effectsoffruitandvegetableconsumptiononinflammatory ...€¦ · design: electronic databases...

Effects of fruit and vegetable consumption on inflammatorybiomarkers and immune cell populations: a systematic literaturereview and meta-analysis

Banafshe Hosseini,1 Bronwyn S Berthon,1 Ahmad Saedisomeolia,2,3 Malcolm R Starkey,1 Adam Collison,1

Peter AB Wark,1 and Lisa G Wood1

1Grow Up Well Priority Research Centre and Priority Research Centre for Healthy Lungs and, Hunter Medical Research Institute, University of Newcastle,Newcastle, Australia; 2School ofMedicine,Western Sydney University, Sydney, Australia; and 3School of Nutritional Sciences and Dietetics, Tehran Universityof Medical Sciences, Tehran, Iran

ABSTRACTBackground: Inflammation is associated with an increased risk ofa range of chronic diseases. A diet high in fruit and vegetables mayhelp to reduce inflammation, as fruit and vegetables are rich sourcesof antioxidants and other biologically active substances, which mayimprove immune function.Objective: To summarize the evidence, we executed a systematicreview and meta-analysis examining the effects of fruit and/or veg-etable intake on inflammatory biomarkers and immune cells in hu-mans with different diseases and conditions.Design: Electronic databases including PubMed, Cochrane,CINAHL, and EMBASE were systematically searched up toMarch 2018.Results: Eighty-three studies were included. Of these, 71 (86%)were clinical trials, and 12 were observational studies (n= 10 cross-sectional and n = 2 cohort). Amongst the observational research,n = 10 studies found an inverse association between intakes of fruitor vegetables and inflammatory biomarkers. Similarly, the majorityof the intervention studies (68%, n = 48) reported beneficial effectsof fruit or vegetable intake on ≥1 biomarker of systemic or airwayinflammation. A meta-analysis of included studies showed that fruitor vegetable intake decreased circulating levels of C-reactive proteinand tumor necrosis factor-α (P < 0.05) and increased the γ δ-T cellpopulation (P < 0.05).Conclusions: In conclusion, this review suggests that higher intakesof fruit and vegetables lead to both a reduction in proinflammatorymediators and an enhanced immune cell profile. Am J Clin Nutr2018;108:136–155.

Keywords: fruits, vegetables, antioxidants, inflammation,immunity

INTRODUCTION

The relation between oxidative stress, inflammation, andthe risk of a wide range of chronic health conditions has beenfrequently described in the literature (1–3). Inflammation is

essential for protecting the body against insult and injury.However, when inflammation becomes persistent, the mediatorsproduced by activated immune cells can lead to tissue damageand development of disease (3). A chronic inflammatory stateis characterized by increased levels of circulating inflammatorybiomarkers such as C-reactive protein (CRP), TNF-α, and IL-6(4). Therapeutic strategies that target reducing inflammationhave the potential to dramatically reduce the burden of manychronic diseases.

Sufficient fruit and vegetable (F&V) intake is one of thecornerstones of a healthy diet, and may provide protectionagainst cardiovascular disease (CVD), several cancers, and otherchronic diseases (5). F&Vs are rich dietary sources of variousimmune-protective substances such as fiber, folate, vitamins, aswell as non-nutrient phytochemicals, including carotenoids andflavonoids, such as β-carotene, anthocyanins, flavanols, and fla-vanones (6). These substances can have profound effects on cel-lular growth and differentiation, and are needed for the optimalfunctioning of the immune system (7).

Various studies have reported that a high F&V consumptioncan decrease systemic inflammation (3). Some studies have ex-amined the effect of F&V interventions on immune cell popula-tions. Increased natural killer cell (NK cell) cytotoxicity and lym-phocyte proliferation have been reported following consumptionof different F&V juices (8–10). In addition, some epidemiologicstudies have also reported that F&V intake is inversely associ-

Address correspondence to LGW (e-mail: [email protected]).Abbreviations used: CRP, C-reactive protein; CVD, cardiovascular dis-

ease; F&V, fruit and vegetable; GPR, G protein-coupled receptor; hsCRP,high-sensitivity C-reactive protein; ICAM-1, intercellular adhesionmolecule-1; iNOS, inducible nitric oxide synthase; MCP-1, monocyte chemotacticprotein-1; MD, mean difference; NK cell, natural killer cell; PBMC, pe-ripheral blood mononuclear cell; sICAM-1, soluble intercellular adhesionmolecule-1; sVCAM-1, soluble vascular adhesion molecule-1; VCAM-1,vascular adhesion molecule-1; WBC, white blood cell count.Received December 15, 2017. Accepted for publication March 28, 2018.First published online 0, 2018; doi: https://doi.org/10.1093/ajcn/nqy082.

136 Am J Clin Nutr 2018;108:136–155. Printed in USA. © 2018 American Society for Nutrition. All rights reserved.

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FRUIT AND VEGETABLE INTAKE AND IMMUNE RESPONSES 137

FIGURE 1 Example of search strategy with the use of PubMed for studies investigating the effect of fruit and/or vegetable on inflammatory biomarkers andimmune cell population in humans. CRP, C-reactive protein; eNO, exhaled nitrico oxide; ICAM-1, intercellular adhesion molecule; IFN, interferon; VCAM-1,vascular cell adhesion protein 1.

ated with proinflammatory biomarkers, such as CRP (1, 11, 12)and TNF-α (13). However, there is heterogeneity in the literatureand not all studies have reported beneficial effects (14, 15).

Although previous meta-analyses have assessed the relationbetween F&V intake and risk of CVD (16) or other chronic dis-eases such as type 2 diabetes (17), to our knowledge, there is nocomprehensive study that reviews the effects of F&V intake oninflammation and immune cell populations. Hence, the aim ofthis systematic literature review and meta-analysis is to evalu-ate the association between F&V consumption and inflammationand immunity. We specifically aimed to identify and examine theavailable evidence for the effects of F&V intake on inflammatorybiomarkers and immune cell populations in humans.

METHODS

Search strategy

A systematic search of relevant papers published beforeMarch 2017 was performed with the use of PubMed, Cochrane,CINAHL, and EMBASE with the keyword search term only(inclusion and exclusion criteria were not considered in the

search strategy). Studies were limited to humans with no timerestriction. In addition, the reference lists of retrieved articles andrelevant systematic reviews were searched to identify other rele-vant studies. See Figure 1 for an example of the search strategyused. The search was conducted again in March 2018 to ensurethat any relevant articles published after the initial search wereidentified. The Medical Subject Headings search terms included:fruit, fruit extract, vegetable, vegetable products, fruit and veg-etable juices, inflammatory markers, IL, CRP, TNF-α, IL-6, im-mune cells, T cells, NK cells, B cells, dendritic cells, lympho-cytes, and antigen-presenting cells.

Study selection

This systematic review considered only original studies withthe following designs: randomized controlled trials, cohortstudies, case-control studies, before and after studies, and cross-sectional studies. Animal models, in-vitro studies, systematicreviews, narrative reviews, opinion papers, case studies, casereports, and conference abstracts were excluded. Review articleswere collected for the purposes of reviewing the reference listsand did not contribute to the final number of included studies.


138 HOSSEINI ET AL.

TABLE 1Methodologic quality rating of each study as determined by the judgments of the authors1

