Perspectives of the potential implications of wine polyphenols on human oral and gut microbiota

Trends in Food Science & Technology 21 (2010) 332e344

Review

Perspectives of the potential implications of wine polyphenols on human oral and gut microbiota T. Requenaa, M. Monagasb, M.A. Pozo-Bayo´nb, ´ lvarezb, P.J. Martı´n-A B. Bartolome´b, R. del Campoc, ´ vilaa, M. A M.C. Martı´nez-Cuestaa, C. Pela´eza and M.V. Moreno-Arribasb,* a

Instituto del Frı´o/CIAL (CSIC), Madrid, Spain Instituto de Fermentaciones Industriales/CIAL (CSIC), Juan de la Cierva, 3. 28006 Madrid, Spain (Tel.: D34 915622900; fax: D34 915644853; e-mail: [email protected]) c Servicio de Microbiologı´a, Hospital Ramo´n y Cajal and CIBERESP, Madrid, Spain

b

Food polyphenols are able to selectively modify the growth of susceptible micro-organisms. Wine is a good source of polyphenols and thus, the moderate consumption of this beverage can lead to the modulation of both oral and gut microbiota. This review aims to bring together the knowledge acquired concerning the potential effects of wine polyphenols on human microbiota, as well as taking into account the ability

* Corresponding author. 0924-2244/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tifs.2010.04.004

of bacteria to metabolize these compounds. Red wine phenolic composition, characterized by the occurrence of flavan-3-ols, flavonols, anthocyanins, hydroxybenzoic and hydroxycinnamic acids, stilbenes and phenolic alcohols as the main phenolic compounds, will determine the microbiota-modulating effects of wine consumption. Moreover, although the same bacterial genera can be found in oral and gut ecosystems, their relative amount is different, which can influence the metabolic transformations of wine polyphenols. Taking all this into account, the potential implications of these studies on human microbiota are finally discussed together with perspective and future research trends in this field.

Introduction Diet and nutrition affect gastrointestinal health in many ways and provide a key link between gut and systemic well-being. In recent years, the importance of oral health and its impact on overall health has been emphasized by dental researchers, doctors and related professionals (Signoretto & Canepari, 2009). The oral cavity is a complex system of tissues and organs used for the selection of acceptable food during intake as well as for its processing into suitable forms for digestion in the rest of the gastrointestinal tract. One of the main functions of the gut microbiota is the conversion of carbohydrates, proteins and non-nutritive compounds into more absorbable molecules which serve as nutrients for the host as well as for resident bacteria. Moreover, gut microbiota is also considered to play an essential role in the host defence system. In this regard, it is well-recognized that a balanced gut microbiota protects against amongst others: intestinal disorders, inflammatory diseases, cancer, obesity, etc. (Carroll, Threadgill, & Threadgill, 2009). Any undesirable changes in the composition of this microbiota would be able to modify its protective function. In addition to other factors, diet influences the establishment of bacteria and their degree of intestinal colonization and thus, the composition and activity of the human microbiota. Therefore, it is important to determine whether the consumption of specific food components is able to modify the colonization of the oral/gut microbiota. In recent years, the interest in the interactions between food polyphenols and gut microbiota has increased, and literature regarding this topic is available in a recent review (Selma, Espı´n, & Toma´s-Barbera´n, 2009). Wine and grape derivatives have been attracting ever-growing attention due to their high

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polyphenol content and their structural diversity, which may have potential gut health benefits (Forester & Waterhouse, 2009). The main transformations of wine polyphenols take place in the colon, where they can be transformed into metabolites which are even more bioactive than their precursors (Aura, 2008; Selma et al., 2009). Physiologically, these changes are associated to the bacterial metabolism of polyphenols along with the ability of wine polyphenols and their resultant metabolites to selectively inhibit or stimulate the growth of gut bacteria, also known as modulation of gut microbiota. Therefore, at the intestinal level, both phenolic metabolism and modulation aspects seem to be directly related in a two-way interaction (Fig. 1). In regard to oral microbiota, the role of wine components on oral health has been recently shown (Kongstad et al., 2008), and efforts have been directed to the detection and characterization of different beneficial polyphenolic compounds displaying antimicrobial activities (Furiga, Lonvaud, & Badet, 2009). However, as far as the metabolic transformation of phenolic compounds on the oral cavity is concerned, very little information is available at present. Therefore, the two-way interaction between the metabolism of phenolics by bacteria and the modulation of bacteria by wine polyphenols is less established for oral than for gut microbiota (Fig. 1). The aim of this paper is to provide a state-of-the-art overview of our current knowledge of the role that wine polyphenols and their microbial metabolites play on the oral and gut microbiota of humans, and to summarise the future trends in which such knowledge may be developed over the coming years. The potential impact of these studies for human oral and gut health will also be discussed.

