake of a

polyphenol-rich diet) or before-and-after studies (one arm following a

polyphenol-rich diet for a certain period); 4) evaluating the effect of a

polyphenol-rich diet; 5) published in English; and 6) data presented in a

usable format. Conversely, the following exclusion criteria for this step

were dened: 1) reviews; 2) preclinical studies; 3) observational studies;

4) studies based on supplementation with a single food or additive; 5)

languages other than English; 6) absence of extractable data (see below).

2.2. Quality assessment

The JADAD score evaluation system was applied for assessment of

the methodological quality of the 5 clinical trials selected (Reis et al.,

2019). The studies were scored according to key methodological fea-

tures: randomization (R), sequence of randomization (SR), blinding (B),

method of blinding (MB), withdrawals/dropout (WD), inappropriate

randomization (IR) and inappropriate blinding (IB) (Bisol et al., 2020).

The studies with a JADAD score ≥ 3 were considered to have high-

quality methodology (Bisol et al., 2020).

2.3. Data collection

Data were extracted from the clinical trial studies selected with a

JADAD score ≥ 3; although characteristics of the study design, such as

randomization, would not affect the results of the present systematic

review, focused on diet design, at the same time it was considered that

the higher the quality of the overall study design was, the higher the

probability for the existence of a detailed and justied polyphenol-rich

diet was. The selected studies included: bibliographic data, study char-

acteristics (aim, design, and location), participants (age, sex, and char-

acteristics), and a description of the dietary intervention. Since this last

aspect is the main point of interest of this systematic review, the

following information was collected, when it was available: 1) specic

intervention concept (polyphenol-rich diet, avonoid-rich diet and

others); 2) food groups included or excluded in the diet; 3) individual

foods included or excluded in the diet; 4) instructions about number and

size of servings per day or week; 5) degree of detail in the instructions

(specic meals to be consumed, and general lists of recommended

foods); 6) expected polyphenol intake of the subjects and degree of

detail (by class or individual compounds); 7) actual polyphenol intake of

the subjects and degree of detail (by class or individual compounds); 8)

source of polyphenol content information (in-house data or public da-

tabases); and 9) follow-up strategy for assessing dietary adherence.

2.4. Data processing

The information provided on polyphenol intake in the selected

studies was quite varied: in some cases, no information on polyphenol

intake was provided (Malaveille et al., 2004), while other studies

specied the value of total polyphenol intake (Della Peppa et al., 2020)

or avonoid content in the recommended foods (Chong et al., 2013).

Due to this diversity, the only way to process all the studies together and

obtain data on individual and total polyphenol intake, in order to

address the question we have proposed for this systematic review, was to

calculate the polyphenol intake for all the studies based on the infor-

mation they provided on the study design. To do this, we used the

validated Phenol-Explorer (Neveu et al., 2010) and USDA (Bhagwat &

Haytowitz, 2007) databases, which provide composition data for thou-

sands of individual foods from the literature, and we took into account

the amount of individual foods consumed weekly. When the polyphenol

content of individual foods was not available in these databases, specic

research papers were used to obtain the missing information, as was the

case of rocket (Santos et al., 2014), blueberry jam (

Scibisz & Mitek,

L. Condezo-Hoyos et al.

Food Research International 149 (2021) 110655

2007), cherry tomatoes (Je

z et al., 2018) and watercress (Giallourou

et al., 2016).

In the case of the study by Chong et al., (Chong et al., 2013), since the

subjects received an additional polyphenol dose on top of their basal

intake, which was not indicated in the study, this was taken from the

quintile with the lowest polyphenol intake (since these subjects were

characterized by a low fruit and vegetable intake) determined in a

similar cohort. Furthermore, since the subjects were instructed to

consume a certain amount of fruit and vegetables distributed in several

items, but without further instructions, it was assumed that all the food

items were consumed in the same proportion. Finally, in that same study

the weight (g) was considered equal to volume (mL) for liquid foods.