First author (year) Q12 Q23 Q34 Q45 Q56 Q67 Q78 Q89 Q910 Q1011 QA

Amagase (2009) (25) Y Y Y N Y Y Y Y Y Y PosVidal (2012) (52) Y Y Y Y Y Y Y Y Y UC PosGuo (2014) (37) Y Y Y Y Y Y Y Y Y UC PosKarlsen (2010) (39) Y Y Y Y N Y Y Y Y UC PosKolehmainen (2012) (41) Y Y Y Y N Y Y Y Y Y PosLarmo (2008) (43) Y Y Y Y Y Y Y Y Y UC PosMcAnulty (2011) (45) Y Y N N N Y Y Y Y UC NeuRiso (2013) (47) Y N Y Y NA Y Y Y Y Y NeuBasu (2014) (28) Y Y Y Y N Y Y Y Y Y PosXie (2017) (55) Y Y Y Y Y Y Y Y Y Y PosNilsson (2017) (58) Y Y Y Y Y Y Y Y Y UC PosDuffey (2015) (59) Y Y Y Y N Y Y Y Y N PosHosseini (2016) (2) Y Y Y Y Y Y Y Y Y Y PosAsgary (2013) (26) Y Y N Y N Y Y Y Y Y NeuDavidson (2009) (33) Y Y Y Y Y Y Y Y Y UC PosShema-Didi (2012) (49) Y Y Y Y Y Y Y Y Y Y PosSohrab (2014) (50) Y Y Y Y Y Y Y Y Y Y PosHan (2016) (38) Y Y Y N Y Y Y Y Y Y PosTomé-Carneiro (2012) (51) Y Y Y Y Y Y Y Y Y UC PosCastilla (2006) (31) Y Y Y Y N Y Y Y Y Y PosZunino (2014) (54) Y Y Y Y Y Y Y Y Y Y PosBarona (2012) (27) Y Y Y Y Y Y Y Y Y UC PosBell (2014) (29) Y Y Y Y N Y Y Y Y Y PosKelley (2013) (40) Y N N Y NA Y Y Y Y UC NeuKent (2017) (56) Y Y Y Y Y Y Y Y Y UC PosBuscemi (2012) (30) Y Y Y Y N Y Y Y Y Y PosDalgard (2009) (32) Y Y Y N Y Y Y Y Y Y PosSanchez-Moreno (2003) (48) Y Y N N NA Y Y Y Y UC NeuDeopurkar (2010) (34) Y UC Y NA NA N Y Y Y Y NeuGammon (2014) (36) Y N Y Y N Y Y Y Y Y NeuHunter (2012) (53) Y Y Y Y Y Y Y Y Y UC PosDow (2013) (35) Y Y Y N N Y Y Y Y UC NeuLeelarungrayub (2016) (44) Y Y N Y N Y Y Y Y UC NeuKanellos (2017) (57) Y Y Y Y Y Y Y Y Y Y PosNishizawa (2011) (46) Y N Y N Y Y Y Y Y N NeuKuntz (2014) (42) Y N Y N Y Y Y Y Y Y NeuBub (2003) (8) Y N Y N N Y Y Y Y UC NeuGhavipour (2013) (4) Y N Y Y N Y Y Y Y Y NeuWatzl (2003) (9) Y N Y Y Y Y Y Y Y Y NeuWatzl (1999) (10) Y N N Y N Y Y Y Y UC NeuBriviba (2004) (14) Y N Y Y Y Y Y Y Y UC NeuWatzl (2000) (15) Y Y Y Y Y Y Y Y Y UC PosAalami-Harandi (2015) (60) Y Y Y N Y Y Y Y Y Y PosRiso (2014) (61) Y N Y Y NA Y Y Y Y UC NeuUpritchard (2000) (62) Y Y Y Y N Y Y Y Y UC PosInserra (1999) (65) Y Y N Y NA Y Y Y Y Y NeuJin (2010) (3) Y Y Y Y Y Y Y Y Y Y PosMacready (2014) (6) Y Y Y Y N Y Y Y Y UC PosBaldrick (2012) (1) Y Y Y Y N Y Y Y Y Y PosFreese (2004) (11) Y Y Y NA N Y Y Y Y N PosMcCall (2011) (12) Y Y Y Y NA Y Y Y Y Y PosLamprecht (2007) (13) Y N Y Y Y Y Y Y Y UC NeuBobe (2010) (63) Y Y Y Y N Y Y Y Y Y PosHunter (2012) (64) Y Y Y Y N Y Y Y Y Y PosKnab (2013) (66) Y N Y Y N Y Y Y Y Y NeuKnab (2014) (67) Y Y Y N N Y Y Y Y Y PosLamprecht (2013) (68) Y N Y Y Y Y Y Y Y UC NeuNadeem (2014) (69) Y Y Y Y NA Y Y Y Y Y PosNantz (2006) (70) Y Y Y Y Y Y Y Y Y UC PosWatzl (2005) (71) Y N Y NA Y Y Y Y Y UC NeuWilliams (2017) (72) Y Y Y Y Y Y Y Y Y Y PosWood (2012) (73) Y Y Y Y NA Y Y Y Y Y PosRomieu (2009) (23) Y Y Y Y N Y Y Y Y Y Pos

(Continued)



TABLE 1(Continued)

First author (year) Q12 Q23 Q34 Q45 Q56 Q67 Q78 Q89 Q910 Q1011 QA

Holt (2009) (20) Y Y Y Y N Y Y Y Y Y PosHermsdorff (2010) (74) Y Y Y Y N Y Y Y Y Y PosLopez-Garcia (2004) (75) Y N Y Y N Y Y Y Y Y NeuRoot (2012) (76) Y Y Y Y N Y Y Y Y Y PosWannamethee (2006) (77) Y N Y Y N Y Y Y Y Y NeuAlmeida-de-souza (2017) (22) Y Y Y Y NA Y Y Y Y Y PosRowe (2011) (80) Y Y Y Y Y Y Y Y Y Y PosKontiokari (2005) (24) Y Y Y Y Y Y Y Y Y UC PosZunino (2013) (81) Y Y Y Y Y Y Y Y Y Y PosMcAnulty (2014) (78) Y Y Y N N Y Y Y Y UC PosNantz (2013) (79) Y Y Y Y Y Y Y Y Y UC PosBohn (2010) (82) Y N Y Y N Y Y Y Y Y NeuNantz (2012) (84) Y Y Y Y Y Y Y Y Y UC PosMurashima (2004) (83) Y N N Y N Y Y Y Y Y NeuLiu (2012) (85) Y N Y Y N Y Y Y Y UC NeuGibson (2012) (5) Y Y Y Y Y Y Y Y Y Y PosWinkler (2004) (86) Y Y Y Y NA Y Y Y Y UC PosHendricks (2008) (87) Y N Y Y N Y Y Y Y Y NeuNettleton (2010) (88) Y Y Y Y N Y Y Y Y Y PosKruzich (2004) (21) Y Y Y Y N Y Y Y Y Y Pos

1N, no; NA, not applicable; Neu, neutral; Pos, positive; Q, question; QA, quality assessment; UC, unclear; Y, yes.2Q1: Was the research question clearly stated?3Q2: Was the selection of study subjects/patients free from bias?4Q3: Were study groups comparable?5Q4: Was the method of handling withdrawals described?6Q5: Was blinding used to prevent introduction of bias?7Q6: Were intervention/therapeutic regimens/exposure factor or procedure and any comparisons described in detail? Were intervening factors described?8Q7: Were outcomes clearly defined and the measurements valid and reliable?9Q8: Was the statistical analysis appropriate for the study design and type of outcome indicators?10Q9: Are conclusions supported by results with biases and limitations taken into consideration?11Q10: Is bias due to study’s funding or sponsorship unlikely?

The target study population was humans of all ages, genders, orethnicities, with any health status. The exposure of interest wasconsumption of whole or extracted fruit or vegetables. The studyoutcome measures were inflammatory biomarkers such as ILs,CRP, and TNF-α, as well as markers of immune function suchas immune cell populations.

Citations from electronic databases were imported into thereferencing software Endnote X8. Two reviewers (BH andAS) independently reviewed and evaluated all articles by ti-tle and abstract, and thereafter performed independent full-text assessments. A third independent reviewer (BSB) wasconsulted in cases where reviewers’ evaluations were notin agreement.

Study quality

Eligible studies were assessed independently in terms of theirmethodological quality by 2 reviewers (BH and AS) based on astandardized critical appraisal checklist designed by the Ameri-can Dietetic Association (18). The tool considered the reliability,validity, and generalizability of the included studies. This toolcomprises 4 relevance questions that address the applicabilityof the study findings to practice and 10 validity questions thataddress scientific rigor, including risk of bias. Based on the re-sponses to these questions as determined by the reviewers (BH

and AS), each study was rated as having negative, positive, orneutral quality. The methodologic quality rating of the includedstudies is detailed in Table 1.

Data extraction and study synthesis

Study details were extracted and recorded into a custom-designed database. Data extracted included title, authors,country, study design, participant characteristics, study factor(e.g., dosage/dietary intake of fruits and vegetables), studyduration, main outcome measures, findings including statisticalsignificance, analysis with adjustment for confounding factors,and limitations. The Preferred Reporting Items for SystematicReviews and Meta-Analyses (PRISMA) protocol was followedduring data extraction and study synthesis (19).

Statistical methods

A meta-analysis was performed to investigate the effects ofF&V intake on inflammatory biomarkers (CRP, TNF-α, andIL-6) and immune cell population percentage (αβ-T cells, γ δ-T cells, and NK cells) with Review Manager (RevMan, version5.3, Nordic Cochrane Centre). Only studies thatmet the followinginclusion criteria were included in the meta-analysis: 1) F&V in-take reported; 2) the mean and SD, SE, or IQRs were reported; 3)


140 HOSSEINI ET AL.

FIGURE2 Search and inclusion process flowchart of studies for inclusion in a systematic review of the effects of fruit and vegetable intakes on inflammatorybiomarkers and immune cell population.

the OR or the relative risks and the corresponding 95% CIs werereported. All reported SEs, 95% CIs, and IQRs were converted toSDs. However, due to the differences in exposure and outcome as-sessments, meta-analysis of all included studies was not possible.Appreciable heterogeneity was assumed if I2 > 50 and P < 0.1.Meta-analysis was performed with the use of fixed-effect mod-elling if I2 < 50, and random-effectmodellingwas used if I2 > 50.Included studies used different interventions; thus meta-analysiswas performed in studies with similar outcome measurements.The inverse-variance statistical method was used, and the meandifference (MD) and corresponding 95% CIs were calculated.

RESULTS

Search results

A flow chart showing the article retrieval and inclusion processis presented in Figure 2. A total of 8853 articles were identified

with n= 530 duplicates identified and excluded. The titles of theremaining 8323 articles were reviewed with n= 295 retrieved forabstract appraisal. Abstracts from 131 articles met the inclusioncriteria and full texts were retrieved for the further review. Eighty-three articles met the criteria and were included in this systematicliterature review.