Wine polyphenols Wine is a food product in which the major component, after water, is ethanol, usually above 10%. Nevertheless, in spite of the potential toxic effects of ethanol, it is generally accepted that the moderate consumption of wine has beneficial health effects (Pozo-Bayo´n, Monagas, Bartolome´, & Moreno-Arribas, in press). In recent years, there has been a significant increase in the research related to the bioactivity of wine compounds and, especially, to their bioavailability in the human body. Most of these studies have revealed that phenolic compounds may play a key role on the positive health effects derived from the moderate consumption of wine (Pozo-Bayo´n et al., in press), particularly in relation to cardiovascular diseases such as atherosclerosis and coronary heart disease (Da´valos & Lasuncio´n, 2009; Renaud & De Lorgeril, 1992). On the basis of this scientific evidence, there has been an increase in the design and commercialisation of ingredients or dietary supplements enriched in polyphenols from grape or wine by-products for human and animal consumption (Monagas et al., 2005). Phenolic compounds in wine can be classified into nonflavonoids (hydroxybenzoic and hydroxycinnamic acids, hydroxybenzoic aldehydes, phenolic alcohols and stilbenes as well as ellagitannins extracted from oak barrels) and flavonoids (anthocyanins, flavonols, dihydroflavonols, flavan-3-ols and their oligomeric and polymeric forms, also called proanthocyanidins or condensed tannins) (Fig. 2). Anthocyanins are characteristic of red wines whereas the major phenolic compounds in white wines are hydroxybenzoic acids and tartaric acid esters of hydroxycinnamic acids

Wine

Modes of interaction

Mouth

Phenolic metabolism by oral microbiota

? Modulation of oral bacteria by wine phenolics

Extent of the interaction

- Limited transformation of polyphenols by oral bacteria (hydrolysis, oxidation) - In vitro antimicrobial effects of polyphenols: protective role on dental caries, anti-adhesion properties

Stomach Small Intestine

Large Intestine

Modes of interaction

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Extent of the interaction

Phenolic metabolism by gut microbiota

- Extensive microbial metabolism of wine polyphenols depending on their chemical structure (hydrolysis, reduction, dehydroxylation, demethylation, decarboxylation, isomerization)

Modulation of gut bacteria by wine phenols and their metabolites

- Maintenance of intestinal health: pathogen inhibition; protective actions by microbial derived metabolites; possible prebiotic effects

Excretion Fig. 1. Two-way interaction between wine polyphenols and oral and gut microbiota.

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Fig. 2. Individual phenolic compounds representative of the main groups present in wine.

(coutaric and caftaric acids). Polyphenol content in wine varies depending on the grape variety and the oenological practices performed. In this regard, based on chromatographic analysis, the average content is 10.38 mg/100 ml for white wines, and 107.44 mg/100 ml for red wines (Neveu et al., 2010). In order to make use of the health properties of wine polyphenols, they should be absorbed to reach the target tissues and organs. However, the bioavailability of wine polyphenols is limited by their recognition as xenobiotics by the human organism. Moreover, the chemical structure of wine phenolic compounds has been shown to directly influence their bioavailability, for example, limiting the site of intestinal absorption either to the small intestine or colon, and influencing their pharmacokinetics of absorption, extent of metabolism, and the amount finally excreted in the urine (Donovan, Manach, Faulks, & Kroon, 2006; Manach, Scalbert, Morand, Re´me´sy, & Jime´nez, 2004). Non-glycosylated phenolic compounds present in wine, such as monomeric flavan-3-ols and to a lesser extent dimeric procyanidins, are directly absorbed in the small intestine with no prior chemical modification. In the case of glycosylated polyphenols including anthocyanins, flavonols and resveratrol glucosides, their transformation could start in the mouth with the hydrolysis of the glycosidic unit by the action of b-glucosidases from bacteria and/or epithelial cells from the oral cavity, as has been reported for several glucosides of quercetin (Walle, Browing, Steed, Reed, & Walle, 2005). Further hydrolysis occurs in the gut by intestinal b-glucosidases such as lactase phloridzin hydrolase (LPH) followed by passive diffusion of the aglycone into the enterocytes (LPH/diffusion pathway) (Donovan et al., 2006). Alternatively, glycosylated