Regarding the study by Malaveille et al. (2004) total and individual

polyphenols were not calculated because the intake of individual foods

was not provided.

The data for total and individual polyphenol intake from each study

were then integrated in order to obtain p25 (percentile 25), median, p75

(percentile 75), minimum and maximum values for polyphenol intake in

the studies selected. Unless expressly stated, all the results provided in

the Results section below correspond to median values.

3. Results

3.1. Search and study selection

The workow for paper selection is shown in Fig. 1A. While the

initial bibliography search of the Scopus and PUBMED databases pro-

vided a total of 1,756 publications, the application of the two inclusion

criteria to the titles and the exclusion of duplicated papers, resulted in

the identication of 33 publications for potential inclusion. From these,

reading the abstract and application of the six additional exclusion

criteria explained above nally left us with just 5 nutritional interven-

tion studies for our systematic review (Fig. 1A). The JADAD score of

each of these selected publications was 3 or 4 (Fig. 1B), reecting a high-

quality methodology.

3.2. Nutritional intervention studies

Characteristics of the selected nutritional studies are summarized in

Table 1. The interventions lasted from 8 to 12 weeks using mostly ran-

domized, controlled, parallel, single-blinded designs. The studies were

focused on several primary and secondary outcomes; four of the ve

studies selected found that the polyphenol-rich diet signicantly

improved the primary outcome established in each case.

Regarding subject characteristics, excepting one study (Malaveille

et al., 2004) where inclusion criteria did not consider cardiovascular risk

factors, ie., it was focused on male smokers of at least 15 cigarettes/day

for the last 10 years, the other ones considered some aspects related to

cardiovascular risk. Thus, they included both male and female subjects,

aged at least 30 and with a limit between 65 and 70 years old. And,

depending on the study, they should have some cardiovascular risk:

hypertension; overweight/obesity alone or combined with another fac-

tor of Metabolic Syndrome; cardiovascular risk according to Framing-

ham score

3.3. Polyphenol sources in the nutritional intervention studies

Once information on the diet in the selected studies was compiled, it

was possible to establish the food groups and individual food items

recommended to the volunteers in those studies. This information is

shown In Fig. 2. Fruit (100%), vegetables (80%), beverages (60%) and

cocoa products (60%) were the polyphenol sources in the intervention

studies included. Regarding individual foods, oranges (60%), blue-

berries (40%), strawberries (40%) and kiwis (40%) were the most

common fruit, while onion (80%), rocket (40%), spinach (40%), cab-

bage (40%) and tomato (40%) were selected as the richest polyphenol

sources in the vegetable group. In relation to the beverage intake,

decaffeinated green tea and coffee (40%) were the sources of poly-

phenol. Other specic food products were extra virgin olive oil (40%)

and dark chocolate (60%).

