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3

May 2012

Proceedings of the symposium

11th European Nutrition Conference - Madrid (Spain),October 26-29, 2011

Do we need dietarypolyphenols for health?State-of-the-art and perspectives

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NutrInsight • Do we need dietary polyphenols for health?

Editorial

1 Types, food sources, consumption and bioavailability of dietary polyphenols

1.1 Typesandfoodsources

1.2 Consumptionofdietarypolyphenols

1.3 Bioavailabilityandmetabolism

2 Dietary polyphenols and disease prevention: a review of the evidence from epidemiological and intervention studies

2.1 Polyphenolsandcardiovasculardisease

2.2 Effectofpolyphenolsondiabetes

2.3 Polyphenolsandcancer

2.4 Polyphenolsandbonehealth

3 Mechanisms of action of polyphenols: newly emerging evidence

3.1 Antioxidantactivitiesofpolyphenols

3.2 Inflammation

3.3 Increasingnitricoxidebioavailability

3.4 Prebioticeffects

3.5 Metalchelation

Future perspectives Appendix: Biographies of the speakers

Bibliography

Abbreviations

C o n t e n t s

3

4

4

7

9

13

13

18

19

19

20

21

22

23

23

23

25

26

28

31

2

Polyphenols exhibit a range of in vitro biological activities that

are potentially in keeping with them protecting against age-

related diseases such as cardiovascular disease (CVD), diabetes

and cancer (Chapter 2). More importantly, there have been many

observational and clinical studies on human subjects using

polyphenol rich foods showing that biomarkers of cardiovascular

risk, energy utilisation, digestion, inflammation, lipid metabolism

and diabetes are often significantly improved. Many mechanisms

of action have been proposed and it is quite clear that their role

as antioxidant does not explain all the effects of polyphenols

(Chapter 3).

This booklet is a summary of the symposium presentations by

Prof F A. Tomás-Barberán (Research professor, CEBAS-CSIC,

Murcia, Spain), Dr Paul Kroon (Research Leader - Polyphenols

and Health Group, Institute of Food Research, Norwich, UK) and

Dr Francesco Visioli (IMDEA-Food, Madrid, Spain).

Professor Tomás-Barberán set the scene by covering types,

sources, consumption and bioavailability of dietary polyphenols

(Chapter 1). Dr Kroon then gave an overview of the evidence of

potential health benefits of polyphenols from epidemiological

studies and intervention trials (Chapter 2). Finally, Dr Visioli

discussed possible mechanisms by which these benefits could

occur (Chapter 3).

The timing was particularly opportune since this FENS symposium

followed very shortly after the 2011 International Conference of

Polyphenols & Health held in Sitges, Barcelona [http://www.

icph2011barcelona.com]. All three speakers had attended this

comprehensive conference and this ensured that the information

presented at this symposium was fully up to date. The symposium

was very well attended and lively discussions followed each

paper, which reflects the interest of the nutrition community for

polyphenols and their potential for health.

E d i t o r i a l

3

10 TH European Nutrition ConferenceParis, 10-13 July 2007

The regulation of appetite is a vital component of general health – both physical and psychological.

About the value of controlling appetite

1

Dr Margaret Ashwell OBENutrition Consultant, Ashwell Associates, UK.

Kraft Foods Europe R&D organised a symposium at the 11th

European Nutrition Conference organised by the Federation of

European Nutrition Societies (FENS) [http://www.fensmadrid2011.

com]. The purpose was to share evidence about the potential

health benefits of polyphenols including polyphenols from fruits,

as well as from other food sources such as cocoa, coffee, and

cereals.

The main dietary sources of polyphenols in the European diet

appear to be beverages (coffee, tea, wine), fruits, cocoa products,

and, to a lesser extent vegetables, legumes and cereals.

Polyphenols are a large group of compounds which protect

plants against a variety of stresses (Chapter 1). When consumed

in our diet, they might be beneficial for health and wellbeing

in adulthood and in the elderly population. Evidence for their

protective effect is based on many epidemiological, clinical,

animal, cellular in vitro and mechanistic studies.


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TyPES, FOOD SOURCES, CONSUMPTION AND BIOAVAILABILITy OF DIETARy POLyPHENOLS

1

This chapter will describe what polyphenols are, where they are found in our diet and how much we eat. It will deal also with the level of bioavailability of polyphenols and their metabolites pointing out potential effectiveness on the body.

by Prof Francisco A. Tomás-Barberán

Polyphenols, a complex group of phytochemicals

Polyphenols includeachemicallycomplexand largefamilyofphytochemicals.Theyare,by far, themainsecondary metabolites in plants, and therefore are present in all foods of plant origin. The commonstructural feature of all polyphenols is the presence of phenolic hydroxyl group(s). Simple monomericphenolics,suchasbenzoicacidderivativesandhydroxycinnamicacidderivatives,usuallyco-existinplantswith oligomeric and polymeric derivatives (tannins and lignans etc). Figure 1 shows some of the mostcommongroupsofpolyphenols(phenolicacids,lignans,flavonoidsandstilbenes)withsomemoleculesofinterestandexamplesoftheirmainfoodsources.

Flavonoids,awell-studiedclass,formalargepolyphenolsubgroupwithacarbonskeletonbuiltof2phenylrings(C6)bridgedbyachainof3carbonatoms(C3)formingaheterocyclic6-memberedringwithoxygenand2carbonatomsfromanadjacentphenylring.Theseincludeflavonesandflavanones(foundincitrusfruits); flavonols (found in tea, onions, apples) and flavan-3-ols (catechins and epi-catechins andproanthocyanidins) which are found in tea, red wine, cocoa/chocolate, apples. Other anthocyanins arefoundinfruits,vegetablesandnutsincludingcolouredberriesandaubergine.Isoflavones(foundinsoy)areanotherimportantclassofflavonoids.

Thereisalsomuchinterestinstilbenessuchasresveratrol(inredwine)andotherphenolicssuchasthehydroxycinnamates- incoffee(chlorogenicacids), inwholegrain(ferulicacids).Minorphenolicssuchashydroxytyrosol,foundinolives,shouldnotbeoverlooked.Currently,oliveoilpolyphenolscharacterisedbytheircontentofhydroxytyrosolanditsderivativesaretheonlypolyphenolssofartohaveachievedapositiveopinionforahealthclaiminEurope[EFSA,2011].ThehealthclaimapprovedbyEFSAstatesthatconsumptionofoliveoilpolyphenolscontributestotheprotectionofbloodlipids.

1.1 Types and food sources

TyPES, FOOD SOURCES, CONSUMPTION AND BIOAVAILABILITy OF DIETARy POLyPHENOLS

1


5

Figure 1: The classification of polyphenols with some relevant examples of food sourcesSource: Adapted from D’Archivio et al., 2007; Cheynier, 2005

Polyphenols

Flavonoids Stilbenes OthersLignans

Syringic acid

Ferulic acid Chlorogenic acidCaffeic acid

Phenolic acids

Hydroxybenzoicacids

Anthocyanins

Flavonols

Flavanols

Flavanones

Iso�avones

Others

Hydroxycinnamicacids

Others

Epicatechin

Hesperidin

Apigenin

Quercetin Kaempferol

Catechin

ResveratrolTyrosol

Alkylresorcinols

Flavones

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Figure 2: Total polyphenols content in some foods and beverages (mg/100g or mg/100ml as Gallic Acid Equivalent measured by Folin-Cicalteu method)Source: 1Kraft Foods internal data; 2Phenol-Explorer Database,

http://www.phenol-explorer.eu/, consulted in August 2011

The content of polyphenols in foods

Figure 2showsthetotalpolyphenolcontentofcommonfoodsourcesexpressedasgallicacidequivalentsmeasuredbytheFolin-Ciocalteumethod(gallicacidisoneofthebasichydroxybenzoicacidstructures,andisusedasareferencefortotalphenolicsquantification).Thismethodevaluatesthereducingabilityofallphenol groups. Because of the extraction process, some reducing sugars can react as well, leading toanoverestimationoftotalpolyphenolcontent.

Cocoa powder and chocolate are rich in polyphenols (5953 mg/100g and 2160 mg/100g, respectively)– mainly catechins and proanthocyanidins – and dark berries such as blueberry are high too(471 mg/100g) – anthocyanins.The polyphenols content of some other foods can be lower (coffee, tea)buttheirhighconsumptionmayresultinanimportantcontributiontototalpolyphenolsintake.