flavonoids could be hydrolyzed by cytosolic b-glucosidases (CBG) within the epithelial cells (Donovan et al., 2006) which firstly requires transport of the glycosylated polyphenol into the cells, probably by the active sodium-dependent glucose transporter SGLT1 (transport/CBG pathway). After passing across the small intestine brush border, polyphenols are subjected to extensive metabolism firstly in the small intestine and then in the liver, being converted into methyl, glucuronide and sulphate conjugates by phase II enzymes (Manach et al., 2004; Donovan et al., 2006). Glucuronidation occurs in the luminal part of the endoplasmic reticulum by the superfamily of uridine-50 -diphosphate glucuronosyltransferases (UGTs), in particular by UGT1 (Donovan et al., 2006; Manach et al., 2004). Sulfation and methylation occur in the cytosol by sulphotransferases (SULT) and catechol-O-methyltransferases (COMT), respectively. In particular, SULTA1 and SULTA2 participate in the sulfation of phenolic compounds (Donovan et al., 2006; Manach et al., 2004). These metabolites can then enter the systemic circulation and are finally eliminated mainly in the bile but also in the urine. Other wine polyphenols, such as oligomers with a mean degree of polymerisation (mDP) > 3 and polymers of flavan-3-ols, ellagitannins, esters of hydroxycinnamic acids and polyphenols conjugated with rhamnosides (i.e. rutin), are not absorbed in their native forms. These compounds would be metabolized by the colonic microbiota, together with some phase-II metabolites reaching the colon by entero-hepatic circulation, before absorption. Colonic metabolism involves the formation of simple phenols, phenolic and aromatic acids, and lactones with different degrees of hydroxylation and side chain length that could be further absorbed and subsequently submitted to intestinal and

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hepatic metabolism by phase II enzymes (Aura, 2008; Selma et al., 2009). Consequently, gut bacteria which are able to metabolize polyphenols may play a major role in the production of new phenolic compounds in situ, which could have better bioavailability and higher biological activity than their parent compounds, and be involved in both body systemic and local protective action. In addition to the effects of the chemical structure; other exogenous factors such as the complexity of the food matrix, as well as the structure and amount of co-ingested compounds are known to influence the bioavailability of dietary polyphenols (Donovan et al., 2006). Considering that wine is a complex mixture of macro-components from different natural origins (i.e., grape, fermentation and wood ageing) or intentionally added (i.e., fermentation enhancers, clarifying substances, etc.), one aspect that should be studied in-depth is the effect of the wine matrix on the bioavailability and metabolism of wine polyphenols. Among these macro-components, wine peptides, proteins and polysaccharides are of special interest since they can be associated to polyphenols, giving rise to relatively stable complexes (Moreno-Arribas, Pozo-Bayo´n, & Polo, 2009), which can influence the effect of polyphenols on the oral microbiota after the wine has been ingested. Even if these wine components could interact with polyphenols influencing their bioavailability and thus their effects on human health, it is still an unexplored subject. Oral and gut microbiota Both ends of the orogastrointestinal tract of humans have an abundance of microbiota dominated by anaerobic bacteria. The number of bacteria in the oral cavity is about 1011 bacteria/g in dental plaque and 108e109 bacteria/ml in saliva, whereas in faeces the corresponding numbers are 1011e1012 bacteria/g (Carroll et al., 2009; Guarner and Malagelada, 2003). Some studies (Maukonen, Ma¨tto¨, Suihko, & Saarela, 2008) have indicated that the same bacterial genera can be found in oral and colonic samples. For example, bifidobacteria and lactobacilli can be detected in both regions, but their relative amount is different, lactobacilli are commonly found in the oral cavity, whereas bifidobacteria are detected more frequently in colonic samples. The oral cavity contains different micro-environments (cheeks, palate, tongue, tooth surface, gingival areas and saliva) each with their own microbiota. Therefore, oral microbiota varies in composition on distinct surfaces (e.g. tooth, mucosa), and at sites on a specific surface (e.g. fissures, gingival crevice), demonstrating that slight differences in habitat can influence the ability of individual species to colonise and dominate (Marsh & Percival, 2006). However, species common to all sites have been reported to belong to the genera Gemella, Granulicatella, Streptococcus, and Veillonella (Aas, Paster, Stokes, Olsen, & Dewhirst, 2005). Oral microbiota comprises of a large number of diverse organisms, which grow within biofilm communities attached to the surfaces of the teeth and tongue.