3.4. Intake of total polyphenols and main polyphenol classes in the

nutritional intervention studies

From the dietary recommendations given to the participants in the

studies included in our review, it was possible to establish the range of

total polyphenol intake as well as the intake of the different polyphenol

classes for each study, as shown in Fig. 3. Total polyphenol intakes

ranged from 11,394 (p25) to 27,060 (p75) mg/week, with a median

value of 17,945 (Fig. 3A), which we categorized into three polyphenol

groups according to the amount consumed: high, intermediate and low

(Fig. 3B-D). In the high group (Fig. 3B), hydroxycinnamic acids (4,659

mg/week) were the predominant polyphenol class, followed by avo-

nols (4,144 mg/week), avanols (1,593 mg/week), hydroxybenzoic

acids (880.1 mg/week), anthocyanins (239 mg/week), and proantho-

cyanidins (>100 mg/week). In the intermediate intake category, the

polyphenol classes present were avanones (45.3 mg/week), tyrosols

(35.3 mg/week) and avones (8.7 mg/week) (Fig. 3C). Finally, the

polyphenol classes with low intake were lignans (4.95 mg/week),

alkylmethoxyphenols (3.78 mg/week), stilbenes (0.725 mg/week), and

dihydrochalcones and isoavones (0.0 mg/week) (Fig. 3D). It should be

highlighted that most polyphenol classes showed considerable data

dispersion (for instance, for hydroxycinnamic acids, p25 was 301.1 mg/

week and p75 was 12,370 mg/week; and in avonols, these values were

353.1 and 7,288 mg/week), which may lead to different physiological

effects on individuals, all of whom were subjected to an overall high

polyphenol intake. In contrast, in some classes such as avanols, the

values were much more tightly grouped, with a p25 value of 853.3 mg/

week and a p75 value of 2,156 mg/week.

3.5. Intake of individual polyphenols in the nutritional intervention

studies

We obtained the mean intakes for individual polyphenols in the

different polyphenol classes in the studies included, and they are rep-

resented in Figs. 3-6. To facilitate clear data visualization, in categories

where the range of intakes for the different individual compounds were

very wide, they are represented as high, intermediate and low intake

(for instance, for hydroxycinnamic acids) or as high and low intake (as in

the case of anthocyanins).

3.5.1. Hydroxycinnamic acids

5-Caffeoylquinic acid was the hydroxycinnamic acid that was most

consumed in whole-diet intervention studies (1,742 mg/week), followed

by 3-caffeoylquinic acid (910.8 mg/week) and 4-caffeoylquinic acid

(846.2 mg/week) (Fig. 4A-1). The intermediate group of hydroxycin-

namic acid intake included 4-feruloylquinic acid (133.1 mg/week), 5-

feruloylquinic acid (125.8 mg/week), 4,5-dicaffeoylquinic acid (116.8

mg/week), ferulic acid (106.2 mg/week), 3,4-dicaffeoylquinic acid

(105.7 mg/week) and 3,5-dicaffeoylquinic acid (88.76 mg/week)

(Fig. 4A-2). Finally, three individual minor hydroxycinnamic acids were

found in the intervention studies: caffeoyl glucose (0.28 mg/week),

feruloyl glucose (0.28 mg/week) and cinnamic acid (0.17 mg/week)

(Fig. 4A-3).

3.5.2. Flavonols

Quercetin (2,418 mg/week) was the main avonol present in the

polyphenol-rich diets in the intervention studies (Fig. 4B-1). In the in-

termediate consumption group, myricetin (59.4 mg/week), quercetin 3-

O-rutinoside (40.9 mg/week), kaempferol (39.3 mg/week), iso-

rhamnetin (29.1 mg/week) and quercetin 3-O-galactoside (22.2 mg/

week) were found in the dietary intervention studies (Fig. 4B-2). Minor

L. Condezo-Hoyos et al.

Food Research International 149 (2021) 110655

Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) owchart of study inclusion (A); and JADAD scores of the selected publi-

cations according to key methodological features (B).

L. Condezo-Hoyos et al.

Food Research International 149 (2021) 110655

avonols included kaempferol 3-O-galactoside (11.8 mg/week), patu-

letin 3-O-(2

′

’-feruloylglucosyl)(1->6)-[apiosyl(1->2)]-glucoside (7.3

mg/week), quercetin 3-O-glucuronide (4.5 mg/week) and spinacetin 3-

O-glucosyl-(1->6)-glucoside (3.5 mg/week) (Fig. 4B-3).

3.5.3. Flavanols

(-)-Epigallocatechin 3-O-gallate (380.2 mg/week), (-)-epi-

gallocatechin (275.7 mg/week), (-)-epicatechin (151.3 mg/week),

(-)-epicatechin 3-O-gallate (106.6 mg/week) and cinnamtannin A2

(94.2 mg/week) were the avanols with the highest intake in the dietary

interventional studies (Fig. 4C-1). While procyanidin dimer B2 (84.9

mg/week), procyanidin trimer C1 (75.5 mg/week), (+)-catechin (55.5

mg/week), (+)-gallocatechin (31.8 mg/week), and procyanidin dimer

B4 (26.9 mg/week) were identied in the intermediate intake group

(Fig. 4C-2). Finally, procyanidin dimers B1 (15.7 mg/week) and B7

(13.2 mg/week) were the minor avanols in the nutritional intervention

studies (Fig. 4C-3).