Study characteristics

The majority of studies (94%, n = 78) were performed inadults (≥18 y of age) with only 3 in adolescents (20–22) and 2 inchildren (23, 24). In terms of study design, experimental was themost common (86%, n= 71), with 10 cross-sectional studies and2 cohort studies. A total of n = 5420 participants were includedin clinical trials with a mean intervention period of 85 d, rangingfrom 6 h to 4 y. Overall, 17,710 participants were included fromcross-sectional studies, and 556 individuals with a mean follow-up of 5.22 y from cohort studies. The methodological quality of



TABLE2

Summaryof

includ

edstud

iesexam

iningtheeffectsof

fruitand

vegetableintake

oninflammatorybiom

arkers1

Firstautho

r(year)

Cou

ntry

Design

Popu

latio

n,n

Age,y

Interventio

nEffectson

inflammatorybiom

arkers

Amagase(2009)

(25)

USA

RCT

Health

y,60

55–7

212

0mLstandardized

barberry

fruitjuice

(equ

ivalentto

≥150

gfreshfruit)or

placebodaily

for30

d↑S

erum

levelsof

IL-2

Vidal(201

2)(52)

China

RCT

Health

y,15

065

–70

Lacto-w

olfberry

orplacebo(13.7g/d)

for3mo

↔Any

biom

arkers

Guo

(201

4)(37)

China

RCT

Obesity,44

18–2

525

0mLof

either

barberry

juiceor

placebotw

icedaily

for4wk

↓Plasm

alevelsof

TNF-

α,and

IL-8

Karlsen

(201

0)(39)

USA

RCT

Atriskof

CVD,

6230

–70y(m

en)

and45

–70y

(wom

en)

330mLbilberry

juice(n

=31

)or

water

(n=

31)for4wk

↓Plasm

aconcentrations

ofCRP,IL-6,IL-15,and

MIG

,↑TNF-

α,↔

otherbiom

arkers

Kolehmainen(201

2)(41)

Finland

RCT

Metabolic

synd

rome,27

BLB:5

3±

6CO:5

0±

7Adietrich

inBLB(400

gfreshBLB)or

acontrold

ietfor

8wk

↓Serum

hsCRP,IL-6,IL-12

Larmo(200

8)(43)

Finland

RCT

Health

y,25

419

–50

28gfrozen

seabuckthornpu

reeor

placebofor90

d↓S

erum

CRPconcentrations

McA

nulty

(201

1)(45)

USA

RCT

Welltrained,25

BB (31.1

±12

.6)

CO

(33.4

±16

.0)

250gblueberries/dfor6wkand37

5ggiven1hpriorto

2.5h

ofrunn

ingor

placebo

↔Any

biom

arkers

Riso(201

3)(47)

Italy

Crossover

RCT

Atriskof

CVD,

1847

.8±

9.7

AWB(25gfreeze-dried

powder,providing37

5mgof

ACNs)

oraplacebodrinkfor6wk,

spaced

bya6-wkwash-ou

t↔

Serum

levelsof

IL-6,T

NF-

α,C

RP,sV

CAM-1

Basu(201

4)(28)

UK

RCT

Abd

ominal

adiposity,60

49±

10One

ofthefollo

wing4beveragesfor12

wks:1

)LD-FDS(25

g/d),2)LDcontrol,3)

HD-FDS(50g/d),and

4)HDcontrol

↔Serum

levelsof

hsCRP,sICAM,and

sVCAM

Xie(201

7)(55)

USA

RCT

Health

y,49

18–6

550

0mgberryextracto

rplacebofor12

wk

↔Any

biom

arkers

Nilsson(201

7)(58)

Sweden

Crossover

RCT

Health

y,40

50–7

0Berry

beverage

basedon

amixture

ofberries(150

gblueberries,50

gblackcurrant,50gelderberry,50g

lingo

nberries,50gstrawberry,and10

0gtomatoes)or

acontrolb

everage,daily

for5wk

↔PlasmaIL-6

andIL-18levels

Duffey(201

5)(59)

USA

Cross-

sectional

Health

y,10,334

≥19

Average

404mLof

CJC

vs.<

404ml

↓Serum

levelsof

CRP

Hosseini(20

16)(2)

Iran

RCT

Overw

eight/

obese,42

30–6

010

00mgpo

megranateextract,or

aplacebo,daily

for30

d↓P

lasm

alevelsof

IL-6

andhsCRP

Asgary(2013)

(26)

Iran

Exp

erim

ental

13hypertensive

men

39–6

8NaturalPJ

(150

ml/d

)follo

winga12

-hfast

↔Blood

levelsof

hsCRP,ICAM-1,V

CAM-1,

E-selectin

,and

IL-6

Davidson(200

9)(33)

USA

RCT

Atriskof

CHD,

289

45–7

424

0mlP

J/dor

controlb

everagefor18

mo

↔Blood

levelsof

CRP

Shem

a-Didi(20

12)

(49)

Israel

RCT

Chron

ichemod

ialysis

patie

nts,10

1

>18

100mLPJ,ormatchingplacebodu

ring

each

dialysis(3/w

k)for1y

↓Plasm

alevelsof

IL-6,T

NF-

α

Sohrab

(201

4)(50)

Iran

RCT

T2D

M,50

40–6

525

0mLPJ/d

oracontrolb

everagefor12

wk

↓Plasm

aCRPandIL-6

levels

Han

(201

6)(38)

Korea

RCT

Overw

eigh

t/ob

ese,76

30–7

0Con

trol

(starch,4g/d,n

=24),low-G

O[low

-doseGO,g

rape

pomaceextract(34

2.5mg/d)

+om

ijafruitextract(57.5

mg/d),n

=26

],andhigh

-GO[high-do

seGO,g

rape

pomace

extract(68

5mg/d)

+om

ijafruitextract(115

mg/d),n

=26

]grou

psfor10

wk

↓Plasm

aIL-1b,andTNF-

αlevels

Tomé-Carneiro(201

2)(51 )

Spain

RCT

Und

ergo

ing

prim

ary

preventio

nof

CVD,7

5

18–8

0A:resveratrol-richgrapesupp

lement(resveratrol8

mg);B

:conventio

nalg

rape

supp

lementlacking

resveratrol;C:

placebo(m

altodextrin)

forthefirst6moandado

ubledo

seforthenext

6mo

A:↓

PlasmahsCRP;

B:↔

anybiom

arker

(Continued)


142 HOSSEINI ET AL.

TABLE2

(Continued)

Firstautho

r(year)

Cou

ntry

Design

Popu

latio

n,n

Age,y

Interventio

nEffectson

inflammatorybiom

arkers

Castilla(200

6)(31)

Spain

RCT

Receiving

hemod

ialysis,

38;h

ealth

y,15

30–7

0Hem

odialytic

patie

nts:RGJ(100

mL/d)or

controlfor

14d.

Health

ycontrols:1

00mLRGJ/dfor14

d↓P

lasm

alevelsof

MCP-1,

↔VCAM1,IC

AM1,andCRP

Zun

ino(201

4)(54)

USA

Crossover

RCT

Obesity,24

20–6

092

ggrapepowder(∼

4servings

ofgrape)

orplacebofor9wk

↔Plasmalevelsof

CRP

Baron

a(201

2)(27)

USA

RCT

Metabolic

synd

rome,24

30–7

046

glyop

hiliz

edgrapepowder(equ

ivalentto25

2gfreshgrapes),

orplacebofor4wk

↑mRNAexpression

ofIL-10,

andtheindu

cibleiN

OSin

thoseindividu

alswith

outd

yslip

idem

ia,↔

plasmaIL-6,

IL-8,and

TNF-

αlevels

Bell(20

14)(29)

UK

RCT

Trained

cyclists,

1630

±8

30mLMCor

placebo,2tim

es/d

for7consecutivedays

↓Plasm

alevelsof

IL-6

andhsCRP,

↔IL-1-β

orTNF-

α

Kelley(201

3)(40)

USA

Beforeand

after

Health

y,18

45–6

1Su

pplementedthedietswith

Bingsw

eetcherries(280

g/d)

for28

d↓P

lasm

alevelsof

CRP,plasminog

enactiv

ator

inhibitor-1,endo

thelin-1,epiderm

algrow

thfactor,and

IL-18,

↑IL-1

receptor

antago

nist

Kent(20

17)(56)

Australia

RCT

Mild

-to-mod

erate

dementia

,49

>70

200mLeither

acherry

juiceor

controlb

everage/dfor12

wk

↔PlasmaCRPandIL-6

levels

Buscemi(20

12)(30)

Italy

Sing

le-blin

dcrossover

stud

y

Atriskof

CVD,

18;h

ealth

y,12

27–5

62period

sof

7deach

with

a3-dinterval,eachparticipant

alternativelyrand

omized

toreceive50

0mLorange

juiceor

placebo

↓Plasm

aconcentrations

ofhsCRP,IL-6,and

TNF-

α

Dalgard

(200

9)(32)

Denmark

2×

2factorial,

crossover

RCT

Periph

eralarterial

disease,48

60.57

Juice

+vitamin

E,juice

+placebo,referencebeverage

(sugar

drink)

+vitamin

E,reference

beverage

+placebofor28

d,separatedby

a4-wkwash-ou

tperiod

↓Plasm

alevelsof

CRPandfib

rino

genby

11%

and3%

,respectiv

ely,

↔IL-6

Sanchez-Moreno(200

3)(48)

Spain

Exp

erim

ental

Health

y,12

20–3

250

0mLhigh

-pressureorange

juice/dfor14

d↓P

lasm

alevelsof

PGE2,

↔CRP

Deopu

rkar

(201

0)(34)

USA

Trial

Health

y,48

25–4

730

0-kcaldrinks

ofeither

glucose,saturatedfatascream,o

rang

ejuice,or

only

water

toingestin

afastingstate

↔Exp

ressionof

TLR-4,N

F-kB

bind

ing,TNF-

α,IL-1

β

inMNCsandin

plasmaLPS

.Gam

mon

(201

4)(36)

New

Zealand

Crossover

RCT

Hyp

er-

cholesterol,85

27–7

34-wkhealthydietrun-in,beforetwo4-wkinterventio

nsof

2green

kiwifruit/dplus

healthydiet(intervention)

orhealthydietalon

e(con

trol)

↓Serum

CRPandIL-6

concentrations

Hun

ter(201

2)(53)

New

Zealand

Crossover

RCT

Elderly,32

≥65

The

equivalent

of4kiwifruitor

2bananas/dfor4wk,with

treatm

entsseparatedby

a4-wkwasho

utperiod

↔Plasmalevelsof

hsCRP,ho

mocysteine

Dow

(201

3)(35)

USA

RCT

Overw

eigh

t/ob

ese,69

;metabolic

synd

rome,29

>18

Alowbioactivedietplus

1.5grapefruit/dfor6wk(n

=37

,n=

14with

MetS)

oracontrolcon

ditio

nin

which

alowbioactivediet

devoid

ofcitrus

was

consum

ed(n

=32

,n=

15with

MetS)