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Within biofilms, resident bacteria gain significant advantages such as protection from host defences and antimicrobial agents and thus, the major diseases associated with the human oral cavity result from the activity of microbial communities rather than from individual micro-organisms (Jenkinson and Lamont, 2005). Adhesion to the oral cavity is the first step for the development of communities of many species of Streptococcus, Actinomyces, Veillonella and Neisseria. The retention of Porphyromonas spp. is favoured by their association with streptococci. Anaerobic conditions promote the incorporation of Fusobacterium spp., and these latter genera facilitate the growth of Treponema spp., which are part of the so-called red group of periodontal pathogens identified by Socransky et al. (2004). Initial adhesion invariably involves the interaction of bacterial surfaces with the acquired pellicle derived from salivary constituents adsorbed onto the surfaces of the oral cavity, which serves as a substratum for the adhesion of the so-called early colonizers (Bodet et al., 2008). Bacteria from saliva attached to the pellicle proliferate on the surface, give rise to micro-colonies, of which streptococci (Streptococcus mutans, S. sobrinus, S. criceti, and S. rattus) are frequently associated with carious lesions. Subsequently, new bacterial species are able to adhere to bacteria cells already present in the biofilm and proliferate. The adhering ability of the early colonising bacteria gives rise to a major selective advantage in starting biofilm formation. Therefore, the intake of non-invasive colonising bacteria may delay or prevent colonization by cariogenic bacteria or periodontal pathogens (Kaufman and Lamster, 2000). Another important characteristic of the oral cavity is that it can be an important source of respiratory tract infective bacteria, such as Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus that cause infections in the lungs (Paju and Scannapieco, 2007). When studying oral microbiota, an important aspect to consider is that bacteria in biofilms are considerably less sensitive to antibiotics and antimicrobial treatments than free-living planktonic cells. This increased resistance to antimicrobials is one of the main reasons for studying bacteria in biofilm models to be able to reliably predict in vivo efficacy of antimicrobials. Experimental models for short-term studies involve a solid surface for the adhesion of bacteria (Guggenheim, Guggenheim, Gmur, Giertsen, & Thurnheer, 2004). Results obtained with an in vitro biofilm system on experimental tooth decay has led to the same results obtained using its in vivo counterpart, thus providing an interesting and reliable tool in the fight to reduce animal experimentation (Thurnheer, Giertsen, Gmur, & Guggenheim, 2008). The large intestine contains a complex and dynamic microbial ecosystem with several hundred grams of bacteria living within the colonic lumen, consequently affecting host homoeostasis (Guarner and Malagelada, 2003). Part of the population consists of commensal bacteria (Bacteroides thetaiotaomicron), potentially harmful opportunistic bacteria (coliforms, Bacteroides fragilis group, Fusobacterium spp., clostridia), and a microbial