Table 1

General characteristics of the nutritional intervention studies included in this systematic review.

Diet design Study design References

Serving size Degree of detail Strategy for assessing

dietary adherence

Study type Subject characteristics Primary

outcome

Secondary

outcomes

NS Meals were prepared

by a qualied

catering service

under the supervision

of the team of

dietitians

Every week participants

were given meals and

beverages, for the

whole duration of

intervention, in

amounts sufcient to

cover overall household

needs

Randomized,

controlled,

parallel, single-

blinded

Men and women aged

between 35 and 70 years

with overweight or

obesity (BMI 27–35),

high waist

circumference (above

102 cm for men or 88 cm

for women), and at least

one more feature of the

metabolic syndrome

based on the National

Cholesterol Education

Program/Adult

Treatment Program

Postprandial

lipid response*

Glucose, insulin,

GLP-1,

microbiota,

oxidative stress

Della et al.

(2020)

Vetrani et al.

(2020)

Vetrani et al.

(2018)

Bozzetto et al.

(2015)

Based on UK Food

Standards

Agency

guidelines

6 daily portions of

F&V including one

portion of berries and

50 g of chocolate

(70% cocoa) , per

day.

The high-polyphenol

diet had a self-selected

weekly delivery of the

diet, free of charge, to

participants’ homes

from a local

supermarket. Each

participant was also

contacted by telephone

at weekly intervals

Randomized,

controlled,

parallel, single-

blinded

Men and women aged

40–65 years, with

documented grade I

(140–159/90–99 mm

Hg) or grade II

(160–179/100–109 mm

Hg) hypertension.

Forearm

blood ow

responses to an

endothelium-

dependent

vasodilator*

Blood pressure,

lipid prole,

body mass index

Noad et al.

(2016)

Green tea 400 ml,

dark chocolate

25 g, blueberry

jam 50 g,

artichokes 300 g,

onions 200 g,

spinach 150 g

and rocket 90 g

Meals were prepared

by a qualied

catering service

under the supervision

of the team of

dietitians

To improve diet

adherence, meals and

beverages were

provided to the

participants for the

whole study period in

amounts sufcient to

cover their household

consumption

Randomized,

controlled,

parallel, single-

blinded

Men and women aged

between 35 and 70 years

with overweight or

obesity (BMI 27–35),

high waist

circumference (above

102 cm for men or 88 cm

for women)

Postprandial

triglycerides*

Fasting lipid

prole, urinary

isoprostanes

Annuzzi et al.

(2014)

2 portions per day

additionally

every 6 weeks of

the study

reaching a

maximum of 6

extra portions

per day by week

Participants were

encouraged to

consume a variety of

F&V or composite

foods from the list

each week and have

equal proportions of

F&V

Participants in the

intervention groups

indicated the type and

number of additional

portions of F&V they

consumed each day on

record forms. A

minimum of two

random structured 24 h

dietary recalls

Randomized,

controlled,

parallel, single-

blinded

Male and women aged

30–70 years.

Framingham risk score

system was used for

recruitment based on

scoring a minimum of 2

points in one or more of

the following criteria:

(1) total plasma

cholesterol, (2) high-

density lipoprotein

(HDL) cholesterol, (3)

blood pressure, (4)

smoking status; (5)

obesity/adiposity and

(6) body mass index

(BMI)

Vascular

reactivity*

Plasma and

urine vitamin C,

carotenoids,

avonoids, uric

acid, antioxidant

capacity

Chong et al.