The content and chemical nature of these phytochemicals differ largely from one food to another andsomefoodscontainawidemixtureofpolyphenols.TheFolin-Ciocalteumethoddoesnotgivethenatureofindividualphenoliccompoundsineachfood.However,therearesomespecificanalyticalmethodstoassesscontentofindividualphenoliccompounds.Thesemethodsareverydiverseandcanvaryfromonelabtoanotherleadingtoadisparityofresultsforasamemoleculeanalysed.

Total polyphenols content(mg/100g or 100ml)

expressed as Gallic acid equivalents*

Cocoa

powder 2

0

100

200

300

400

500

600

700

800

900

2.100

2.200

5.900

6.000 5.953

Dark

choco

late

+70%

1

2.160

Milk

choco

late

2

854

Hazeln

ut 2

495

Blueb

erry

2

471

Strawber

ry 2

289

Soluble

Coffee

2

267

Red w

ine

2

215

Apple 2

202

Whole

grain

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bstitu

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170

Bread

, Wholem

eal �

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154

Whole

grain

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149

Black

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104

Extra

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in o

live

oil 2

55Series

Importance of extraction process for accurate analysis of the polyphenols content in foods

Thedifferentanalyticmethodsoftenunderestimatethepolyphenolscontentincertainfoodsthatcontainssomenon-extractablephenolics.Non-extractablephenolicshavebeengenerallyoverlookedinfoodcompositionanalysisanddatabases.Applesandberriescontainmainlyextractablepolyphenols,butinotherfruits,suchaspears,redcurrants


7

Table 1: Distribution of polyphenols between extractable and non-extractable compounds in some fruitsSource : Adapted from Tarascou et al., 2010

Appleandberries

Grape

Pear

Cranberry

Redcurrant

Kiwifruit

Banana

90-100

50

50

50

50

20

0

0-10

50

50

50

50

80

100

1.2 Consumption of dietary polyphenols

Estimation of daily diet intake of total polyphenols

Themeandailytotalpolyphenolintakecouldreachmorethanonegram[Pérez-Jiménez et al., 2011].ThisFrench study has given us recent information on total polyphenol intake based on the SUVIMAX Frenchcohort(1995-1996).TheSUVIMAXcohortconsistedof4942middle-agedparticipantswhoconsumedatotalof337polyphenolswithatleasthalfofthepopulationconsuming258polyphenols[Pérez-Jiménez et al., 2011].

AUSDAdatabasehasbeenavailablesince2004[www.ars.usda.gov] toestimateproanthocyanidincontentsoffoods;databasesforisoflavonesandflavonoidshavebeenavailablesince2008and2011.Thesehaveallbeenbasedonacompilationofliteraturesources.

AveryexcitingrecentdevelopmentisthePhenol-Explorerwebbaseddatabase [www.phenol-explorer.eu]whichhasbeencollatedfrompublishedpapersbyDrAugustinScalbertandcolleaguesfromtheInstitutNationaldelaRechercheAgronomiqueinFrance(INRA).Thisdatabasecovers502polyphenolsin452foods.It includes not only flavonoids, but also phenolic acids, lignans, and stilbenes, with invidualglycosides and esters. The database provides information about the type of polyphenols, their foodsourcecontent,theirmetabolites,andtheirpharmacokinetics.The EuroFIR BASIS is also an on-line database developed within the EuroFIR NoE (European FoodInformationRessourceNetworkofExcellence).Itgatherscompositionandbiologicalactivitydataforplantsandplantfoods,compiledfromcriticallyevaluatedpublisheddata[http://ebasis.eurofir.org/Default.asp].

However, the problems of non-extractable polyphenols and non-homogeneity of analysis methodsstill exists; even the most comprehensive database will only be as good as the analytical data that hasbeenpublished in the literature.Goodqualitypolyphenoldatabasesarekey foraccurateestimationsofpolyphenol intake of foods in populations. We urgently need standardisation of the analysis methods,especiallyfornon-extractablepolyphenols,tobettercharacterisethepolyphenolprofileinfoodsinourdiet.

Polyphenols food composition database

Themeasuresofpolyphenolscontentinfoodshaveallowedbuildingfoodcompositiondatabasesonpolyphenolcontent,eitherglobalorfocussedonspecificsubclasses.

and kiwi fruits, up to half their polyphenols are non-extractable by standard methods. Bananas are anextremeexampleandvirtuallyalltheirpolyphenolsarenon-extractable [Tarascou et al., 2010].Thismeansthatthevaluesindatabasesareunderestimatedandthereforepolyphenolconsumptionisprobablyhigherthanestimates.

FOOD % EXTRACTABLE % NON-EXTRACTABLE


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Intake was estimated by using the recent Phenol-Explorer database. They found that 98 polyphenolswere consumed at levels of more than 1 mg/day and the mean total intake was 1193 mg/day.Themaximumintakewas1.8g/day.Previous studies in other countries reported daily polyphenol intake of 863 ± 415 mg/d in Finland[Ovaskainen et al., 2008] and853±512mg/dfrombeveragesinJapan [Fukushima et al., 2009].Differentculturalhabitsandfoodpreferencescouldexplainpopulationdifferencesandthegreatvariabilityobservedinpolyphenolintake.

Estimation of daily intake of specific subclasses of polyphenols

Earlierestimationsofintakesfocussedonsubclassesofpolyphenolsandwerefairlylowat23mg/dayofflavonolsand200-300mg/dayofflavonoids [Hollman & Katan, 1999].TheZamora-Rosstudyprovidesamorerecentestimationofflavonoidintakeof313mg/dfromtheEPIC-Spaincohort[Zamora-Ros et al., 2010]. SomeofthemostrecentdataonsubclassescomefromtheFrenchstudy[Pérez-Jiménez et al., 2011],whereaverageflavonoidintakewas512mg/dayperpersonandhydroxycinnamatesintakereached599mg/dayperperson.Thesetwoclasseswerethemajorpolyphenolsconsumed.Thedifferenceinestimatesobservedabovecancomefromunderestimationofsomecompounds(polymeric,non-extractable,condensedcompounds)byusualmethodsandtheheterogeneityintheanalyticalmethodsused.

Main food contributors to intake of polyphenols

In the SUVIMAX French cohort, coffee and fruits are the main polyphenol providers with respectivecontributionsof520mg/dand206mg/d.Tea,alcoholicbeverages,cocoaproducts,andvegetablesprovidearound100mg/deach;cerealsprovides50mg/d,andseeds,oilsandseasoningscontribute toamuchlesserdegree(Figure 3).Consideringthepolyphenolssubclasses,fruitsarethemainsourcesofflavonoidsintakeinthediet(35%),whereasnonalcoholicbeverages(mainlycoffeeandtea)werethemainsourcesofphenolicacids(nearly80%).

Dietary polyphenols intake in France

0

Source: Dietary intake of 337 polyphenols in French adults, Pérez-Jiménez et al, AJCN, 2011.

200

400

600

800

1000

1200

1400

520

1193 ± 510 mg/day

Coffee

206 Fruits

112 Tea

99 Alcoholic beverages

90 Cocoa products

81 Vegetables46 Cereal products39 Other products

mg/

d

Figure 3 : Total dietary polyphenols intake in France (mg/day)Source: Adapted from Pérez-Jiménez et al., 2011.


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Althoughthedailyintakeofphenolicscanbequitehigh,theabsorptionofthesephytochemicalscanrangewidely according to their structure. Whatever their bioavailability, these compounds can already have adirect effect on digestive tract. Moreover, their metabolism can lead to active metabolites that can bebioavailableandactiveinthebody.

Biological effects of polyphenols in the gastro-intestinal (GI) tract Beforebeingabsorbedintothebloodstreamandmetabolized,thepolyphenolsgothroughtheGItractwheretheycanalreadyhavesomeusefuleffects.These includeanti-inflammatoryeffects [Larrosa et al., 2010], prebiotic effects on the microbiota [Selma et al., 2009; Tzounis et al., 2011; Larrosa et al., 2010],interaction with other nutrients in the gut (such as lipid peroxidation) [Ligumsky et al., 2008; Kanner et al., 2011]andinteractionwithenzymessuchasalpha-glucosidases,alpha-amylasesandpancreaticlipases[Frei et al., 2011]. There is also evidence of in vitro effects with gut cell lines which could indicateanti-tumoralproperties[González-Sarrías et al., 2009].