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population that can confer important health benefits to the human host (bifidobacteria, lactobacilli), representing the organisms that first colonise the intestine after birth. These latter genera are widely used as probiotics (Ventura et al., 2009). Gut microbiota has important and specific metabolic functions able to supply the host with certain metabolic capabilities lacking in human intestinal cells, such as fermentation of non-digestible dietary residues, methanogenesis, gluconeogenesis, processing of xenobiotics, and biosynthesis of essential amino acids, vitamins and isoprenoids (Walter, Cerdeno-Tarraga, & Bentley, 2006). Fermentation of non-digestible dietary residues allows the recovery of metabolic energy production in the form of short-chain fatty acids, which in turn reduces pH, facilitates absorption of ions, and is a direct source of energy for epithelial cells (Blaut and Clavel, 2007). On the other hand, gut microbiota with the potential of being harmful can be responsible for putrefactive processes, production of toxins and substances related with carcinogenic processes (Guarner and Malagelada, 2003). Besides, it has been suggested that environmental factors, such as microbial infections and imbalances in the composition of the gut microbiota, are associated with intestinal disorders such as chronic inflammatory bowel diseases and with other immune related disorders (Salzman and Bevins, 2008; Sanz et al., 2007). Interactions of wine polyphenols with oral and gut microbiota Metabolism of wine polyphenols by oral and gut bacteria Although the mouth plays an important role favouring the release of phenolic compounds from the food matrix, it has only been until recently that the interaction between wine polyphenols and oral microbiota has received special attention. Pathways involved in the metabolism of phenolic compounds by oral microbiota are still largely unknown. By means of in vitro studies using cell cultures, it has been shown that flavonol-3-O-glycosides can be hydrolyzed by mouth bacteria and/or by epithelial cells giving rise to the corresponding aglycones (Walle et al., 2005). The hydrolysis of these compounds seems to be related to a b-glycosidase activity from some lactic acid bacteria strains present in the oral cavity and is similar to that described in human saliva. Although it has been described that a Streptococcus milleri strain isolated from the oral cavity, is able to deglycosylate rutin into quercetin (Parisis and Pritchard, 1983), there are virtually no studies focusing on the microbial groups possessing this metabolic activity or other activities involved in the degradation of phenolic compounds of different chemical structures (Fig. 2). Besides, it is also important to consider the effect of the saliva per se, since it can modify the structure of wine phenolic compounds (Hirota et al., 2001; Yang, Lee, & Chen, 1999). The colon is an active site for polyphenol metabolism. It has been estimated that 90e95% of dietary polyphenols are

not absorbed in the small intestine and therefore accumulate in the colon (Clifford, 2004). As in the case of small intestine absorption and metabolism, the microbial metabolism of wine polyphenols is also largely influenced by their chemical structure (Fig. 2). Metabolic pathways have been partially elucidated for some groups of phenolic compounds (Crozier, Jaganath & Clifford, 2009). In the case of flavonoid compounds, the degradation pathway by the gut microbiota usually starts with the C-ring breakage, resulting in hydroxylated aromatic compounds derived from the A-ring (i.e. phloroglucinol, 3,4-dihydroxybenzaldehyde, acetate, butyrate and 3,4-dihydroxytoluene), and in numerous phenolic acids derived from the B-ring. Flavonols are directly transformed into 3,4- or 3,5-dihydroxylated phenylacetic acids (Aura, 2008; Selma et al., 2009). Anthocyanins are converted into 3,4-dihydroxy-, 4-hydroxy-, 3,4-dimethoxy- or 3-methoxyl-4-hydroxyl- benzoic acids according to the substitution pattern of the B-ring of the precursor anthocyanin molecule (Aura, 2008). However, in spite of the fact that anthocyanins are abundant in wine, their recovery from biological fluids is very low partly due to their relatively low chemical stability. In the case of flavan-3-ols, the C-ring is opened, rather than cleaved, into diphenylpropan-2-ol which is further converted into 3,4-dihydroxy-phenylvalerolactone. The valerolactone ring is then cleaved into 3,4-dihydroxyphenylvaleric acid and further degraded into other B-ring derived phenolic acids such as 3,4-dihydroxyphenylpropionic and 3,4-benzoic acids by successive carbon loss from the side chain. Although it has been suggested that 3,4-dihydroxyphenylacetic acid could be formed by a-oxidation of 3,4-dihydroxyphenylvaleric acid, as in the case of tyrosine (Gonthier et al., 2003), it has been thought that this metabolite was only characteristic of the degradation pathway of dimeric procyanidins (Appeldoorn, Vincken, Aura, Hollman, & Gruppen, 2009; Groenewoud and Hundt, 1986). However, recent studies have reinforced that a-oxidation could be responsible for the formation of 3,4-dihydroxyphenylacetic acid from both monomeric and dimeric flavan-3-ols (Stoupi, Williamson, Drynan, Barron, & Clifford, 2010), although other pathways such as those proposed by Appeldoorn et al. (2009) could occur at the same time. According to latter authors, 3,4-dihydroxyphenylacetic acid could be released from the top unit of a dimeric procyanidin whereas the bottom unit could lead to the formation of 3,4-dihydroxyphenyl-g-valerolactone and to the subsequent pathway described above. A possible depolymerisation of dimeric procyanidins into its monomeric units, as first proposed by Groenewoud and Hundt (1986), could also occur but to a lesser extent (Appeldoorn et al. 2009; Stoupi et al., 2010) accounting for >10% of the yield in the case of procyanidin B2 (Stoupi et al., 2010). Other metabolites possibly derived from the A-ring of the top unit of dimers including interflavan linkage (i.e., 5-(2,4-dihydroxyphenyl)-2-eno-valeric acid) have also been identified (Stoupi et al., 2010), indicating that an