(2013);

McReady

et al. (2014)

NS The dietician

developed a food-

nutrient-intake

matrix specically

focused on

avonoids, to

quantitatively assess

the intake

All participants lled in

a food-frequency

questionnaire (FFQ) at

the beginning of the

study, and then lled in

a daily dietary diary

during the experimental

month

Randomized,

controlled,

parallel, single-

blinded

Male smokers of at least

15 cigarettes/day for the

last 10 years

Urine DNA

adducts

Urine phenolic

compounds

Malaveille

et al. (2004)

NS, non-specied.

Signicant differences (p > 0.05) were observed between low- and high- polyphenol diet, showing benecial effects of high-polyphenol diet.

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Food Research International 149 (2021) 110655

Fig. 2. Food groups and individual foods used as polyphenol sources in the nutritional intervention studies included in this systematic review.

Fig. 3. Intake of total polyphenols (A), and main polyphenol classes (B-D), calculated from diets used in the nutritional intervention studies included in this sys-

tematic review. Polyphenol contents were obtained from Phenol-Explore and USDA databases, and from some specic research papers for foods missing from those

databases. The values are expressed as mg/week.

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Food Research International 149 (2021) 110655

Fig. 4. Intake of individual hydroxycinnamic acids, avonols and avanols in the nutritional intervention studies included in this systematic review. For polyphenol

class, individual compounds were grouped as high, intermediate or low intake. The values are expressed as mg of individual polyphenol/week.

Fig. 5. Intake of individual anthocyanins in the nutritional intervention studies included in this systematic review. Individual compounds were grouped as high or

low intake. The values are expressed as mg of individual anthocyanin/week.

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Food Research International 149 (2021) 110655

3.5.4. Anthocyanins

Forty-seven individual anthocyanins were found in the polyphenol-

rich diets of the intervention studies (Fig. 5). We divided them into

two categories. The rst included those with a mean intake higher than

5 mg/week: pelargonidin 3-O-glucoside (37.2 mg/week), cyanidin 3-O-

galactoside (11 mg/week), pelargonidin 3-O-(6

′

’-succinyl-glucoside)

(8.0 mg/week), cyanidin-3-O-glucoside (10.8 mg/week), cyanidin 3-O-

glucosyl-rutinoside (8.1 mg/week), cyanidin 3-O-(6

′

’-malonyl-3

′

’-glu-

cosyl-glucoside) (6.6 mg/week), cyanidin 3-O-arabinoside (6.2 mg/

week) and cyanidin 3-O-(6

′

’-acetyl-glucoside) (4.7 mg/week). The other

anthocyanins had an intake of less than 5 mg/week. However, some

anthocyanins in the rst category, showed extremely dispersed data: for

cyanidin 3-O-rutinoside and cyanidin 3-O-glucoside, intake data ranged

from 0 to 300 mg/week.

3.5.5. Hydroxybenzoic acids

In the case of hydroxybenzoic acids, 2-hydroxybenzoic (377.6 mg/

week) was the most consumed in the dietary intervention studies

(Fig. 6A-1). 5-O-Galloylquinic acid (131.8 mg/week), gallic acid (97.8

mg/week), sanguiin H-6 (29.0 mg/week), ellagic acid (19.68 mg/week)

and lambertianin C (11.8 mg/week) were also among the most

consumed hydroxybenzoic acids (Fig. 6A-1). As minor hydroxybenzoic

acids, the study diets also contained ellagic acid glucoside (2.2 mg/

week) and 4-hydroxybenzoic acid 4-O-glucoside (2 mg/week) (Fig. 6A-

2).

3.5.6. Tyrosols, avanones and alkylmethoxyphenols

The predominant tyrosols found in the polyphenol-rich diets in the

studies were 3,4-DHPEA-EDA (57.7 mg/week), p-HPEA-EDA (32.7 mg/

week), 3,4-DHPEA-EA (16.6 mg/week), p-HPEA-EA (8.7 mg/week) and

oleuropein-aglycone (8.4 mg/week). Minor tyrosols included ligstroside

(3.6 mg/week) and ligstroside-aglycone (4.0 mg/week) (Fig. 6D). In

addition, the diets provided hesperetin (29.4 mg/week) and naringenin

(8.9 mg/week) as avanones (Fig. 6B). The only alkylmethoxyphenols

provided by the diets were 4-ethylguaiacol (6.5 mg/week) and 4-vinyl-

guaiacol (10.5 mg/week) (Fig. 6F).