↓Plasm

alevelsof

hsCRP,

↔sV

CAM-1

Leelarung

rayu

b(201

6)(44)

Thaila

ndBeforeand

after

Elderly,29

54–7

8A2-wkcontrolp

eriodwas

follo

wed

by4wkof

100gfreshstar

fruitjuice

consum

ption2tim

es/d

aftermeals

↓Blood

levelsof

NO,T

NF-

αandIL-23

,↔IL-2

Kanellos(201

7)(57)

Greece

RCT

Health

y,36

20–4

0Raisins

equalto5fruitserving

s(90g/d)

orplacebofor4wk

↔PlasmaCRPandleptin

levels

Nishizawa(201

1)(46)

Japan

RCT

Run

ners,20

20.6

±1.25

Twice-daily

FRLFE

(100

mg/d,or

50mg/do

se)or

placebofor2

mo

↓Serum

levelo

fIL-6,↔

IL-10

Kun

tz(201

4)(42)

Germany

Crossover

RCT

Health

y,30

23–2

733

0mLbeverages(placebo

,fruitjuice,andfruitsmoo

thiewith

8.9

±0.3,98

3.7

±37

,and

840.9

±10

mgACN/L,respectively)

over

14d

↔Any

biom

arkers

Bub

(200

3)(8)

Germany

Crossover

RCT

Health

y,27

35±

42po

lyph

enol-richjuices

[236

mg(A

)and22

6mg(B

)po

lyph

enols

with

cyanidin

glycosides

(A)andepigallocatechin

galla

te(B

)](330

mL/d)supp

lementedfor2wk

↑IL-2

secretionby

activ

ated

lymph

ocytes

(Continued)



TABLE2

(Continued)

Firstautho

r(year)

Cou

ntry

Design

Popu

latio

n,n

Age,y

Interventio

nEffectson

inflammatorybiom

arkers

Ghavipo

ur(201

3)(4)

Iran

RCT

Overw

eigh

t/obese,

106

22–2

433

0mLof

tomatojuiceor

water/d

for20

d↓S

erum

levelsof

IL-8

andTNF-

α

Watzl(200

3)(9)

Germany

Crossover

RCT

Health

y,22

28.7

±5.9

330mLof

either

tomatojuice(37.0mglycopene)or

carrot

juice

(27.1mg

β-caroteneand13

.1mg

α-carotene/d)

for2wkon

alow-carotenoiddietwith

a2-wkdepletionperiod

afterjuice

interventio

n

Low

-carotenoiddiet:↓

IL-2;juice

interventio

n:↔

any

biom

arkers

Watzl(199

9)(10)

Germany

Exp

erim

ental

Health

y,23

27–4

0Weeks

1–2:

low-carotenoidperiod

,throu

ghou

tweeks

3–8:

daily

consum

ptionof

330mLtomatojuice(40mg)

(weeks

3–4),330

mLcarrot

juice(w

eeks

5–6),10gdriedspinachpowder(w

eeks

7–8)

Low

-carotenoiddiet:↓

IL-2

andIL-4

secretion;

tomato

juiceconsum

ption:

↑IL-2

andIL-4

secretion;

carrot

juiceandspinachpowderconsum

ption:

↔any

biom

arker

Briviba

(200

4)(14)

Germany

RCT

Non

smoker,30;

smoker,25

30–4

5Three

tomatooleoresinextractcapsulesdaily

(eachcontaining

4.88

mglycopene,0.48mgphytoene,0.44mgphytofl

uene,and

1.18

1mg

α-tocop

herol)or

placebofor2wk

↔IL-2

andTNF-

αsecretion

Watzl(200

0)(15)

Germany

RCT

Health

y,50

63–8

633

0mLtomatojuice/d(47.1mglycopene/d)or

mineralwater

for

8wk

↔Se

cretionof

TNF-

α,IL-2,and

IL-4

Aalam

i-Harandi

(201

5)(60)

Iran

RCT

Pregnant

wom

enat

27wkof

gestation,44

18–4

0One

garlictablet(equ

alto

400mggarlicand1mgallic

in)

(n=

22)or

placebo(n

=22

)on

cedaily

for9wk

↓Serum

levelsof

hsCRP

Riso(201

4)(61)

Italy

Crossover

trial

Smokers(>

10cigarettes/d),17

21.8

±2.7

Broccolid

iet(25

0g/d)/wash-ou

t/con

trol

dietvs.con

trol

diet/wash-ou

t/broccolid

iet.Eachanalysiswas

separatedby

15d

ofwash-ou

tperiod

↓Plasm

aCRP,

↔TNF-

α,IL-6,IL-6sR

oradipon

ectin

,

Upritc

hard

(200

0)(62)

New

Zealand

RCT

T2D

M,57

<75

Tomatojuice(500

mL/d),or

vitamin

E(800

U/d)or

vitamin

C(500

mg/d)

orplacebofor4wk

↑Plasm

alycopene

levels,↔

CRP,VCAM

Inserra(199

9)(65)

USA

Beforeand

after

Elderly,53

60–8

6Fruitjuice

supp

lementscontained85

0mgfruitp

owder/capsule

madefrom

extractsof

apples,orang

es,pineapp

les,papaya,

cranberries,andpeaches.Vegetablesupp

lementscontained75

0mgvegetablepowder/capsuleandcontainedextractsof

carrots,

parsley,beets,broccoli,

kale,cabbage,spinach,and

tomatoes.

Participantsconsum

edextractfor

80d

↑IL-2

secretion,

↔TNF-

α

Jin(201

0)(3)

USA

RCT

Health

y,11

722

–55

Placebo,FV

,orFV

Bcapsulefora60

-dperiod

Bothinterventio

ns:↓

MCP-1,MIP-1b,andRANTES

Macready(201

4)(6)

UK

RCT

Atriskof

CVD,

174

26–7

0High-flavono

idFV

,low

-flavon

oidFV

,orhabitualdiet,w

ithhigh

-andlow-flavon

oidFV

amou

ntssequ

entia

llyincreasing

by2,

4,and6(+

2,+4

,and

+6)po

rtions/d

every6wkover

habitual

intakes

Low

-flavon

oidFV

diet:↓

CRP,Eselectin,and

VCAM

with

14po

rtions/d

Baldrick(201

2)(1)

UK

RCT

COPD

with

ahabitually

low

FVintake

(≤2

portions

FV/d),

81

Low

FV:

61.2

±8.3;

HighFV

:63

.2±

9.1

≥5po

rtions

ofFV

/dor

≤2po

rtions

FV/d

for12

wk

↔Any

biom

arkers

Freese

(200

4)(11)

Finland

RCT

Health

y,77

19–5

2A6-wkdietcontaining

either

810or

196gof

vegetables,berries,

andapples/d,and

rich

either

inlin

oleicacid

(11%

energy

)or

oleicacid

(12%

energy

)

↔Plasmalevelsof

ICAM,and

hsCRP

(Continued)


144 HOSSEINI ET AL.

TABLE2

(Continued)

Firstautho

r(year)

Cou

ntry

Design

Popu

latio

n,n

Age,y

Interventio

nEffectson

inflammatorybiom

arkers

McC

all(20

11)(12)

UK

RCT

Hyp

ertensive,11

740

–65

1,3or

6po

rtions

ofFV

/dfor8wk

↔Se

rum

levelsof

hsCRP,sICAM,V

CAM

Lam

prech(200

7)(13)

Austria

RCT

Health

y,41

34±

5Placeboor

JPCcapsules

for28

wk

↓Serum

concentrations

ofCRPandTNF-

α

Bob

e(201

0)(63)

USA

RCT

Colorectal

adenom

a,87

252

–71

Extensive

dietaryandbehavioralcoun

selling

toachievethePP

Tdietarygo

alsof

20%

oftotalenergyfrom

fat,18

g/10

00kcalof

dietaryfib

er,and

5–8daily

servings

(depending

ontotalcaloric

intake)of

FV;o

rcontrol(didno

treceive

such

coun

selling

and

wereexpected

tocontinue

theirusualintake)

grou

psfor4y

↓Serum

IL-6

concentrations

Hun

ter(201

2)(64)

New

Zealand

Crossover

RCT

Smokers,42

30–6

3Non

supp

lementedmilk

,prototype

milk

Acontainedacombinatio

nof

grapeseed

extract(0.21

3g/serving),app

leextract(0.21

3g/serving),and

tomatoconcentrate(0.106

g/serving),prototype

milk

Bcontainedboysenberryjuiceconcentrate(0.285

g/serving)

andappleextract(0.28

5g/serving)

for6wk

↔Any

inflammatorybiom

arkers

Knab(201

3)(66)

USA

Cross

over

RCT

Swim

mers,9

24.6

±0.7

Com

pleted

10-d

training

with

orwith

out1

6floz

offreshFV

juice

(230

mgflavono

ids)ingested

before

andafer

workout

↔Any

inflammatorybiom

arkers

Knab(201

4)(67)

USA

RCT

Cyclists,34

In:3

5.1

±8.0;

Pl:

35.5

±8.2

Afreeze-dried

FVjuicepowder(230

mgflavono

ids/d)

orplacebo

for17

d↔

Exercise-indu

cedalteratio

nsin

inflammatory

biom

arkers(IL-6,IL-8,T

NF-

α,M

CP-1,CRP)

Lam

precht

(201

3)(68)

Austria

RCT

Obese

prem

enop

ausal,

42

41±

5FV

Bcapsules

thatprovided

7.5mg

β-carotene,20

0mgvitamin

C,

60mgRRR-α-tocop

herol,60

0mgfolateand63

kJ/d

orplacebo

for8wk

↓Serum

levelsof

CRPandTNF-

α

Nadeem

(201

4)(69)