Pharmacokinetics Thepharmacokineticsofpolyphenolscangiveclues towhere they,andtheirmetabolites,areabsorbed,their distribution in tissues and also about bioavailability. Animal model studies and analysis of humanbiopsiesandtissuesaftersurgeryshowthemetabolitesandconcentrationsthatreachthetissues.TheseareusuallyinthenMrange [González-Sarrías et al., 2010; Azorín-Ortuño et al., 2011]. Stalmach and colleagues [Stalmach et al., 2009] have analysed the circulating hydroxycinnamatescompoundsandtheirmetabolitesafteringestionofcoffeepolyphenols.Theyfoundthatsomecompounds,like caffeic acid, are absorbed fairly quickly and the peak plasma concentrations can be reached within1hour.Ontheotherhand,othercompoundsormetabolitesreachtheirhighestconcentrationsinplasmain4-5hoursindicatingthattheabsorptionofthesepolyphenolstakeplaceinthecolonandprobablyneedtobemetabolizedpriortobeabsorbed.

Factors affecting the bioavailability of polyphenolsUnderstanding the bioavailability, metabolism and tissue distribution is essential to evaluate the healtheffectsofthepolyphenols.Bioavailabilityofpolyphenolsisaffectedbythreemainfactors(Figure 4):•Foodmatrixandotherconstituentsofthedietexertingtheireffectsintheintestinallumen,•Geneticaspectsofindividualsaffectinguptakeintogutcellsandintothebloodstreamviaasystemofenzymesandtransporters,•Microbiotametabolismaffectingtheformationofmetabolitesinthecolonandtheirsubsequentuptakeintothebloodstream.

Figure 3 : Total dietary polyphenols intake in France (mg/day)Source: Adapted from Pérez-Jiménez et al., 2011.

1.3 Bioavailability and metabolism


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Figure 4: Polyphenols transit and absorption in the GI tractPolyphenol interactions with some other food constituents, gut microbiota and intestinal cells. Sources of interindividual

variability in polyphenol absorption and metabolism. Abbr. LPH (Lactose-phloridzin hydrolase), UGT (Glucuronyl transferases), SULT (Sulpho transferases), MRP (Multidrug resistance related protein).

Source: From F A. Tomás-Barberán.

Polyphenols in the GI tract

Bioavailable metabolites (nM concentrations)Blood

Intestinal lumen

Microbiota metabolismfood

foodfood

food

food

food

food

foodfood

Flavonol rutinosides

Hydroxycinnamates

Alkylresorcinols

Flavan 3-ols

StilbenesProanthocyanidins

Lignans

Flavanone rutinosides

Diffusion

UGT

MRP

SULT COMT

UGT SULT COMTSmall intestine ColonInterindividual variability

LPH

food

food

food food

food

FOODfood

Iso�avonesFlavonol glycosides

Anthocyaninsfood

Ellagitannins

• Food matrix and other constituents of the diet

Thesolubilityof thepolyphenols in the foodmatrix theyoccur, impact theirbioavailabity,with themoresoluble, e.g. orange flavanones, being the most bioavailable [Vallejo et al., 2010]. Presence of pectinsandfibresinthefoodmatrixcouldincreasebioavailability [Richling et al., 2011],aswouldsugarandoils[Martinez-Huelamo et al., 2011].Protein,ontheotherhand,woulddecreasebioavailability.

As an example, in a study of epicatechin pharmacokinetics in cocoa, Neilson et al [Neilson et al., 2010] showedthatinsolidchocolate,sugartendedtoincreasepolyphenolsbioavailabilitywhereasmilkproteinappeared to decrease it. On the other hand, in chocolate beverages, bioavailability of polyphenols washigher compared to solid chocolate and nutrients (especially sugars) impact less their bioavailability.This indicates that the physical state of the product as consumed appeared to be the principal factorgoverningbioavailability.


11

• Genetic susceptibility of individuals

Figure 4 shows that several transportersand enzymesare needed for the uptake of polyphenolsacrossthecellsofthesmallandlargeintestine.Singlenucleotidepolymorphisms(SNP’s)havebeendetectedforseveralofthesesuchasPhaseIIenzymes(SULT,UGT) [Ginsberg et al., 2010],PhaseIenzymes(CYP450)[Chen et al., 2011] and membrane transporters (MRP etc.). It is therefore possible that bioavailabilityofpolyphenolswillbedifferentindifferentindividualsaccordingtotheirgeneticmake-up.

• Microbiota metabolism

Recent research has shown that colon microbiota metabolism of large hydrophylic polyphenolmolecules leads to smaller, more lipophilic metabolites [Selma et al., 2009] that are generally betterabsorbedthantheoriginalcompounds.Thisallowsthemtoreachthebloodstreamandtissueswheretheycanexertrelevantbiologicaleffects.Themetabolicprocessesinvolvedincludeflavonoidringfission,glycosidede-conjugation, de-acylation, de-hydroxylation, de-carboxylation, de-methylation and methylation.Differentphenolicscanleadtosimilarmetabolites,whichcanbeconsideredbiomarkersofcolonicmetabolismiftheyaresubsequentlyabsorbed[Selma et al., 2009].

Thegutmicrobiotaofdifferentindividualscanbeverydissimilarandthereforetheintestinalmetabolismofspecificfoodphenolicscandifferfromonesubjecttoanother.Subjectscanbedividedintoproducersornon-producersofcertainmetabolitesandthismightexplainwhytheycanberespondersornon-responderstotheeffectsofpolyphenols [Braune et al., 2011]. Thus,thepotentialhealtheffectsofpolyphenolscanbediversedependingonthegutmicrobiotacompositionandactivityoftheindividuals.

The newly discovered existence of human enterotypes (i.e. distinct and robust clusters) couldexplain the large variability seen in diet intervention studies and could explain why some peoplerespond to the beneficial effects of nutrients, including polyphenols, and some do not. Thereare three main enterotypes and they can be considered analogous to blood groups. These threeenterotypes are based on three genus gut bacteria: Bacteroides, Ruminococcus and Prevotella; andon their relative importance in the gut [Arumugam et al., 2011]. Fecal metagenomes of human gutmicrobiomes have been examined from 39 people in six countries with previously published data setsand have confirmed that the enterotypes are not nation or continent specific [Arumugam et al., 2011].The enterotypes are mostly driven by species composition, but abundant molecular functions are notnecessarily provided by abundant species, highlighting the importance of a functional analysis tounderstandmicrobialcommunities.

Sotheexistenceofalimitednumberofwell-balancedhost–microbialsymbioticstates,whichmightresponddifferently to diet and drug intake, could be another major factor influencing the bioavailability ofpolyphenolsatindividuallevel.


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• Cocoa, tea, coffee, fruit and cereals are sources of phenolic compounds. The content and chemical nature of these phytochemicals differs largely from one food to another. Cocoa is particularly rich in polyphenols, mainly flavan-3-ols catechin and epicatechin.

• The development of exhaustive databases and standardization of the analytical methods will be a key support for further polyphenols investigation.

• Daily intake of total polyphenols can reach more than one gram. Coffee and fruits are the main polyphenols providers (60%) in the French diet (SUVIMAX cohort).

• Although bioavailability of dietary polyphenols is limited, they already have important effects in the GI tract before being absorbed.

• Most of polyphenols are transformed in the colon by the intestinal microbiota.

This conversion is often essential for absorption and modulates the biological activities of these compounds.

• The transformation of the native phenolics into their metabolites depends on the individuals and their difference in gut microbiota composition. This interindividual variability in gut microbiota could lead to varied health effects of each phenolic compound between different individuals.

Ke

y P

oin

ts


13

DIETARy POLyPHENOLS AND DISEASE PREVENTION: A REVIEW OF THE EVIDENCE FROM EPIDEMIOLOGICAL AND INTERVENTION STUDIES

2

This chapter will give an overview of the evidence relating dietary polyphenols to several diseases. It will look at the evidence for the effect of polyphenols on cardiovascular disease (CVD), diabetes, cancer and bone health.Numerous cohort and case-control studies have been reported describing associations between consumption of polyphenols/polyphenol-rich foods and disease risk, but these studies cannot prove any cause and effect relationship. In contrast to these epidemiological studies, randomised controlled trials can give some indication of cause and effect. In the case of CVD, there is enough evidence to consider both.