3.5.7. Other minor individual polyphenols

Flavones such as apigenin (2.7 mg/week) and luteolin 7-O-glucuro-

nide (1.4 mg/week), the stilbenes resveratrol (0.4 mg/week) and

resveratrol 3-O-glucoside (0.2 mg/week), and the lignans pinoresinol

(1.9 mg/week) and 1-acetoxypinoresinol (1.5 mg/week) were all found

in the diet intervention studies (Fig. 6C, 6G and 6H).

4. Discussion

The exploration of dietary patterns as a whole is increasingly pro-

moted in the eld of nutrition, and it may be applied to the topic of

polyphenol research. However, the characteristics that a diet should

have in order to be considered as genuinely rich in polyphenols have not

been explored or discussed, despite this being a key aspect in order to be

able to compare the efciency of nutritional interventions. In the present

systematic review, we aimed to explore the specic characteristics of the

diets used in nutritional interventions focused on polyphenol-rich diets,

in order to arrive at some general recommendations for future research.

The JADAD score is considered the most valid and reliable tool to assess

the methodological quality of a clinical trial, and has been applied

throughout nutritional studies (Bisol et al., 2020; Neelakantan et al.,

2020; Roman et al., 2018). Nonetheless, some authors have identied

limitations of this system, such as not including a point for blinding

during outcome assessment, only for single blinding (McCormick et al.,

2013).

Fig. 6. Intake of individual avanols, avanones, avones, tyrosols, dihydrochalcones, alkylmethoxyphenols, stilbenes and lignans in the nutritional intervention

studies included in this systematic review. In each group of polyphenols, individual compounds were grouped as high, intermediate or low intake. The values are

expressed as mg of individual polyphenol/week.

L. Condezo-Hoyos et al.

Food Research International 149 (2021) 110655

The rst relevant observation of this study is that clinical trials

assessing the effect of a polyphenol-rich diet as a whole are scarce, since

most interventions involving polyphenols focus on extracts or individual

foods, in order to reduce the interferences from the multiple variables

present in studies on whole diets. Assessment of individual foods is

clearly a necessary stage in the evaluation of the health effects of

polyphenols, but it should be followed by studies of whole diets, since in

a real situation these are what subjects consume. Thus, we consider ef-

forts should be performed for increasing studies evaluating polyphenol-

rich intake within a whole dietary pattern. The studies included in this

systematic review evaluated several primary and secondary clinical

outcomes, but we should emphasize that this systematic review focuses

on the design of a polyphenol-rich diet itself. Also, there were differ-

ences among the studied subjects; although some dietary recommen-

dations for polyphenol intake may be general for any population, in case

some specic recommendation was provided due to the characteristics

of the subjects (for instance, adapting isoavone intake to menopausal

situation), this should be reported.

The clinical trials included in this systematic review showed, rst of

all, considerable variability in terms of the instructions provided to the

volunteers. They varied from studies where participants had to consume

a particular food combination every day (Annuzzi et al., 2014) to others

where they were instructed to consume a daily number of servings of

polyphenol-rich foods which they selected themselves (Chong et al.,

2013), or still others where the participants received pre-prepared meals

(Della Pepa et al., 2020). Regarding the specic food classes or items

recommended, although all the studied included fruit, not all recom-

mended vegetables, cocoa products or beverages as polyphenol sources;

similarly, some foods with rather characteristic polyphenol content,

such as olive oil or green tea, were not included in the food selection of

all the studies. This generates an initial problem when comparing the

trials. At the same time, although the studies suggesting or providing

volunteers with a xed combination of foods generated a more ho-

mogenous intervention and therefore, potentially, biological responses,

those where the volunteers are requested to perform their food selection

are closer to a real situation, where food combinations contribute to

polyphenol intake and, ultimately, to their associated health effects (de

Pascual-Teresa & Clifford, 2017).