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alternative mechanism to that described by Appeldoorn et al. (2009) also exists. Considering non-flavonoid compounds present in wine, hydroxycinnamic esters (i.e. caffeic acid derivatives) are mainly transformed into 3-hydroxyphenylpropionic acid, benzoic acid and 4-ethylcatechol (Gonthier et al., 2006). Ellagitannins are firstly hydrolyzed into ellagic acid in the stomach and then largely metabolized by the colon microbiota leading to urolithins (Selma et al., 2009). Finally, the later stages of the microbial metabolism of phenolic compounds involve dehydroxylation reactions of OH groups at C-4 and predominantly at C-3 (Gonthier et al., 2006; Stoupi et al., 2010). Once absorbed, the microbial metabolites are mainly metabolized in the liver by phase II enzymes as conjugated metabolites, and are then excreted in the faeces and urine. It is important to highlight that due to the presence of highly-polymerised polyphenols in red wine, the concentration of microbial-derived metabolites in plasma and urine could be higher than that of phase II metabolites (Gonthier et al., 2003). In addition, there is evidence that to exert some physiological effects some microbial metabolites could be subjected to enterohepatic circulation, assuring a longer residence time in plasma in comparison to their precursors (Toma´sBarbera´n et al., 2008). Despite the advances recently made in the area of microbial metabolism of phenolic compounds, the specific bacterial species able to metabolize most wine polyphenols in the gastrointestinal tract, the anaerobic degradation pathways as well as the intermediate products and the enzymes involved, still remain largely unknown. Among the bacteria identified, Eubacterium ramulus, a strictly anaerobic human gut bacteria, possess a phloretin-hydrolase able to break the phloretine CeC bond (Schoefer, Braune, & Blaut, 2004) and is also able to metabolize a number of different flavonoids such as quercetin, apigenin, naringenin, daidzein and genistein (Blaut and Clavel, 2007). Similarly, evidence of the health benefits of microbial-derived phenolic metabolites still remains unknown, although some activities have been described, such as the inhibition of platelet aggregation and activation function (Rechner and Kroner, 2005), anti-inflammatory activity (Larrosa et al., 2009; Monagas et al., 2009), antiproliferative activity in prostate and cancer cells (Gao et al., 2006; Gonza´lez-Sarrı´as, Espı´n, Toma´sBarbera´n, & Garcı´a-Conesa, 2009) and estrogenic/ antiestrogenic activity (Larrosa, Gonza´lez-Sarrı´as, Garcı´aConesa, Toma´s-Barbera´n, & Espı´n, 2006). Effect of wine polyphenols and their metabolites on oral and gut microbiota The effect of dietary polyphenols on oral microbiota has been an incipient area of research but is rapidly growing. Studies carried out using different tea polyphenols, especially flavonoids, and tea extracts and infusions have shown a powerful protective effect of this beverage against dental decay in animals and humans (Friedman, 2007). It has