Epidemiological evidence

Manyfactorsinfluencetheinitiationandprogressionofcardiovasculardiseaseandonlysomeofthoseareofdietaryorigin [Ashwell et al., 2000].PolyphenolshaveonlyrecentlybeenacknowledgedtobeagroupofcompoundswithinthedietwhichmightplayaroleinpreventionofCVD.Oneofthemajorfactorsthatpreventedcompletionofhighqualityepidemiologicalstudieswasthelackofacomprehensiveandaccuratedatabaseofpolyphenolcompositionandcontentoffoods.Today,suchdatasourcesareavailable(cf1.1).Epidemiologicalstudies,particularlyprospectivestudiesasopposedtocross-sectionalstudies,canshowwhichsub-classesofpolyphenolsmaybeimportant(bytheireffectsonmortality)buthigh-qualitytrialscanconfirmaneffectandcanoftenindicatethemechanismsofactionofpolyphenols.

• Dietary flavonols and CVD death risk

ThefirstepidemiologicalstudyonflavonoidswasconductedusingtherelativelysmallZutphenelderlycohortin theNetherlands (806men),andarguably thisstudywas responsible fora rapid increase inflavonoidandhealthresearch [Arts et al., 2001a]. Ameta-analysis [Huxley & Neil., 2003]ofsevenprospectivecohortstudiesincludedpapersfrom1993-2001withatotalof105,000subjectsconcludedthathighflavonolintakesmaybeassociatedwithdecreasedriskfromcoronaryheartdisease(CHD)mortality.Forthehighestintakes,mostflavonolscamefromteawhereasforthelowestintakesthemajorsourceswerefruitsandvegetables.Theaveragedailyintakerangesbetween2mgandmorethan34mg.Therewere2087fatalCHDeventsandthecombinedriskratiowas0.80(95%CI0.69-0.93)afteradjustmentforknownCHDriskfactorsandotherdietarycomponentsbetweenthehighesttertileandthelowesttertileofflavonolconsumption.Inotherwords,thoseconsumingthemostflavonolsexhibitedareducedoverallriskacrossallthesestudiesofabout20%.

• Dietary flavanols and CVD death risk

Thereareonlyafewprospectivestudieslookingatflavan-3-ols.TheZutphenElderlyStudy [Arts et al., 2001a] showedthatcatechins,whetherfromteaorothersources,mayreducetheriskofischemicheartdiseasemortality(p<0.02),butnotofstroke.Ontheotherhand,inaprospectivestudyon34,492postmenopausalwomenfromIowa [Arts et al., 2001b],therewasastronginverseassociationbetweentheintakeof(+)-catechinand(-)-epicatechinandcoronaryheartdiseasedeath(riskratiosfromlowest(medianintake3.7mg/day)tohighestquintile(medianintake52.7mg/day):1.00,0.95,0.97,0.77,0.76).

by Dr Paul Kroon

2.1 Polyphenols and cardiovascular disease


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Thisinverseassociationwasmostpronouncedinwomenatlowriskofcoronaryheartdisease(non-smokers,free of diabetes mellitus and cardiovascular diseases). However, a high intake of «gallates» (more than29.2mg/day),catechinstypicaloftea,wasnotassociatedwithcoronaryheartdiseasedeath.Ofthemajorcatechinsources,applesandwinewereinverselyassociatedwithcoronaryheartdiseasedeath.Thisdatasuggeststhatpreventiveeffectsmightbelimitedtocertaintypesofcatechins,orthattheseareindicatorsofotherdietarycomponentsorahealthylifestyleingeneral.

• Flavonoids and CVD death risk

Another prospective study [Mink et al., 2007] looked at 34,489 postmenopausal women from the IowaWomen’s Health Study; this was the first published report that used USDA databases to estimatecardiovasculardisease,coronaryheartdisease,strokeandtotalmortalityrisksassociatedwithconsumptionof all flavonoid classes.The authors compared quintiles of intake and concluded that dietary intakes offlavanones,anthocyanidins,andcertainfoodsrichinflavonoidswereassociatedwitha22%reductioninCHDbetweenthehighest(median=93.7mg/day)andthelowest(median=7.6mg/day)quintileofintake.Anthocyanidinsalsoleadto12%reductioninCHDmortalityriskwhentheyareconsumedversuswhentheyarenotpresentinthediet.

• Flavonoid subclasses and hypertension

Inavery recentstudy,apooledanalysiswasperformedon87,242women fromNursesHealthStudy II,46,672womenfromtheNursesHealthStudyI,and23,043menfromtheHealthProfessionalsFollow-UpStudy.UpdatedUSDAdatabaseswereusedtoquantifytheconsumptionofthedifferentflavonoidclasses.Theassociationbetweenthequintilesofallflavonoidclassesandtheincidentriskofhypertension(HT)wasinvestigated[Cassidy et al., 2011].In14years,therewere29,018and5629casesofHTinwomenandmen,respectively.

For anthocyanins, there was a 8% decrease in HT risk between the highest (mean consumptions rangebetween 16.2 mg/d and 21.9 mg/d depending on the cohorts) and the lowest (mean consumptionsrange between 5.7 mg/d and 6.8 mg/d depending on the cohorts) quintiles of consumption (Figure 5).Apigeninwascorrelatedtoa5%reductioninHTriskwhencomparingthehighesttothelowestquintilesofconsumption.Catechin intakewasalsoassociatedwithadecreaseof6% inHT risk inparticipantsofage lower than 60 years. These authors concluded that anthocyanins and some flavone (apigenin) andflavan-3-olcompoundsmaycontribute to thepreventionofHT.Thesevasodilatorypropertiesmayresultfrom specific structural similarities (including the B-ring hydroxylation and methyoxylation pattern). Thedose-responsecurvesfromthethreedifferentcohortsandforthecombineddataclearlyindicatedthattherewasacleartrendforreducedriskofincidenthypertensionwithhigheranthocyaninintakes.

Figure 5: Risk of hypertension in relation to anthocyanin intake in different surveys Incident hypertension by quintiles (Q) of anthocyanin intake (stratified by age, 60 y). NHS II, Nurses’ Health Study II;

NHS I, Nurses’ Health Study; HPFS, Health Professionals Follow-Up Study. P for trend, 0.001. Source: Cassidy et al., 2011

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Intervention studies

Manytrialshavelookedattheeffectofpolyphenolsonendothelialdysfunction,aprognosticallyrelevantkeyevent inatherosclerosis.Endothelialdysfunction ischaracterizedbyadecreasedbioactivityofnitricoxide (NO) and impaired flow mediated dilatation (FMD), which is a measure of the compliance of theforearm artery in response to sheer stress (caused by blood flow). FMD evaluates the ability of thearteriestodilateinresponsetoanincreaseinthedemandforblood,oxygenandnutrientsandisreducedifendothelialfunctionisimpairedinanyway.SeveralinterventionstudieshavethereforetestedtheeffectofpolyphenolsonFMD.Therearealsoalargenumberofstudiesthathavemeasuredchangesinbloodpressure,andplasmalipidprofiles(particularlythelevelsoflowdensitylipoproteins(LDL)andhighdensitylipoproteins(HDL)andtriglycerides)inresponsetoaflavonoid-richfoodordiet.Several hundred human intervention trials have been conducted with polyphenols – a few with isolatedpolyphenolsbutmorewithpolyphenol-richfoods.Althoughtheformercanpinpointthebeneficialeffectofasubclassofpolyphenols,thelatterrepresentsthereallifesituationandcanbeconsideredmorerelevant,eveniflessinformative.

• Flavanols and isoflavone and CVD

Several trials have been done to evaluate the effect of flavanols on CVD endpoints. Howeverthe duration of the trials has usually been fairly short and the maximum duration is 18 weeks.To determine longer term effects, Curtis et al [Curtis et al., 2012] have recently reported a one yearcombined flavan-3-ol and isoflavone intervention in 118 postmenopausal women (93 completed thestudy) with type 2 diabetes who were on lipid lowering medication. They consumed two portionsof 13.5 g chocolate which contained 850 mg flavan-3-ols (including 90 mg epicatechin) and 100 mgisoflavonesasaglyconeequivalentsperday.Theywereabletodemonstrateimprovedlipoproteinprofilesin patients, even though they were already on lipid lowering therapy (including statins). LDL-cholesteroldecreasedinflavonoidenriched-chocolategroupby5%whereasitslightlyincreasedintheplacebogroup(Figure 6).

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Figure 6: Improvement in lipoprotein profiles with flavonoids intake Source: Adapted from Curtis et al., 2012


16

Taking into account the different parameters measured during this trial, they found that theestimated10-yeartotalcoronaryheartdiseaserisk(derivedfromUKProspectiveDiabetesStudyalgorithm)wasslightlyloweredintheflavonoidgroup(-1.04%inflavonoidversusplacebogroup).