A notable aspect is that, although the clinical trials included were

focused on polyphenol-rich diets, sometimes they did not include an

evaluation of the polyphenol intake of the subjects (either total or by

individual compounds), which we therefore calculated specically for

this study using existing databases. Thus, one recommendation would be

that, in such studies as these, an initial estimation of the polyphenol

intake of the volunteers should be made, in order to know exactly how

far or close to usual polyphenol intake the diet provided will be in that

population or in similar ones. Overall, the median polyphenol intake of

the volunteers in the clinical trials was about 2 g/day, which corre-

sponds to a high polyphenol intake, compared to those reported in

several populations (Nascimento-Souza et al., 2018; P

erez-Jim

enez

et al., 2011; Tresserra-Rimbau et al., 2013), but within the range that

may be achieved by a standard diet, without supplementation. Despite

this general characteristic of a high polyphenol intake, which is in

agreement with the purposes of the studies included, considerable

variation in polyphenol intake was observed between the studies, with a

more than two-fold difference between p25 and p75 values. This

affected most polyphenol classes, (for instance, in hydroxycinnamic

acids, weekly intake p75 values were up to ten-fold higher than p25

values) and also individual polyphenols, although in some classes (e.g.,

avanols) the intake range was very similar between the studies. In

general, these substantial differences in the polyphenol intake of the

volunteers make it rather difcult to compare them between the clinical

trials, and this may contribute to explaining some of the discrepancies

observed in the results. Nevertheless, most of the studies evaluating

biochemical outcomes found benecial effects derived from a

polyphenol-rich diet, independently on whether they were in the low

(Noad et al., 2016) or the high (Annuzzi et al., 2014; Della Pepa et al.,

2020) polyphenol intake range. (Although one of the studies did not nd

any effect on the formation of urinary DNA adducts (Malaveille et al.,

2014) but, as stated below, the information provided did not allow us to

calculate individual polyphenol intake in this case.) This was due to the

fact that, despite the differences in polyphenol intake between the

specic studies, they all corresponded to a high polyphenol intake, so

this is in agreement with the reported biological effects associated with

this condition. To be more precise, the studies with the lowest weekly

polyphenol intake (10 g/week) provided a polyphenol dose which was

clearly higher than that observed for the quartile with the lowest poly-

phenol intake in a Brazilian population, which was about 4 g/week

(Nascimento-Souza et al., 2018).

At the same time, we cannot ignore that the estimation of polyphenol

intake from databases is subject to all the well-known drawbacks that

those databases still possess, due to analytical limitations such as the

problem for properly estimating proanthocyanidin content (P

erez-

Jim

enez et al., 2010) or the lack of inclusion of non-extractable poly-

phenols, despite their contribution to total polyphenol intake (P

erez-

Jim

enez & Saura-Calixto, 2015). This is combined with the potential

lack of or partial compliance on the part of participants, which means

that determination of polyphenol metabolites in biological uids is

highly recommended in this kind of study, as they can be used as bio-

markers of intake according to robust procedures (Dragsted et al., 2018),

and to establish associations between circulating doses and associated

health outcomes, especially as the metabolic fate of polyphenols is

highly affected by inter-individual variability (Morand & Tom

as-Bar-

ber

an, 2019).

A general reection arises from this systematic review. Currently,

there is a tendency to study dietary patterns as a whole. This includes,

for instance, the widely studied Mediterranean diet, but also dietary

patterns focused on both health and sustainability (Willett et al., 2019).