UK

RCT

Hyp

ertensive,11

240

–65

Interventio

nof

1,3,or

6po

rtions

ofFV

/dfor8wkaftera4-wk

washo

utperiod

(1servingFV

/d)

↓Serum

amyloidArelatedinflammation,

↔IL-6,

hsCRP,E-selectin

Nadeem

(201

4)(69)

UK

RCT

Low

FVintake

(≤2serving/d),

82

65–8

5Interventio

nof

2or

5po

rtions

ofFV

/dfor16

wk

FV:↓

serum

amyloidArelatedinflammation,

↔IL-6,

hsCRP,E-selectin

Nantz(200

6)(70)

US

RCT

Health

y,59

21–5

3FV

CJ4capsules/d

orplacebofor77

d↓S

erum

IFN-γ

Watzl(200

5)(71)

Germany

RCT

Low

FVintake

(≤2serving/d),

64

31±

92,5,or

8servings/d

ofcaroteno

id-richvegetables

andfruitfor

4-wkperiod

8servings

FV/d:↓

serum

CRP

Williams(201

7)(72)

Australia

RCT

Overw

eigh

t/ob

esity,56

≥40

6capsules

ofFV

juiceconcentrateor

placebofor8wk

↓Plasm

aTNF-

αlevel

Woo

d(201

2)(73)

Australia

RCT

Asthm

a,13

7HAD:5

4±

14;

LAD:5

8±

15Ahigh

-antioxidant

diet(5

servings

ofvegetables

and2servings

offruit/d

,n=

46)or

alow-antioxidant

diet(<

2servings

ofvegetables

and1servingof

fruit/d

,n=

91)for14

d,andthen

thosewho

consum

edthehigh

-antioxidant

dietreceived

placebo.

Subjectswho

consum

edthelow-antioxidant

dietreceived

placeboor

tomatoextract(45

mglycopene/d).The

interventio

ncontinuedun

tilweek14

orun

tilan

exacerbatio

noccurred

Low

-antioxidant

diet:↑

plasmaCRPatweek14

;tom

ato

extract:

↔airw

ayor

system

icinflammation

Rom

ieu(200

9)(23)

Mexico

Coh

ort

Asthm

atic

child

ren,15

8vs.

50healthy

controlfollowed

foran

average

of22

wk

6–14

>1/dvs.≥

4tim

esFV

/mo

FVI:

↓IL-8

levelsin

nasallavage

Holt(20

09)(20)

US

Cross-

sectional

Health

y,28

513

–17

Highestvs.low

estserving

/d↓P

lasm

alevelsof

CRP,IL-6,and

TNF-

α

(Continued)



TABLE2

(Continued)

Firstautho

r(year)

Cou

ntry

Design

Popu

latio

n,n

Age,y

Interventio

nEffectson

inflammatorybiom

arkers

Hermsdorff(201

0)(74)

Spain

Translatio

nal

Health

y,12

020

.8±

2.6

Highestvs.low

esttertile

↓Plasm

alevelsof

CRP,ho

mocysteine,IC

AM1,IL1-R1,

IL-6,T

NF-

α;↓

NF-

κB1gene

expression

inPB

MC

Lop

ez-G

arcia(200

4)(75)

USA

Cross-

sectional

Health

y,73

243

–69

Highestvs.low

estq

uartile

↓plasm

aCRPandE-selectin

Roo

t(20

12)(76)

USA

Cross-

sectional

Health

y,10

0018

–85

Fruit:

≤2vs.>

2servings/d;v

egetables:

≤3vs.>

3servings/d

↓Serum

levelsof

CRP,IL-6,T

NF-

α

Wannamethee(200

6)(77)

UK

Cross-

sectional

Health

y,32

5860

–79

<1/wkvs.>

7/wk

Fruitintake:

↓serum

CRPlevels;v

egetableintake:↔

Alm

eida-de-souza

(201

7)(22)

Portugal

Cross-

sectional

Health

y,41

212

–18

Highestvs.low

esttertile

Greater

varietyof

vegetableconsum

ption:

↓serum

levels

ofCRP,IL-6

andoverallinfl

ammatoryscore;fruit

variety:

↔1ACN,antho

cyanin;B

B,b

lueberries;BLB,b

ilberries;CHD,coron

aryheartd

isease;CJC

,cranb

erry

juicecocktail;

CO,con

trol;C

OPD

,chron

icob

structivepu

lmon

arydisease;

CRP,C-R

eactiveProtein;

CVD,cardiovasculardisease;FD

S,freeze-dried

strawberries;floz,fl

uidounce;FR

LFE

,flavonol-richlychee

fruitextract;F

V,fruitandvegetable;FV

B,fruitandvegetablejuicepowderconcentratewith

added

berrypowder;FV

CJ,fruitand

vegetableconcentratejuice;FV

I,fruitand

vegetableindex;GO,grape

pomaceandom

ijiafruitethanolextracts;H

AD,highantio

xidantdiet;H

D,highdo

se;hsC

RP,high

-sensitiv

ityC-reactiveprotein;

ICAM,intracellu

laradhesion

molecule;IFN,interferon;

In.,interventio

n;iN

OS,

isoform

ofnitricox

idesynthase;JPC

,juice

powderconcentrate;LAD,low

antio

xidant

diet;L

D,low

dose;

LPS

,lipop

olysaccharide;MC,M

ontm

orency

cherries;M

CP-1,

mon

ocytechem

otactic

protein-1;

MetS,

metabolicsynd

rome;MIG

,mon

okineindu

cedby

interferon

-gam

maMIP-1b,

macroph

ageinflammatory

protein1-b;

MNC,m

onocytes;P

BMC,p

eripheralb

lood

mon

ocytecell;

PGE2,

prostaglandinE2;

PJ,p

omegranatejuice;Pl.,Placebo;

PPT,

polyppreventio

ntrial;RANTES,

regu

latedup

onactiv

ationno

rmal

Tcellexpressedandsecreted;RCT,

random

ized

controlledtrial;RGJ,redgrapejuice;

sICAM,soluble

intracellularadhesion

molecule;

sVCAM,solub

levascular

adhesion

molecule;

TLR,toll-lik

ereceptor;

T2D

M,type2diabetes

mellitus;V

CAM,vascularadhesionomolecule;WB,w

ildblueberries;

↑,increase;↓

,decrease;

↔,noeffect.

n = 55 studies was positive. These studies were methodologi-cally strengthened by their use of random allocation to the in-tervention and control group or treatment arm (cross over trials),double blinding, and comparability of study group; n = 28 stud-ies were neutral. Factors that limited the methodologic quality ofthe studies rated as neutral included, insufficient detail providedregarding the study inclusion/exclusion criteria, group compara-bility, intervening factors, and data collection and analysis. Nostudy was excluded due to negative quality.

Effects of fruit and vegetable intake on systemic/airwayinflammatory biomarkers

Fruit only

Thirty-six experimental trials (2, 8, 25–58), and one cross-sectional study (59) assessed the association of fruit intake and in-flammatory biomarkers and circulating levels of high-sensitivityCRP (hsCRP), TNF-α, IL-6, IL-8, soluble vascular adhesionmolecule-1 (sVCAM), soluble intercellular adhesion molecule-1 (sICAM), or E-selectin (Table 2). Fruit intake was reported tohave beneficial effects on at least 1 marker of systemic inflam-mation such as hsCRP or TNF-α in most of the studies (2, 8,25, 27, 29–32, 35–41, 43–46, 48–51, 59), although some stud-ies (26, 28, 33, 34, 42, 47, 52–58) found no significant effects.The type of fruits investigated varied, and included berries, suchas strawberries, blueberries, or barberry (n = 12) (25, 28, 37,39, 41, 43, 45, 47, 52, 55, 58, 59), pomegranate juice (26, 33,49, 50) or extract (2) (n = 5), grape products such as grape ex-tract (38, 51), powder (27, 54) or juice (31), and cherries (29,40, 56). Other studies examined whether consumption of mixed-fruit juice (8, 42), orange juice (30, 32, 34, 48), kiwifruit (36, 53),grapefruit (35), star fruit (44), raisins (57), or lychee extract (46)beneficially altered circulating levels of hsCRP, TNF-α, IL-6,IL-8, sVCAM, sICAM, or E-selectin.