• Flavonoid-rich foods and cardiometabolic risk factors

Ameta-analysisof133RCTspublishedupuntilJune2007(someacuteandsomechronic)wasperformedtoreviewtheeffectivenessofflavonoidsandflavonoids-richfoodsoncardiovasculardiseaserisk[Hooper et al., 2008].Ofthesetrialsmostofthemassessedtheeffectofflavanols.Interventionshaveshownthatcocoa/chocolate (8 studies) significantly improved endothelial function measured as FMD and reducedbloodpressure,andthatcocoa/chocolate,soy/soyproteinisolates(39studies)andgreentea(4studies)decreasedplasmaLDL(abeneficialeffectonlipidprofile).However,insomecasesitwasnotclearthatthebeneficialeffectscouldbeascribedtothepolyphenolscontainedinthesefoodsorextracts.Formanyoftheotherflavonoids,therewasinsufficientevidencetodrawconclusionsaboutefficacyanddosenecessarytoreachasignificanteffect.Theoptimaldoseofspecificflavonoidsforcardiovascularprotectionneedsfurtherresearch.

• Flavanol-rich cocoa and CVD

Theingestionofflavanol-richcocoabeveragecontaining917mgoftotalflavanolsinhealthymaleadultswasassociatedwithacuteelevationsinlevelsofcirculatingNOspecies,anenhancedFMDresponseofconduitarteries,andanaugmentedmicrocirculation [Schroeter et al., 2006].Inaddition,theconcentrationsandthechemicalprofilesofcirculatingflavanolmetabolitesweredetermined,andmultivariateregressionanalysesidentified(-)-epicatechinanditsmetabolite,epicatechin-7-O-glucuronide,asindependentpredictorsofthevasculareffectsafterflavanol-richcocoaingestion(Figure 7).Risk of hypertension

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Figure 7: Changes in FMD and NO metabolites following high flavanol cocoa drink Ingestion of a high flavanol cocoa drink (hFCD, 917mg of total flavanols) exerted significant increases in FMD (A),

plasma NO metabolites (RXNO) (B), and circulating flavanols (C) compared with a low-flavanol control drink (lFCD, 37 mg). *, P < 0.05 vs. baseline at 0 h of respective day; #, P < 0.05 vs. respective time point on control day.

Source: Schroeter et al., 2006

In another study [Heiss et al., 2007], 306 mg total flavanols were consumed thrice daily. A day-on-dayincreaseinbrachialarteryFMDwasshownwhichisimportantbecauseofthetransientnatureoftheFMDeffect.


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• Orange flavanones and CVD

In a randomised, double-blind placebo-controlled crossover trial lasting 4 weeks, Morand et al showedthat the flavanone, hesperidin, contributes to the vascular protective effects of orange juice [Morand et al., 2011]. In thisstudy,24healthy,overweightmen(age50-65y)weregiveneither500mLorange juice(OJ)naturallycontaining341.9mgofflavonoidsinwhich292mgwashesperidin,500mLcontroldrinkplus2capsulescontainingeach146mgofhesperidin(CDH),and500mLcontroldrinkplus2capsulesofplacebo(CDP)eachday.Inthefastedstate,OJandCDHreduceddiastolicbloodpressurecomparedtoCDP(p< 0.02).Microvascular endothelial activity, measured by combined laser Doppler flowmetry and iontophoresis,wasnotaffectedafterchronicintakeofOJandCDHduring4weeks.Ontheotherhand,acuteintakeofOJandCDHimprovedpostprandialmicrovascularendothelialactivity.Itisinterestingtonotethathesperidinsupplementation didn’t differ in term of effects compared to orange juice with naturally-occurringhesperidin.

• Black tea and FMD and blood pressure

TherearenumerousstudiesthathaveinvestigatedtheeffectsofconsumingteaonFMDandbloodpressure(BP).AdoseresponserelationshipwasdemonstratedbetweenblackteaandFMD [Grassi et al., 2009]. Blackteaintakedecreasedsystolic(-2.6mmHg,P=0.0007)anddiastolic(-2.2mmHg,P=0.006)BPaswellasstiffnessindex(P=0.0159).Butinfact,ithasalsobeenshownthatgreenteaisaseffectiveatimprovingFMDresponsesasblack tea [Jochmann et al., 2008]. This issomewhatsurprisingbecause thenatureofthe polyphenols in black tea are completely different to those in green tea; green tea largely containsmonomeric catechins such as epigallocatechin gallate (EGCG) whereas black tea contains only minorquantities of monomers and instead is rich in higher molecular weight products of catechin oxidationincludingtheaflavins,thearubigensandtheatannins.Thisshouldbeallowedthankstothemetabolisationofthesephenoliccompoundsbythegutmicrobiota[Lee et al., 2006].

Conclusion on polyphenols and CVD

EpidemiologicaldatatendstoshowapositiveassociationbetweenpolyphenolsespeciallyflavonoidsandCVDandCHD(flavonols,flavanolsandflavanonesreducetheriskofCHDmortalitybyaround20%).

Data from intervention trials are less consistent. However, they provide information related to the waypolyphenolsmayhavepositiveeffectsonCVDandCHD, including improvements inendothelial functionand lipoprotein profiles. The positive effect on endothelial function could also be linked to theimprovementobservedinbloodpressureandreducedriskofhypertension.

A precise characterization of food composition in term of polyphenol profile, along with a betterunderstandingofinteractionswiththefoodmatrix,shouldhelpidentifythebioactivecompoundsandallowdeterminingtherequireddoseforexpectedeffect.

There is also a need for well-controlled intervention studies taking into account the inter-individualvariabilityrelatedtopolyphenolbioavailabilityandmetabolism.


18

Coffee and diabetes: epidemiological evidence

Van Dam [van Dam, 2008] has considered the relationship between coffee and diabetes by reviewing17studies(fromdiversepopulationsacrosstheUS,EuropeandJapan)publishedsince2002.Fourteenofthemshowedan inverserelationship.Adose-responserelationshipwasshownwith4cups/dayormorebeingassociatedwithsubstantially lowerriskoftype2diabetes,whereasresultsweremorevariableforlowerlevelsofconsumption.Highcoffeeconsumptionwasassociatedwithlowerpost-prandialglucoseinnon-diabetics(severalcross-sectionalstudies)anddecreasedincidenceofimpairedglucosetolerance(twoprospectivestudies).Coffeeisarichsourceofphenolics,particularlychlorogenicacid,butcontainscaffeinewhichisalsobioactive.Furthermore,allofthefivepublishedstudiesreportingincreasedconsumptionofdecaffeinatedcoffeealsoshowedreducedriskofdiabeteswhichshouldtendtoshowthatthepolyphenolsplayaprotectiveroleinthedevelopmentofdiabetes.

Flavanols, isoflavones and diabetes: an intervention study

TheoneyearinterventiontrialreportedbyCurtisetal.[Curtis et al., 2012]in116postmenopausalwomenwith type2diabetes (seepage15)alsoshowedthat insulinsensitivitywas improvedwithflavanolsandisoflavones in chocolate. In this intervention, the consumption of 2 portions of 27 g flavonoid-enrichedchocolatecontaining850mgflavan-3-olsduring1year leadtoan improvement in insulinsensitivity(netdifference in insulin secretion between the test and the control groups was -1.36 mU/L; p=0.02) and adecreaseofinsulinresistancemeasuredasHOMA-IR(netdifferenceinHOMA-IRindexwas-0.78betweentheinterventionandthecontrolgroup;p=0.004)(Figure 8).

Conclusion on polyphenols and diabetes development

Epidemiological studies tend to show a positive effect of polyphenols, particularly flavonoids, on thepreventionofdiabetes.Thiseffectshouldbeinducedbyareducedinsulinresistanceandanimprovementininsulinsensitivity.Additionalstudiesarealsoneededtobetterunderstandthemechanismofactionsandthedoserequiredtohaveaneffect.