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recently been shown that A-type proanthocyanidins and flavonols from cranberry disrupt the S. mutans biofilm development and acidogenity (Duarte et al., 2006). Up-todate reviews of the literature available on the in vitro, in vivo, animal and human studies demonstrating the effects of tea and cranberry polyphenols on oral pathogens (mainly S. mutans) and the implications of this beverage in the prevention of oral/dental diseases have recently been published (Wu and Wei, 2009; Bodet et al., 2008). Although the mechanisms of action are not completely understood, it seems that tea and cranberry polyphenols inhibit the growth and the adherence of the micro-organisms associated to dental decay on the tooth surface. Data about the anticaries activity of wine and grape polyphenols are still scarce. Antimicrobial activity against oral streptococci has been demonstrated in both red and white wine with no major differences between them (Daglia et al., 2007). The compounds responsible for such activities were succinic, malic, lactic, tartaric, citric and acetic acids. In addition to these wine components, it has recently been reported that wine and grape phenolic extracts (Furiga et al., 2009) as well as pomace phenolic extracts from different red grape varieties (Thimothe, Bonsi, Padilla-Zakour, & Koo, 2007) can also exert antimicrobial effects against different Streptococcus spp. and other bacteria involved in dental decay. Although anthocyanin and flavonol content varied greatly as a function of the grape variety and type of extracts, it was shown that all the grape phenolic extracts induced around 80% inhibition of streptococci enzymatic activity involved in caries (Thimothe et al., 2007). In addition, S. mutans acid production was greatly inhibited by the grape extracts without affecting bacterial viability. The effect of oral rinses with different polyphenolic beverages (including several types of tea and wine) on initial bacterial adherence in the oral cavity has also been investigated. The lowest number of adherent bacteria was found following rinses with red wines which may contribute to prevention of biofilm-induced diseases in the oral cavity (Hannig, Sorg., Spitzmu¨ller, Hanning, & Al-Ahmad, 2009). In a recent study, it was also shown that fractions from raisin extracts, containing 5-hydroxymethyl-2-furfural among other components, could also inhibit the growth of oral pathogens (Wu, 2009). Grape seed extracts containing proanthocyanidins, were also found to positively affect the in vitro demineralization and/or remineralization process of artificial root caries lesions (Wu, 2009). Finally, an in vivo study revealed that raisins prevented the pH of the plaque falling below pH 6 over a 30 min period in 7e11-year-old children, indicating the potential of grape derived products in oral health (Wu, 2009). Concerning the effect of wine polyphenols in colonic microbiota, recent studies suggest that extracts containing some wine polyphenols, as well as pure phenolic compounds and/or their metabolites can produce changes in the colonic microbial population itself (Fig. 1) (Table 1). The antimicrobial activity of grape pomace and diluted wine, against pathogenic species such as Escherichia coli,