Amagase et al. (25) examined the effects of daily barberry juiceon immune function, and reported that the intervention group hadsignificantly decreased serum levels of IL-2 compared to baselineand the control group, whereas serum concentration of IL-4 wasnot altered by the treatment. In contrast, a 3-mo trial by Vidalet al. (52) found that there was no difference in CRP, IL-6, ororosomucoid following barberry supplementation compared toplacebo. Guo et al. (37) described a 4-wk trial comparing bay-berry juice with placebo and reported the intervention group hadsignificantly lower plasma levels of TNF-α and IL-8 compared toplacebo. Similarly, 2 studies (39, 41) showed that supplementa-tion with bilberries resulted in decreased CRP and IL-6; however,plasma concentration of TNF-α unexpectedly increased follow-ing bilberry intervention in 1 study (39). In another trial by Larmoet al. (43) consumption of frozen sea buckthorn berries for 90d significantly decreased serum levels of CRP compared to thebaseline and placebo. Two studies (45, 47) reported that blueberryintervention did not reduce plasma levels of CRP, IL-6, TNF- α,and sVCAM. One study assessed the effects of strawberries onbiomarkers of inflammation, and showed no significant changeon blood levels of hsCRP, sICAM, and sVCAM (28). Two stud-ies reported no significant changes in IL-6, CRP, IL-1β, or TNF-αfollowing consumption of berry extract (55) or mixed-berry bev-erage (58). A cross-sectional study by Duffey et al. (59) reported


146 HOSSEINI ET AL.

TABLE3

Summaryof

includ

edstud

iesexam

iningtheeffectsof

fruitand

vegetableintake

onim

mun

efunctio

n1

Firstautho

r(year)

Cou

ntry

Stud

ydesign

Popu

latio

n,n

Age,y

Interventio

nEffectson

immun

ecells

Row

e(201

1)(80)

USA

RCT

Health

y,85

50–7

536

0mL(12oz)of

beverage

(100

%grapejuiceor

placebo)

daily

for9wk

↑Num

bersof

circulating

γδ-T,↔

proliferationof

γδ-T

cells

Bub

(200

3)(8)

Germany

Crossover

RCT

Non

smok

ing,27

35±

42po

lyph

enol-richjuices

[236

mg(A

)and22

6mg(B

)po

lyph

enolswith

cyanidin

glycosides

(A)and

epigallocatechin

galla

te(B

)](330

mL/d)supp

lemented

for2wk

↑Lym

phocyteproliferativerespon

siveness,the

lytic

activ

ityof

NKcells

Amagase(200

9)(25)

USA

RCT

Health

y,60

55–7

212

0mLstandardized

barberry

fruitjuice

(equ

ivalentto

≥150

gfreshfruit)or

placebodaily

for30

d↑N

umberof

lymph

ocytes,↔

numberof

CD4,CD8,and

NKcells

McA

nulty

(201

1)(45)

USA

RCT

Well-trained

subjects,25

BB: 31.1

±12

.6;

placebo:

33.4

±16

.0

250gblueberries/dfor6wkand37

5ggiven1hpriorto

2.5hof

runn

ingor

placebo

↑NKcellcoun

ts

Kon

tiokari(200

5)(24)

Finland

RCT

341child

ren

4.3

Cranb

erry

juice(5

mL/kg)

oraplacebofor3mo

↔Carriageof

respiratorybacteria

Shem

a-Didi(20

12)(49)

Israel

RCT

Chron

ichemod

ialysis

patie

nts,10

1

>18

100mLPJ,ormatchingplacebodu

ring

each

dialysis

(3/w

k)for1y

↓Infectio

nincidencerate

Nishizawa(201

1)(46)

Japan

RCT

Lon

g-distance

runn

ers,20

20.6

±1.25

Twice-daily

FRLFE

(100

mg/d,or

50mg/do

se)or

placebo

for2mo

↔Neutrop

hilo

rlymph

ocytecoun

ts,totalWBCmod

ified

Vidal(201

2)(52)

China

RCT

Elderly,150

65–7

0Lacto-w

olfberry

orplacebo(13.7g/d)

for3mo

↔Im

mun

ecells

compo

sitio

n,autoantib

odieslevels

Zun

ino(201

4)(54)

USA

Crossover

RCT

Obesity,24

20–6

092

ggrapepowder(∼

4servings

ofgrape)

orplacebofor9

wk

↔Proliferativerespon

sesof

CD4+

orCD8+

Tcells,

cytokine

prod

uctio

nby

activ

ated

Tcells

Zun

ino(201

3)(81)

USA

Crossover

RCT

Obesity,20

20–5

0Strawberrypowder(∼

4servings

offrozen

strawberries/d)

orplacebofor3wk,

andthen

crossedover

toanother

treatm

entfor

thelasttreatm

ent

↔Cellcou

nts,theoverallp

ercentageof

CD4+

and

CD8+

cells

at24

,48,and72

h,cytokine

prod

uctio

nby

T-lymph

ocyte

Hun

ter(201

2)(53)

New

Zealand

Crossover

RCT

Elderly,32

≥65

The

equivalent

of4kiwifruitor

2bananas/dfor4wk,

with

treatm

entsseparatedby

a4-wkwasho

utperiod

↔Innateim

mun

efunctio

n(N

Kcellactiv

ity,

phagocytosis)

McA

nulty

(201

4)(78)

USA

RCT

Health

y,25

18–5

0Blueberry

(equ

ivalentto25

0gberries)or

placebodaily

for6wk

↑AbsoluteNKcells

Nantz(201

3)(79)

USA

RCT

Health

y,45

21–5

0Low

-caloriecranberrybeverage

(450

mL)madewith

ajuice-derived,powderedcranberryfractio

n(n

=22

)or

aplacebobeverage

(n=

23),daily

for10

wk

↑Proliferationindexof

γδ-T

cells,↔

Bcells,N

Kcells,

αβ-T

cells,and

mon

ocytes

Boh

n(201

0)(82)

Norway

Trial

Health

ysm

okers,29

45–7

5Antioxidant-richdiet,a

kiwifruitdiet(3

kiwifruits/d

addedto

theregu

lardiet)or

acontrolg

roup

for8wk

Upregulationgrou

psof

genesinvolved

inregu

latio

nof

immun

ecells

Nantz(201

2)(84)

USA

RCT

Health

y,12

021

–50

2.56

ggarlicextract/d

orplacebofor90

d↑P

roliferationof

NKcells,activationstateof

theNK

popu

latio

n,γδ-T

cells

proliferation

Watzl(200

3)(9)

Germany

Crossover

RCT

Health

y,22

28.7

±5.9

330mL/d

ofeither

tomatojuice(37.0mglycopene/d)or

carrot

juice(27.1mg

β-carotene/dand13

.1mg

α-carotene/d)

for2wkon

alow-carotenoiddietwith

a2-wkdepletionperiod

afterjuiceinterventio

n

Low

-carotenoiddiet:↓

NKcellcytotoxicity,and

lymph

ocyteproliferation;

juiceinterventio

n:↔

Watzl(199

9)(10)

Germany

Exp

erim

ental

Health

y,23

27–4

0Weeks

1–2:

low-carotenoidperiod

;throu

ghou

tweeks

3–8:

daily

consum

ptionof

330mLtomatojuice(40mg)

(weeks

3–4),330

mLcarrot

juice(w

eeks

5–6),10g

driedspinachpowder(w

eeks

7–8)

Low

-carotenoiddiet:↓

proliferationof

PBMCs;tomato

juiceconsum

ption:

↔lymph

ocyteproliferation;

carrot

juiceandspinachpowderconsum

ption:

↔

(Continued)



TABLE3

(Continued)

Firstautho

r(year)

Cou

ntry

Stud

ydesign

Popu

latio

n,n

Age,y

Interventio

nEffectson

immun

ecells

Briviba

(200

4)(14)

Germany

RCT

Smoker,25,

nonsmoker,

30

30–4

53tomatooleoresinextractcapsules/d(eachcontaining

4.88

mglycopene,0.48mgphytoene,0.44mg

phytofl

uene

and1.18

1mg

α-tocop

herol)or

placebofor

2wk

↔Ly

mph

ocyteproliferation,NKcellactiv

ity

Watzl(200

0)(15)

Germany

RCT

Elderly,50

63–8

633

0mLtomatojuice/d(47.1mglycopene/d)or

mineral

water

for8wk

↔Ly

mph

ocyteproliferation

Murashima(200

4)(83)

Japan

Exp

erim

ental

Health

y,12

20–3

6Freshbroccolisprouts(100

g/d)

for1wk

↔NKcellactiv

ityLiu

(201

2)(85)

USA

Self-con

trolled,

long

itudinal

stud

y

HIV-infected

wom

en,77

≥18

“Every

oralmostevery

day”

vs.“on

lyas

needed”

↔Any

immun

olog

icmarkers

Inserra(199

9)(65)

USA

Beforeandafter

Elderly,53

60–8

6y

Fruitjuice

supp

lementscontained85

0mgfruit

powder/capsulemadefrom

extractsof

apples,orang

es,

pineapples,papaya,cranberries,andpeaches.Vegetable

supp

lementscontained75

0mgvegetable

powder/capsuleandcontainedextractsof

carrots,

parsley,beets,broccoli,

kale,cabbage,spinach,and

tomatoes.Participantsconsum

edextractfor

80d

↑Spo

ntaneous

proliferationof

PBMCs,NKcell

cytotoxicity

Gibson(201

2)(5)

UK

RCT

Health

y,83

65–8

5≤2

FVpo

rtions/d

or≥5

FVpo

rtions/d

for16

wk

↑Antibod

ybind

ingto

pneumococcalcapsularLPS

(total

IgG),

↔antib

odybind

ingto

tetanu

stoxo

idJin(201

0)(3)

USA

RCT

Health

y,11

722

–55

Placebo,FV

,orFV

Bcapsulefora60

-dperiod

↔WBCcoun

tsKnab(201

4)(67)

USA

RCT

Cyclists,43

In:3

5.1

±8.0;

Pl:3

5.5

±8.2

Afreeze-dried

FVjuicepowder(230

mgflavono

ids/d)

orplacebofor17

d↔

Immun

efunctio

n(G

-PHAGandM-PHAG)

Nantz(200

6)(70)

USA

RCT

Health

y,59

21–5

3FV

CJ4capsules/d

orplacebofor77

d↑N

umberof

γδ-T

cells

Watzl(200

5)(71)

Germany

RCT

Intake

of<2

servings

FV/d

31±

92,5,or

8servings/d

ofcaroteno

id-richvegetables

and

fruitfor

4-wkperiod

8servings

FV/d

↔im

mun

olog

icmarkers

Winkler

(200

4)(86)

Germany

RCT

HIV,2

3vs.

healthy

controls,18

20–5

31Lfruitjuice

(group

J)or

30mLFV

concentrate(group

C)daily

for16

wk

Fruitjuice:↑

PHA-ind

uced

lymph

ocyteproliferationin

HIV

+andin

HIV-subject,

↔thecoun

tofCD4+

and

CD8+

cells,the

CD4+

:CD8+

ratio

andHIV

viralload

Hendricks

(200

8)(87)