In this context, some intervention studies have explored the role of

polyphenol-rich diets as a whole; especially because, as recently

reviewed, there is evidence of an association between polyphenol-rich

dietary patterns assessed in observational studies and different health

outcomes (Del Bo’ et al., 2019). However, the present systematic review

shows that the amounts of polyphenols provided in these clinical trials

may differ widely. This situation is similar to other aspects of polyphenol

research, where differences in study design (Nú

nez-S

anchez et al., 2015;

Mariano et al., 2020), analytical determinations (Pokimica & García-

Coonesa, 2018), data reporting (Nikolic et al., 2019) or nomenclature

(Kay et al., 2020) have been observed by researchers and have led to

joint recommendations for homogenization. Similarly, a joined effort by

polyphenol researchers community could be made to establish certain

parameters for a polyphenol-rich diet. This does not mean a single,

universal model (clearly, it makes no sense to recommend daily con-

sumption of tropical fruit in northern countries, for example). However,

in the same way that different indexes have been established for the

Mediterranean dietary pattern which does not mean that the diet is the

same in Italy and Turkey, some general concepts about a polyphenol-

rich dietary pattern could be established. These could include ranges

for total polyphenol intake, polyphenol classes and certain individual

polyphenols (based on current knowledge, from both observational and

intervention studies), which could then be adapted to local food con-

sumption patterns. Indeed, it has been observed that some current di-

etary guidelines already promote polyphenol-rich dietary patterns

(Castro-Acosta et al., 2019) so they would not require substantial

modications. And epidemiological studies have shown that it is

possible to reach a similar polyphenol intake based on different char-

acteristic local products, such as black beans in Brazil (Nascimento

–Souza et al., 2018) or olives and olive oil in Spain (Tresserra-Rimbau

et al., 2013). Of course, at the same time, studies focused on individual

compounds or foods are clearly needed in order to advance our

knowledge of the health effects of polyphenols, for which information is

still limited in many aspects.

L. Condezo-Hoyos et al.

Food Research International 149 (2021) 110655

This systematic review is the rst simultaneous comparison of

intervention studies based on the concept of a polyphenol-rich diet, and

it raises some aspects not previously observed, such as the differences in

intake, in particular for some polyphenol classes. This study also has

some limitations though, such as the small number of trials identied

that full our inclusion and exclusion criteria; the differences in the

populations studied; the different approaches for estimating polyphenol

intake in the studies; and the different biases that affect all intervention

studies, particularly nutritional ones. At the same time, it obtained some

useful take-away ndings: more intervention studies should explore the

effects of polyphenol-rich diet; such studies should provide information

as detailed as possible on the dietary recommendations provided to the

subjects (products, amount, cooking conditions, food origin, etc.); in-

formation on expected individual polyphenol intake by study subjects

and how it was determined should also be provided; in case specic

polyphenol intake recommendations were done due to the characteris-

tics of the population, this should be stated.

5. Conclusions

The number of clinical trials that assess the effect of polyphenol-rich

diets on health biomarkers is still limited. Moreover, such studies show

important differences in terms of the details provided to the volunteers

or the foods included, and therefore the total and individual polyphenol

intake. This may affect the results observed and make the comparison of

different nutritional interventions difcult. Due to the evidence on the

health-related properties of polyphenols and the need to develop holistic

approaches to dietary patterns, some general characteristics of a

polyphenol-rich diet may deserve further exploration.

CRediT author contribution statement

J. P

erez-Jim

enez conceived the study and supervised all the tasks; C.

Gazi and L. Condezo-Hoyos performed the bibliography search; L.C.-H.

carried out data curation and visualization; J.P.-J. and L.C.-H. inter-

preted the results and wrote the rst draft of the manuscript. This nal

version of the manuscript has been reviewed and approved by all the

authors.

Declaration of Competing Interest

The authors declare that they have no known competing nancial

interests or personal relationships that could have appeared to inuence

the work reported in this paper.

Acknowledgments

Miss Christina Gazi was the recipient of an Erasmus+grant, a pro-

gramme from the European Union Language revision by Christopher

Evans is acknowledged.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.

org/10.1016/j.foodres.2021.110655.

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