2.2 Effect of polyphenols on diabetes

Figure 8: The improvement in insulin sensitivity by flavonoids intakeSource: Adapted from Curtis et al., 2012

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19

Therearealsonumerousreportsofassociationsbetweenpolyphenolintakeandvarioustypesofcancer.Althoughthedatafromsuchstudiesareoverallequivocal,withsomestudiesshowingnoeffect,thereisadefinitetendencytowardsaprotectiveeffectofincreasedpolyphenolconsumption.Thebestindicationsarise from meta-analyses where the data from several studies investigating the same cancer sites arecombinedandreanalysed.Asanexample,ameta-analysisforflavonoidsandlungcancerreporteddatafromtwelvestudies,locatedinFinland(3),theUS(4),Uruguay,Spain,andtheNetherlands(3)[Tang et al., 2009]. Therewere5073casesand237,981non-cases.Therewasarelativeriskof0.76(CI0.63-0.92).Anincreasein20mgflavonoidsperdaywasassociatedwitha10%reductioninrisk.Thiswillobviouslybeanexcitingareaoffutureresearch.However,therearealmostnoreportsofhighqualitydietaryinterventionstudiesdemonstratingtheeffectsofpolyphenolconsumptiononcancerriskordiseaseprogression.Thisislargelybecauseofthelackofeasilymeasurableandvalidatedbiomarkersforcancer,andthevariabilityintheaetiologyofcancerswithinthesameandbetweendifferenttissues.

Astudyconductedwith3000womenundergoingosteoporosisscreeninginScotland[Hardcastle et al., 2011] demonstratedasignificantpositiveassociationbetweenenergy-adjustedtotalflavonoidintakesandbonemineraldensity(BMD)atthefemoral-neckandlumbarspinesites(p≤0.05).ItwasalsoreportedthattheannualpercentagechangeinBMDwasassociatedwithintakesofprocyanidinsandcatechins(p≤0.05),andthatflavanoneconsumptionwasnegativelyassociatedwithbone-resorptionmarkers(p≤0.001).

Previousresearchhasshownthathesperidin(anorangeflavanone)preventedbonelossinovariectomisedrodents [Horcajada et al., 2008; Habauzit et al., 2009]. However, when the effect of two years dietaryhesperidin supplementation was investigated on bone metabolism in post-menopausal women, noeffect on bone mineral density (BMD) was found at any site [Habauzit et al., 2011]. But, in this parallel,placebo-controlled double-blind trial in which 110 women were randomised to take either 500 mghesperidinorplacebo,asignificantgroupxtimeeffectonboneturnoverindexwasshown.Thereisalsoareportshowingthatsupplementationofratdietswithquercetininhibitedtherateofbonelossinarodentmodelofosteopenia(apre-osteoporosiscondition) [Liang et al., 2011].

2.3 Polyphenols and cancer

2.4 Polyphenols and bone health

Ke

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• Flavonoids are the polyphenols that have been the most studied for their health benefits.

• The strongest evidence supports the effect of polyphenols and especially of flavonoid classes on the risk of CVD and CHD. Cocoa polyphenols could potentially have an effect on CVD via several putative mechanisms: increased vascular reactivity, reduced blood pressure, improved blood lipid profile.

• There is also relevant evidence for their beneficial effect on diabetes development, osteoporosis and some cancers. But it is currently not possible to determine the specific role of polyphenols.

• Evidence for the benefits of polyphenol-rich foods is increasing. There is a need to focus future research on long-term intervention studies specifically designed to estimate the separate effects of polyphenols from the other compounds of the foods.


20

The antioxidant activity of polyphenols potentially explains all the results from epidemiology and trialsdescribed in Chapter 2 and, for many years, this has been assumed to be their major mechanism ofaction.However,althoughtherearemanystudiesshowingin vitroantioxidanteffectsofpolyphenolsoftenathighandnotphysiologicalconcentrations(>10μM),solidscientificevidenceoftheirin vivoantioxidantactivities is scant and the biological relevance of direct antioxidant of polyphenols is being questioned [Visioli et al., 2011; Hollman et al., 2011].

So,howdopolyphenolsimprovecardiovascularprognosis?Thischapterwillexplainthatthemechanismsofactionofpolyphenolsaremanifoldandincludeanti-inflammatory,anddetoxifyingactivitiesandthattheantioxidantactivitiesmaybemoreindirectthanpreviouslythought (Figure 9).

MECHANISMS OF ACTION OF POLyPHENOLS: NEWLy EMERGING EVIDENCEMECHANISMS OF ACTION OF POLyPHENOLS: NEWLy EMERGING EVIDENCE

3

by Dr Francesco Visioli Some of the manifold activities of polyphenols

Polyphenols

Microbiota

Metal chelators(e.g. food during digestion)

Grey areaas yet to beinvestigated?

Anti-oxidants

Anti-in�ammatoryAnti-aggregants(platelets)

Activators of Phase II Enzymes

Figure 9: Some of the manifold activities of polyphenols The activities of polyphenols are complex: from antioxidant effect already well-studied to prebiotic effects on the gut flora

Source: From F. Visioli


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3.1 Antioxidant activities of polyphenols

Direct antioxidant activities?

The antioxidant hypothesis is the term used to describe the oxidative damage to important moleculessuch as proteins, lipids, and DNA which accumulates with ageing.This can lead to the pathogenesis ofmany age-related diseases such as CVD [Hollman et al., 2011]. The moieties producing the damagerange from the highly reactive hydroxyl radical (OH) with a short half-life to the less reactive oxygenand nitrogen species with longer half-lives which are able to diffuse from their initial site of origin.These oxidants are counterbalanced by a range of antioxidant systems, mainly consisting of enzymesbut with some low molecular weight antioxidants. Some enzymes interact directly with oxidants suchascatalase,glutathioneperoxidase/reductase,andsuperoxidedismutaseandsomecontributeindirectlytocounteractoxidationattargetsitese.g.quinonereductases.Thereisalsoasupportsystemofancillaryantioxidantenzymessuchastransportsystems,metabolizingandconjugatingenzymes(PhaseIandPhaseII).

Adirectantioxidanteffectforpolyphenolsin vivoisnowthoughttobeunlikely.Why?

- As discussed in Chapter 1, polyphenols have a limited bioavailability and only very low concentrations(nM) are present in the blood stream and tissues after ingestion of polyphenols compared with otherendogenousandexogenousantioxidants.Incontrast,mostofthein vitrostudieshaveusedpolyphenolsatnonphysiologicaldoses(μmol/Ltommol/L),

- Further, the extensive metabolism of polyphenols during absorption and distribution in the bodymodifiesthestructureofthepolyphenolswhichhighlyimpacttheirbioavailabilityandtheirbiologicalactivity[Visioli et al., 2011].

Now considering the present evidence on physiological effects of polyphenols, it appears that a directeffect of polyphenols is questionable due to the very low concentrations in plasma. However, presently,noevidenceallowtoattributethebeneficialphysiologicaleffectstoadirectantioxidanteffectsratherthanothermechanismsofaction[Visioli et al., 2011; Hollman et al., 2011].

Indirect antioxidant activities of polyphenols

Some phytochemicals, including polyphenols, are processed by the body as xenobiotics.They stimulatestress-relatedcellsignallingpathwaysthatresultinincreasedexpressionofgenesencodingcytoprotectivegenes. One example of a transcription factor is Nrf2 (nuclear factor erythroid-2-related factor).It binds to the Antioxidant Response Element (ARE) in cells and thus regulates enzymes involved inantioxidant functions or detoxification (e.g. thioredoxin reductase-1 and glutathione peroxidases). Polyphenols might increase gene transcription of Nrf2 mediated by such response elements [Yang et al, 2011; Scapagnini et al, 2011] (Figure 10).Thisprovidesgroundsforthetheoryofhormesis,i.e.whenmildstresstriggersdefencemechanisms.Inthecaseofpolyphenolsitindicateshowtheycouldhaveanindirectantioxidantaction[Visioli et al., 2011].

MECHANISMS OF ACTION OF POLyPHENOLS: NEWLy EMERGING EVIDENCE


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Synthesis of antioxidants (GSH)

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Figure 10: Indirect antioxidant activity of polyphenols. GSH: Reduced form of glutathioneSource: From F. Visioli

3.2 InflammationInflammationisinvolvedintheonsetandmaintenanceofseveraldegenerativediseasesand,whileusefulin theshort-term tofight infectionsandpromotewoundhealing,a longer termanti-inflammatoryactionrepresentsan important target forselected foodcomponents.Severalenzymes involved in inflammationdependoncellular“peroxidetone”.Polyphenolshavebeenshowntoexertanti-inflammatoryactions,viamultiplemechanismsofactionsthatincludeinterferencewithsignaltransductionanddirectinhibitionofpro-inflammatoryenzymes.