USA

Coh

ort

HIV,3

48≥1

8Highestvs.low

estm

eanintake

↑CD4coun

tRoo

t(20

12)(76)

USA

Cross-sectio

nal

Health

y,10

0018

–85

Fruit:

≤2vs.>

2servings/d;v

egetables:

≤3vs.>

3servings/d

↓WBCcoun

ts

Nettle

ton(201

0)(88)

USA

Cross-sectio

nal

Health

y,11

01F:

70.7

±5.4;

M:71.8

±5.5

Highestvs.low

estq

uartile

↔Im

mun

olog

icmarkers

Kruzich

(200

4)(21)

USA

Cross-sectio

nal

HIV-infected,

264andHIV

uninfected,

127

13–2

3Maxim

umvs.m

inim

umscore

↔Im

mun

olog

icmarkers

1BB,blueberries;C

D,cluster

ofdifferentia

tion;

FRLFE

,flavon

ol-richlychee

fruitextract;F

V,fruitandvegetables;F

VB,fruitandvegetablejuicepowderc

oncentratewith

addedberrypowder;FV

CJ,fruit

andvegetableconcentratejuice;G-PHAG,g

ranulocytephagocytosisandoxidativeburstactivity

;HD,H

eartDisease;In.,intervention;

M-PHAG,m

onocyteph

agocytosisandox

idativeburstactivity

;NKcells,

naturalk

iller

cells;P

BMC,p

eripheralb

lood

mon

ocytecell;

PHA,p

hytohemagglutinin;P

J,po

megranatejuice;Pl.,placebo;

RCT,

rand

omized

controlle

dtrial;WBC,w

hitebloo

dcell;

↑,increase;↓

,decrease;

↔,n

oeffect.


148 HOSSEINI ET AL.

FIGURE 3 Forest plot of randomized controlled trials investigating the effects of fruit and vegetable intake on circulating C-reactive protein levels (mil-ligrams per liter). Values are mean differences with 95% CIs determined with the use of generic IV random-effects models. Heterogeneity was quantified byI2 at a significance of P < 0.10. IV, inverse variance.

that consumption of cranberry juice was significantly associatedwith lower CRP levels.

We have previously investigated the effects of pomegranateextract consumption on inflammation (2), and reported thatpomegranate extract intervention for 30 d reduced plasma CRPand IL-6. Similarly, consumption of pomegranate juice resultedin reduction of plasma IL-6, TNF-α, and CRP levels in 2 stud-ies (49, 50). However, some studies (26, 33) did not observe anychanges in circulating inflammatory biomarkers, such as hsCRP,intercellular adhesion molecule-1 (ICAM-1), vascular adhesionmolecule-1 (VCAM-1), and IL-6, following pomegranate juiceconsumption. Three studies reported significantly decreased lev-els of TNF-α (38), CRP (51), or monocyte chemotactic protein-1(MCP-1) (31) following grape supplement intervention. In con-trast, intake of grape powder for 9 wk had no significant effecton blood CRP level (54). In another trial by Barona et al. (27)consumption of grape powder for 4 wk increased expression ofinducible nitric oxide synthase (iNOS) and IL-10. However, nosignificant changes were observed in any inflammatory biomark-ers, such as IL-6 and TNF-α.

Interventions to increase cherry consumption reduced circulat-ing levels of IL-6 and hsCRP, compared with control groups in 2studies (29, 40); however, 1 study reported no significant changein plasma CRP and IL-6 concentrations (56). Four trials exam-ined inflammatory responses following orange juice intake, with3 showing a protective effect against systemic inflammation (pri-marily hsCRP, IL-6, or prostaglandin E2) (30, 32, 48). However,Deopurkar et al. (34) found no effect in a similar orange juiceintervention trial.

Gammon et al. (36) described a 4-wk trial of 2 greenkiwifruit/d plus healthy diet compared with healthy diet, and

reported that kiwifruit resulted in a significant reduction in serumlevels of CRP and IL-6. In another trial by Hunter et al. (53), nosignificant difference was observed in the serum level of hsCRPbetween those who received kiwifruit compared with those whoreceived bananas daily for 4 wk.

Three studies investigated the effects of consumption of grape-fruit (35), star fruit (44), or lychee extract (46), and all showed asignificant reduction in either hsCRP or TNF-α compared withplacebo. No changes in plasma levels of CRP and leptin werereported in a raisin intervention study (57). Two trials assessedthe effects of mixed-fruit juice intake on IL-2, IL-6, IL-8, CRP,or TNF-α. One study (42) did not observe any changes, whereasthe other (8) reported a significant increase in IL-2 secretion byactivated lymphocytes compared with baseline.

Vegetables only

Eight trials (4, 9, 10, 14, 15, 60–62) examined anti-inflammatory responses to increased vegetable intake, with3 showing a protective effect on inflammation including reducedhsCRP, TNF-α, and IL-6 (4, 60, 61) (Table 2). In a 9-wk trial(60), intake of garlic supplements decreased serum levels of CRPcompared to placebo. In another trial (14), no change in TNF-αwas observed following a low-carotenoid diet supplemented witha tomato extract for 2 wk. Daily consumption of tomato juicealso had no significant effect on CRP, IL-2, IL-4, and TNF-α (9,10, 15, 62). In contrast with these findings, we previously showedthat supplementation with tomato juice for 20 d resulted in asignificant reduction in serum concentrations of IL-8 and TNF-αcompared to placebo and baseline (4). In another study (61), 10-dbroccoli consumption significantly decreased plasma CRP levels.



FIGURE 4 Forest plot of randomized controlled trials investigating the effects of fruit and vegetable intake on circulating TNF-α (pg/mL). Values aremean differences with 95% CIs determined with the use of generic IV random-effects models. Heterogeneity was quantified by I2 at a significance of P< 0.10.IV, inverse variance.

Fruit and vegetables

Twenty-five studies, including 17 experimental trials (1, 3, 6,11–13, 63–73), 1 cohort (23) and 6 cross-sectional studies (20,22, 74–77), assessed the effects of F&V intake on systemic orairway inflammation (Table 2). One cohort (23) and 5 cross-sectional studies (20, 22, 74–76) reported that F&V intake wasinversely associated with circulating levels of inflammatory cy-tokines, such as CRP, IL-6, and TNF-α. Wannamethee et al. (77)reported that fruit intake was significantly associated with lowerplasma CRP levels, though vegetable intake was not. The major-ity of experimental trials (3, 6, 13, 63, 65, 68–73) (66%, n = 11)

reported a significant reduction in systemic inflammation as indi-cated by inflammatory biomarkers including hsCRP, TNF-α, IL-6, and E-selectin following F&V consumption, whereas 6 trials(1, 11, 12, 64, 66, 67) found no effect of F&V intake on systemicor airway inflammation.

Studies on the effects of F&V intake on immune cellpopulations

Fruit only

Twelve experimental trials (8, 25, 45, 46, 52–54, 78–82) ex-amined the effects of fruit intake on immune cell function, and

FIGURE 5 Forest plot of randomized controlled trials investigating the effects of fruit and vegetable intake on circulating IL-6 (pg/ml). Values are meandifferences with 95% CIs determined with the use of generic IV random-effects models. Heterogeneity was quantified by I2 at a significance of P < 0.10. IV,inverse variance.


150 HOSSEINI ET AL.

FIGURE 6 Forest plot of randomized controlled trials investigating the effects of fruit and vegetable intake on γ δ-T cell population percentage. Values aremean differences with 95% CIs determined with the use of generic IV random-effects models. Heterogeneity was quantified by I2 at a significance of P< 0.10.IV, inverse variance.

1 study (24) assessed whether fruit intake can beneficially affectrespiratory bacterial flora (Table 3). Nine studies (8, 45, 46, 54,78–82) reported that fruit consumption induced beneficial alter-ations in immune cell function, whereas some studies (24, 25, 52,53) found no effect (on immune cell populations).More than 50%of studies (n= 7) (24, 25, 45, 52, 78, 79, 81) examined the effectsof different kind of berries, mostly cranberries and blueberries,on immune cell function. Other studies tested the hypothesis thatconsumption of grapes (54, 80), kiwifruit (53, 82), lychee extract(46), or mixed-fruit juice (8) can modify immune function.

Two studies (45, 78) found that intake of blueberries increasedthe NK cell population. In another trial by Nantz et al. (79) in-take of a low-calorie cranberry beverage increased the prolifera-tion index of γ δ-T cells. In agreement with these findings, Bub etal. (8) found that fruit juice consumption significantly increasedlymphocyte proliferative responses as well as the lytic activity ofNK cells. In another study (81), consumption of strawberries for 3wk was found to increase the production of TNF-α by the mono-cyte population after stimulation with LPS, which may improvethe effectiveness of an immune response to invading pathogens.In contrast, 3 studies examining consumption of either barberries(25), goji berries (52), or kiwifruit (53) found no significant effecton immune cell proliferation. Similarly, consumption of lycheeextract (46) for 2 mo did not change proliferation of neutrophilsor lymphocytes; however, total white blood cell counts weremod-ified. Increased numbers of circulating γ δ-T cells were reportedfollowing grape juice consumption for 9 wk (80). In contrast, inanother trial (54) consumption of grape powder for 9 wk did notaffect the immune cell population; however, a significant increasein the production of IL-6 and IL-1β was reported in LPS-activatedmonocytes.

In terms of other effects on immunity, adding kiwifruits dailyto a regular diet resulted in upregulation of 11 genes involved inimmune-related processes compared to baseline and control (82).

Also, composition of respiratory bacteria was not altered aftercranberry juice intake for 3 mo (24).