E.g. a prospective study of premenopausal women has shown that whole grain cereal consumptionis associated with decreased C-reactive protein and it is believed that the polyphenols in wholegrainmay be responsible for this effect [Gaskins et al., 2010]. Recently, bioprocessed whole wheat breadwith increased bioavailable polyphenols has shown an anti-inflammatory on ex-vivo LPS-challengedblood.Inthistrial,theratiosofpro-anti-inflammatorycytokineswasimprovedafter3daysofconsumptionofthebioprocessedbreadcomparedtocontrolbyhealthymen[Mateo Anson et al., 2011].

One example is found in the paper by Visioli et al [Visioli et al., 2009] who reported a study in which98 Chinese Malay subjects ingested an olive preparation which was high in phenolics. After 1h, nodifferenceinplasmaantioxidantcapacitywasobservedbutasignificantincreaseintotalplasmaglutathioneconcentration was measured. The authors postulated that the observed effects of the olive phenols onglutathionelevelsmightbegovernedbytheantioxidantresponseelement(ARE)-mediatedincreaseinphaseIIenzymeexpression.


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Inamouseprostatecancermodel,Siddiquietal,havealsodemonstratedthatteapolyphenolsinhibittheNFkBsignalling,whichisacentralcontrolforinflammatoryconditions [Siddiqui et al., 2008].Inthesameway,cocoapolyphenolsareabletoreduceNFkBactivationindifferentcellmodel[Vazquez-Agell et al., 2011].

3.3 Increasing nitric oxide bioavailability There isnowquiteconvincingevidencethatflavanols(epicatechin)andprobablyotherpolyphenolsalsoincreaseNObioavailability [Schroeter et al., 2006]withincreasedplasmaNOmetabolitescoincidingwithimprovedFMD.SohowdopolyphenolsimproveNObioavailability?Thereareanumberofpossibilitiesandseveralhavebeenshowntobeplausible.Theseinclude(butarenotlimitedto)inhibitionofNADPHoxidase(NOX) [Steffen et al., 2008] andincreaseinlevelsofendothelialnitricoxidesynthase(eNOS)oritsactivation[Schini-Kerth et al., 2010].

3.5 Metal chelation

Finally, one often overlooked mechanism of action of polyphenols, in particular of ortho-diphenols,is metal chelation [Mladenka et al., 2010]. Metals are normally circulated in blood and are alsostored as part of other molecules. Examples are iron in hemoglobin and copper in ceruloplasmin.Unbound metals are toxic since they catalyse oxidative reactions, e.g. Fenton’s formation offree radicals. Metal chelation by polyphenols, e.g. during food digestion when large amountsof peroxides are formed, lessens the risk of oxidative damage [Kanner & Lapidot, 2001]. Therefore,consumptionofpolyphenol-richfoods,e.g.extravirginoliveoil[Visioli et al., 1995]withmealsmightlessenoxidativedamageindependentoftheirmereantioxidantaction.

3.4 Prebiotic effectsIncreasing evidence also suggests that polyphenols can modulate the microbiota in the large intestine,potentiallyactingasprebiotics,thusinfluencingtheimmuneresponseandmodulatingsomeaspectsoflipidmetabolism.

Recently, Tzounis et al [Tzounis et al., 2011] have shown the ability of cocoa polyphenols to modulategut microbiota. In this trial, high-flavanol diet led to an increase in enteric Bifidobacteria,Enterococcus, and Lactobacilli whereas Clostridia were decreased. This kind of change in microbiotacomposition is thought tobebeneficial forhealth [Saulnier et al., 2009].Notably,bacterialchangeswasassociatedwithachangeinC-reactiveproteinconcentration,acirculatingmarkerofinflammation.


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• The potential mechanisms of action of polyphenols in improving cardiovascular prognosis are complex, manifold, probably interrelated and extended beyond their antioxidant properties.

• Their antioxidant properties appeared to be rather indirect due to their very low concentration in blood and tissues.

• Polyphenols have also been shown to exert anti-inflammatory actions (e.g. interference with signal transduction, direct inhibition of pro-inflammatory enzymes).

• They might also increase nitric oxide bioavailability leading to improved vascular reactivity.

• Increasing evidence also suggests that polyphenols can modulate the microbiota in the large intestine, potentially acting as prebiotics.

• Metal chelation by polyphenols, e.g. during food digestion when large amounts of peroxides are formed, may lessen the risk of oxidative damage.

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Doweneeddietarypolyphenolsforhealth?Accordingtothecurrentstate-of-the-artonpolyphenolsscience,it isclear that thebiological functionsofpolyphenols inhumanscouldplaya role forhealthprotection.But there are still areas to explore to better understand the potential of polyphenols in preventingnon-communicablediseases.

Thereisastrongneedtocontinuedevelopingappropriate nutrient database usingstandardizedmethodsto analyse polyphenols content in foods with special attempts on non-extractable polyphenols andmetabolites.Thiswillallowhomogenizedandprecisecharacterizationoffoodsinepidemiologicalstudiesandinterventiontrials.

Furtherresearchonpolyphenol bioavailabity isrequired,withregardstotheeffectsoffoodmatricesonabsorption,influenceofage,gender,genotypeandmicrobiotabothonabsorptionandmetabolism.Thesewill help determine the physiological metabolic forms responsible for activity in vivo and biomarkers ofpolyphenolsintake.Theimprovementofbioavailabilityandthedevelopmentofpolyphenolswithenhancedbiological activity protected in foods (e.g. by encapsulation) could be a future way to propose healthierfoodsingeneralorfoodswithspecifichealthbenefits.

Ontheotherhand,metabolomicsaimedatthe investigationofthewholemetabolome(combiningfood,microbial and endogenous metabolomes), has been proposed as a powerful tool to characterize boththe intakeand theeffectsofdietarycomponentson themetabolism. Itwillhelp to identifyandvalidatenovel markers of polyphenol intake and these will allow much better estimates of the consumption ofpolyphenol-richfoodsandcorrelationswithhealthoutcomes.

Finally, future research should focus on long-term randomized, controlled dietary intervention trials to conclude clearly on the unequivocal role that polyphenols play in preventing chronic disease.Attentionshouldfocusonthestudydesigntoallowtheeffectsofpolyphenolstobeseparatedfromtheothercomponentsofthefood/dietandontheappropriateselectionofcontrols.Furthermarkersforestablishedriskfactorsarealsoessentialinthesetrialstoconfirmthebeneficialeffectsofthesecompoundsandtheirmechanismsofactions.TheuseofOmicswillalsoopenupareasforthisaim.Theoutcomesofwell-designedstudies(epidemiologicalandinterventional)willbeusefultodevelopspecific dietary recommendations on polyphenols.

Thescienceofpolyphenolsisalreadyatanexcitingstageintermsofpotentialhealthbenefitsandweareabouttowitnessevengreateradvancesinthefuture.

Future perspectives

26


PaulKrooncompletedanhonoursdegreeinbotanyattheUniversityofDurhamandaPhDinplantsecondarymetabolismattheUniversityofHullbeforejoiningtheInstituteofFoodResearchinNorwichasabiochemist.Afterafewyearsworkingontheenzymologyofplantcellwall-degradingenzymes,Paulstartedtoworkonflavonoidsandotherdietaryphenolics.HehasledthePolyphenolsandHealthgroupatIFRsince2001.

Dr Paul KroonResearch Leader, Plant Natural Products & Health Programme

Institute of Food Research, Norwich, UK

[email protected]

Appendix: Biographies of the speakers

Prof Francisco A. Tomás BarberánResearch Professor, CEBAS-CSIC, Murcia, Spain

[email protected]

PhD in Pharmacy, Valencia University, Research Professor of CSIC in Murcia (Spain). Co-author of more250publicationsinscientificjournalsoftheareasofPhytochemistry,AgriculturalChemistry,andFoodScienceandNutrition.Thesearticleshavebeencitedover7000timeswithanHindexof48.Hehasdevelopedmorethan80researchprojectsandcontractswithindustry.Heisinterestedintheroleofphenolicphytochemicalsonfoodqualityandhealth.Hiscurrentresearchaimstotheidentificationofthosefoodconstituentsthatprovide health benefits, the mechanisms by which they act and the effect of genetic, agronomic andprocessingfactorsonthesemetabolites,theirbioavailabilityandtheefficacyinhumans.Hehassupervised20PhDThesisandhascarriedoutresearchinlaboratoriesfromEngland(Reading),Switzerland(Lausanne),France(Lyon),andtheUSA(Davis).Hisresearchhasalsobeenorientedtothetransfertoindustryandhehasregistered6patentsofwhich3havebeenlicensedandderivedproductsareactuallyinthemarket.HewasawardedwiththeRhonePoulencRorerAwardbythePhytochemicalSocietyofEuropein1997,theRamónFrialAward,onFoodandHealthResearchin2004andtheDanoneAwardtoNutritionandHealthResearchin2006.HeisAssociateeditoroftheJournalofAgriculturalandFoodChemistryoftheAmericanChemicalSociety.HeisamemberoftheScientificAdvisoryBoardofdifferentCompaniesandoftheEuropeanJointProgrammingInitiative‘AHealthDietforahealthyLife’.

27


FrancescoVisioliearnedadegreeinPharmacyandPharmaceuticalChemistryfromtheUniversityofMilanandaPhDinBiotechnologyfromtheUniversityofBrescia.AfterbeingFullProfessorofphysiopathologyat the UR4 of the Université Paris 6 “Pierre et Marie Curie”, where he directed the “Micronutrients andcardiovascular disease” unit, he is now Senior Investigator at the Madrid Institute for Advanced Studies(IMDEA)-Food.HeisalsoAssistantProfessorattheCollegeofPharmacy,OregonStateUniversity.Afterbeinginvolvedinneurochemistry,Dr.Visioli’sresearchcurrentlyconcernsessentialfattyacids,namelythoseoftheomega3,andseriesnaturalantioxidants,asrelatedtoatherosclerosisandcardiovasculardisease.Inparticular,Dr.Visioli’sgroupdiscoveredthebiologicalandpharmacologicalpropertiesofoliveoilphenolics,including hydroxytyrosol. In addition, Dr. Visioli is being studying bioactive components of plant foods,includinglycopenefromtomatoandbiophenolsfromwildgreens.Hisresearchrangesfrominvitrostudiesofbioactivity(testtubes,cellcultures)to in vivotests,performedonlaboratoryanimalsand/orhumans.Dr Visioli has a publication record of over 170 papers and book chapters, which have been cited over4000times.Hegaveinvitedlectures inover60meetings.Asrelatedtohumanhealth,Dr.Visiolicreatedamethodtoevaluate thenutritionalprofileof foods (foodprofile.org),whichwaspublished in2007andfield-tested in 2009. Dr.Visioli is member of the Board of Directors of the International Society for theStudyofFattyAcidsandLipids(ISSFAL),memberofEFSA’sexpertdatabase,andmemberofseverallearnedsocieties,includingtheBritishNutritionSociety.Currently,Dr.VisioliistheEditor-in-ChiefofPharmacologicalResearch,AssociateEditorofLipidsandofProstaglandins,LeukotrienesandEssentialFattyAcids,andFirstEditoroftheBritishJournalofNutrition,inadditiontobeingamemberoftheEditorialBoardofseveralotherjournals.

Dr Francesco VisioliMadrid Institute for Advanced Studies-Food, Madrid, Spain

[email protected]

Hisearlyworkfocussedonmechanismsofabsorptionfromthegut, includingworkthatestablishedthatlactasewasessentialforsmallintestinalabsorptionofdietaryflavonoids.Subsequently,hehasfocussedhisresearchonunderstandinghowflavonoidsaremetabolisedinhumansincludingmethodsformeasuringtheir appearance in blood, and exploiting this knowledge in two ways: firstly, by allowing the design ofin vitro mechanistic studies that are physiologically relevant, and secondly by exploring what factorsaffectbioavailabilityanddevelopingfoodswithimprovedbioavailabilitycharacteristics.Hehaspublished>100 peer-reviewed papers concerned with flavonoid absorption and metabolism in humans, theeffectsofmetabolismonthepropertiesofpolyphenols,theeffectsoffoodprocessingandfoodmatrixon polyphenol content, composition and bioavailability, and the efficacy and mechanisms by whichpolyphenolsaffectvascular function.Kroon’spapershavebeencited>3000timesandhisH-index is33.Hehasbeenawarded>£2.5milliontofundhisresearchoverthepast8years.Hechairedthecompositiongroup of the EuroFIR BASIS project which developed an online database of composition and bioactivitydataforbioactivesubstancesinfoods,andhasledIFR’scontributiontovariousEuropeanresearchprojectsincludingFLAVOandtwocurrentprojects(BaSeFoodandATHENA).KroonisanExecutiveEditorforaleadingfoodsciencejournal,andaneditorforthetop-rankedfoodscience/technologyjournalMolecularNutrition&FoodScience.HewasVicePresidentoftheInternationalSocietyGroupePolyphenols(2008-2010),andregularlypresentshisresearchatinternationalscientificconferences.

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31

NUTRINSIGHT N°3Doweneeddietarypolyphenolsforhealth?State-of-the-artandperspectives

EDITING BOARDKraftFoodsEurope-R&DElisabethRiou,CarolineHeyraud,AlexandraMeynier,SophieVinoy,MarielleConrad,MichelInfantesWRITERS

Dr Margaret AshwellNutrition Consultant, Ashwell Associate (Europe) Ltd.,UK

Prof Francisco A. Tomás Barberán Research Professor, CEBAS-CSIC, Murcia, Spain

Dr Paul KroonResearch Leader, Plant Natural Products & Health Programme Institute of Food Research, Norwich, UK

Dr Francesco VisioliMadrid Institute for Advanced Studies-Food, Madrid, Spain

EDITORKraftFoodsEurope-BiscuitsR&DUnétablissementsecondairedeLUFrance*6rueRenéRazel-91400Saclay-France

*LUFranceSAS–RCSCréteil4330851493rueSaarinen–94150Rungis-FranceCopyrightKraftFoodsEurope-BiscuitsR&D.Allrightsreserved.Itisforbiddentoreproduceentirelyorpartiallythepresentwork,withoutwrittenauthorisationofthepublisher(editor).ConformémentàlaloiInformatiqueetLibertésN°78-17du06/01/1978,vousdisposezd’undroitd’accès,derectificationetderadiationdesdonnéespersonnellesvousconcernant,sursimpledemandeformuléeàl’éditeur.

Tirage:2000ex./Dated’achèvementdutirage:mai2012Créditsphotos:©Fotolia/INRA/KraftFoods/IDSourceConceptionetréalisation:IDSource+33155850540Prixeneuros:gratuitDépôtlégal:mai2012

ABBREVIATIONS:

ARE:AntioxidantResponseElementCEBAS-CSIC:CentrodeEdafologíayBiologíaAplicadadelSegura–ConsejoSuperiordeInvestigacionesCientíficasCHD:CoronaryHeartDiseaseCI:ConfidenceIntervalCVD:CardiovascularDiseasesEFSA:EuropeanFoodStandardAgencyEPIC:EuropeanProspectiveInvestigationofCancerEuroFIR:EuropeanFoodInformationResourceFENS:FederationofEuropeanNutritionSocietiesFMD:FlowMediatedDilatationHDL:HighDensityLipoproteinHOMA-IR:HomeostaticModelEstimatedInsulinResistanceHT:HypertensionIMDEA:MadridInstituteforAdvancedStudiesINRA:InstitutNationaldeRechercheAgronomiqueLDL:LowDensityLipoproteinLPS:LipopolysaccharideNFkB:NuclearfactorkappaBNO:NitricOxideNrf2:Nuclearfactorerythroid-2-relatedfactorRCT:RandomizedControlledTrialSNP’s:SingleNucleotidePolymorphismsSULT:SulphotransferasesSUVIMAX:SUpplémentationenVItaminesetMinérauxAnti-oXydantsUGT:GlucuronyltransferasesUSDA:UnitedStatesDepartmentofAgriculture

10 TH European Nutrition ConferenceParis, 10-13 July 2007

The regulation of appetite is a vital component of general health – both physical and psychological.

About the value of controlling appetite

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Foradditionalinformation,pleasecontact:

KraftFoodsEurope-BiscuitsR&DNutritionDepartment6rueRenéRazel91400Saclay–FranceE-mail:[email protected]

ThisdocumentisexclusivelyreservedtoHealthProfessionalsandAcademics.

Key wordsPolyphenols; flavonoids; phenolic acids; bioavailability; metabolites; microbiota; cardiovascular disease; diabetes; antioxidant; inflammation; prebiotic.

proceedings of the symposium do we need dietary ... nutrinsight polyphenols.pdf · nutrinsight •...

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