Vegetables only

Seven studies (9, 10, 14, 15, 83–85) examined immune cellpopulations following vegetable intake, with n= 3 showingmod-ulation of immune cell function (9, 10, 84) (Table 3). In a 3-motrial (84), intake of garlic supplements increased proliferation ofNK cells and γ δ-T cells compared to placebo, whereas garlic hadno effect on immune cells in another supplementation study (85).Watzl et al. (10) found that carotenoid depletion decreased prolif-eration of peripheral blood mononuclear cells (PBMCs). In onestudy (9), supplementation with tomato juice increased lytic ac-tivity of NK cells, although no effects were seen in other studiesinvestigating tomato extract (14) and tomato juice (15). In addi-tion, no beneficial effect was observed on immune cell functionfollowing consumption of broccoli (83).

Fruit and vegetables

Twelve studies, including 8 experimental trials (3, 5, 65, 67,70, 71, 82, 86), 1 cohort (87) and 3 cross-sectional studies (21,76, 88), assessed the effects of F&V intake on immune cells(Table 3). More than 60% of studies (n = 7) showed a beneficialassociation of F&V consumption and function of immune cells(5, 65, 70, 76, 82, 86, 87). Bøhn et al. (82) reported upregulationof genes involved in the immune-related processes followingconsumption of a high antioxidant diet (>5 servings of F&V/d)compared to baseline and a control group. In 3 studies (65,70, 86), increased proliferation of lymphocytes were observedin the group supplemented with F&V extract compared toplacebo. Similarly, a prospective study (87) of 348 HIV-positiveadults reported that F&V intake was correlated with number

FIGURE 7 Forest plot of randomized controlled trials investigating the effects of fruit and vegetable intake on αβ-T cell population percentage. Values aremean differences with 95% CIs determined with the use of generic IV random-effects models. Heterogeneity was quantified by I2 at a significance of P< 0.10.IV, inverse variance.



FIGURE 8 Forest plot of randomized controlled trials investigating the effects of fruit and vegetable intake on NK cell population percentage. Values aremean differences with 95% CIs determined with the use of generic IV random-effects models. Heterogeneity was quantified by I2 at a significance of P< 0.10.IV, inverse variance.

of CD4+ T lymphocyte cells. A cross-sectional study by Rootet al. (76) showed that fruit intake was inversely associated withwhite blood cell count (WBC), although, they did not find anyassociation between vegetable intake and WBC. In contrast, 5cross-sectional studies (3, 21, 67, 71, 88) found no significantassociation between F&V intake and immune function.

Findings from meta-analysis

Through the use of meta-analysis, we examined changes incirculating levels of the most commonly evaluated inflammatorybiomarkers, including CRP, TNF-α, and IL-6, following F&Vintervention. Higher F&V intake was correlated with lower bloodlevels of CRP (MD: –0.34; 95% CI: –0.58, –0.11; P < 0.01;I2 = 71%) (Figure 3) and TNF-α (MD: –0.87; 95% CI: –1.59,–0.15; P= 0.02; I2 = 86) (Figure 4). However, the meta-analysisshowed F&V intervention did not have a significant effect onIL-6 levels (MD: –0.12; 95% CI: –0.31, 0.08; P = 0.2; I2 = 0)(Figure 5). Changes in immune cell populations following F&Vconsumption were also analyzed. F&V intake was associatedwith a higher percentage of γ δ-T cells (MD: 1.68; 95% CI:0.29, 3.07; P = 0.02; I2 = 72) (Figure 6), although F&V intakehad no significant effect on other immune cell populations(Figures 7 and 8). No meta-analysis was possible on theobservational research, as the studies used heterogeneousmethods in reporting outcomes of interest.

DISCUSSION

This systematic review and meta-analysis supports the epi-demiologic evidence that higher consumption of F&V is asso-ciated with reduced inflammation. We found that the majority of

studies (n = 56; 71%) reported protective effects of F&V intakeon inflammation or immune function. The meta-analysis showedthat higher intake of F&V is associated with lower levels of CRPand TNF-α (P < 0.05) (Figure 9). The effect of F&V intake onimmune cell function was less clear due to the limited numberof available studies; however, meta-analysis showed that higherconsumption of F&V was associated with an increased γ δ-T cellpopulation (P < 0.05) (Figure 10).

Chronic systemic inflammation leads to reduced human lifespan, because it increases the prevalence of various diseasespredominantly found in developed countries, including obesity(4), diabetes (50), and some cancers (63). The ability of F&Vto protect against the development of these chronic conditionsis well documented (3, 16, 17, 89, 90). The mechanisms of pro-tection are not yet clear; however, there are numerous beneficialnutrients in F&V that have antioxidant and anti-inflammatoryproperties, such as carotenoids, vitamin C, vitamin E, flavonoids,and soluble fiber. Individually these nutrients have been shownto be protective against systemic inflammation. For example, across-sectional study (77) of 3254 elderly participants found aninverse association between vitamin C intake and plasma CRPlevels. Similarly, in another study, high plasma vitamin C levelswere correlated with a reduced circulatory CRP concentration(91). Another study reported that supplementation with vitaminE (800 IU/d) significantly decreased CRP levels in diabeticpatients (62). Hence, it is likely that the positive effects ofF&V can be attributed to the combination of these nutrients andsubsequent displacement of proinflammatory nutrients from thediet, such as dietary fat.

Epidemiologic data across the general population has demon-strated that plasma lycopene and β-carotene were inverselyassociated with inflammatory biomarkers, including CRP and

FIGURE 9 Overall effects of fruit and vegetable intake on inflammatory biomarkers. CRP, C-reactive protein; N, number of participants included in themeta-analysis; n, number of studies included in the meta-analysis.


152 HOSSEINI ET AL.

FIGURE 10 Overall effects of fruit and vegetable intake on different immune cell population percentage. N, number of participants included in the meta-analysis; n, number of studies included in the meta-analysis; NK cells, natural killer cells.

sICAM (92). In addition, consumption of carotenoid-rich foodhas been shown to reduce systemic inflammation in overweightand obese people (4). In another study, lycopene inhibited TNF-α–induced endothelial ICAM expression (93). Flavonoids area group of polyphenols found in F&V with antioxidant andanti-inflammatory effects (94). Short-term supplementation ofpure flavonoids, including quercetin and epicatechin, decreasedIL-1β and E-selection (95). The exact mechanism by whichflavonoids inhibit inflammation is not clear. It has been suggestedthat quercetin, in particular, inhibits both cyclo-oxygenase andlipoxygenase activities, thus diminishing the formation of inflam-matory metabolites (96). Another immune-protective compoundof F&V is fiber. Recently, we reported that dietary fiber was in-versely associated with airway inflammation (97). In line withthese findings, several studies in the general population reportedthat dietary fiber intake was inversely related to systemic inflam-mation (98, 99). It has been suggested that dietary soluble fiber in-take can modulate inflammatory responses, due to production ofshort-chain fatty acids, which activate the free fatty acid receptorsG protein–coupled receptor 41 and 43 (GPR41 and GPR43), andinhibit histone deactylases, with both of thesemechanisms havinganti-inflammatory actions (100, 101). Since various phytochem-icals have mutually beneficial effects, it has been suggested thatcombinations of such nutrients, found in F&V, can enhance theirroles in immune responses to inflammation (102).

To our knowledge, the present systematic literature reviewand meta-analysis is the first to assess the effects of F&V con-sumption on inflammation and immune function. Previous meta-analyses have investigated the effects of F&V intake on the riskof chronic diseases such as type 2 diabetes (89, 90), and coronaryheart disease (16). A meta-analysis of 5 clinical trials (103) as-sessed the effects of pomegranate juice consumption on plasmaCRP levels, and showed no significant effect, which may be aresult of the small number of studies.

The strengths of this review include the broad systematic lit-erature search, defined inclusion criteria and clear approach tocollecting data, thorough assessment of the evidence, inclusionof studies with various designs, and meta-analysis. Furthermore,all studies were assessed for quality and validity.

However, our study has some limitations worth noting that arecommon to analysis of dietary interventions. First, the includedstudies were heterogeneous with respect to the intervention or thediet exposure, design, study size, and duration of follow-up. Somestudies assessed the effects of specific types of F&V, whereas oth-ers investigated the effects of total F&V intake. However, this

limitation has been addressed by presenting the results accordingto study exposure. The meta-analysis was also performed basedon the intervention employed. Second, dissimilar populations interms of age and health condition were observed among the stud-ies. Some studies were performed in healthy populations (11, 14,25, 34), whereas other studies were conducted in patients withtype 2 diabetes (50), metabolic syndrome (27), high blood pres-sure (26), high risk of CVD (30), or in other conditions such aspregnancy (60). Due to the limited number of studies availablefor inclusion in the meta-analysis, separating the analysis accord-ing to health status was not possible. Moreover, different studiesused different methods of dietary assessments, such as 24-h re-call, food record, or food-frequency questionnaire. Finally, thepossibility of publication bias exists, as studies with positive find-ings are more likely to be published.

In conclusion, this systematic review of the literature suggeststhat a higher intake of F&V decreases inflammation, and also en-hances immune cell populations. These findings support recom-mendations to increase F&V intake for the primary prevention ofmany chronic diseases. However, well-designed randomized con-trolled trials are needed to confirm our results. Future research isalso required to explore potential mechanisms underlying the ob-served associations.

The authors’ responsibilities were as follows—BH, BSB, and LGW: de-signed the study; BH and AS: conducted the search; BH: analyzed the dataand wrote the paper; BSB, AS, and LGW: revised the paper; MRS, AC, andPABW: reviewed the paper; LGW: had primary responsibility for the finalcontent; and all authors: read and approved the final manuscript. None of theauthors reported a conflict of interest.

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