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S. aureus or Salmonella spp., amongst others, has been documented (Dolara, Arrigucci, Cassetta, Fallani, & Novelli, 2005; Ozkan, Sagdic, Baydar, & Kurumahmutoglu, 2004) (Table 1). In the case of pure compounds, monomeric flavan-3-ols, (þ)-catechin and ()-epicatechin, have been reported to inhibit the growth of Clostridium difficile, whereas gallic acid and 3-Omethyl gallic acid were more efficient against Clostridium perfringens. On the other hand, microbial-derived phenolic acids such as caffeic acid, 3-(4-hydroxyphenyl)-propionic acid, 3-phenylpropionic acid, and 4-hydroxyphenylacetic acid significantly inhibited the growth of Staphylococcus spp., E. coli and Salmonella spp. (Lee, Jenner, Low, & Lee, 2006) (Table 1). These results are in line with those of Alakomi et al. (2007) who reported that phenolic acids, dihydroxylated phenolic acids in particular, exhibited antimicrobial activity against Salmonella spp. through the destabilization of their outer membrane (Table 1). However, probiotic bacteria like Lactobacillus spp. and Bifidobacterium spp. were found to be relatively unaffected by some of the above mentioned polyphenols or by their metabolites (Lee et al., 2006) (Table 1). Similarly, batch fermentations performed with human faeces inoculated with (þ)-catechin positively affected the growth of the Clostridium cocccoides-Eubacterium rectale group, and Bifidobacterium spp., while inhibiting the growth of the Clostridium histolyticum group, suggesting a moderate prebiotic effect of monomeric flavan-3-ols on the microbial population (Tzounis et al., 2008). These results seem to be in agreement with the fact that among flavonoids (þ)-catechin and ()-epicatechin are not precisely the most active compounds against pathogenic bacteria (Parkar, Stevenson, & Skinner, 2008) (Table 1). Following this, in vitro studies performed with trimeric fractions isolated from grape skins presented a higher antimicrobial activity than monomers against a series of pathogenic bacteria including S. aureus, Streptococcus pyogenes, H. influenzae, Staphylococcus epidermidis and Enterococcus faecalis (Mayer et al., 2008) (Table 1). The effects of monomeric flavan-3-ols on potential beneficial bacteria have been partially confirmed in vivo after the administration of green tea extracts (60% catechins) to chickens, pigs and, to healthy and elderly human subjects (Goto et al., 1998; Hara, 1997; Okubo et al., 1992; Yamakoshi et al., 2001), in which it was observed that there was an increment in Lactobacillus together with a decrease in Enterobacteriaceae in all the subjects (Table 2). Similar results were found after the administration of resveratrol to colitis-induced rats (Larrosa et al., 2009). Considering proanthocyanidin-rich diets, an increase in Lactobacillus and Bifidobacterium species was also shown after the administration of dealcoholized red wine polyphenols (2.4% of monomers; 28% of proanthocyanidins) to rats (Dolara, Luceri, et al., 2005) or after the intake of a grape seed supplement (2.4% monomers; 38.5% procyanidins) by humans (Yamakoshi, 2001) (Table 2). In addition, a reduction in the number of stools was reported after the administration of a carob pod extract (40% tannins) to babies with diarrhoea,

suggesting an inhibition of the pathogenic microflora. However, long-term administration of condensed tannins from Acacia angustissima (72% condensed tannins), a forage legume, to rats resulted in a shift in the microbial population towards Gram-negative bacteria species (i.e. Enterobacteriaceae and Bacteroides) and in a reduction of Gram-positive Clostridium leptum group, indicating that Gram-negative bacteria are also among the bacteria able to tolerate high concentrations of these compounds (Smith and Mackie, 2004) (Table 2). Concluding remarks and perspectives Although data about the biotransformation of wine phenolic compounds by colonic bacteria exist, most of these studies have been carried out in vitro, taking into account in very few cases the identification of bacterial species implicated in this metabolism or their mechanisms of action. In vitro studies using isolated bacterial strains and batch fermentation with human faeces have shown that some polyphenols (e.g. monomeric flavan-3ols) and/or their metabolites can inhibit several non-beneficial bacteria from the human microbiota, with no noticeable effects on the growth of probiotic bacteria or even slightly promoting their growth (Lee et al., 2006; Tzounis et al., 2008). In spite that some of these effects have been partially shown in vivo, human studies are still scarse (Goto et al., 1998; Yamakoshi et al., 2001). However, in the case of other polyphenol compounds (proanthocyanidins), it has been suggested that there is a predominant microbiota inhibitory effect which could affect the microbiota capacity to metabolize these compounds (Aura, 2008), although it has not yet been proven. On the other hand, metabolic-approach studies have confirmed a significant modification in the metabolic profile of biological fluids following the ingestion of grape/ wine extracts (Gru¨n et al., 2008; Jacobs et al., 2008). Nevertheless, this has not been directly related to the presence of bacteria able to modify the phenolic metabolome. Among the compounds described in wines, proanthocyanidins are of special interest due to their high abundance and even though they are not absorbed in the large intestine, they are metabolized by the colonic microbiota. At the same time, the resultant phenolic metabolites can also exert a selective effect on the gut bacteria species, thereby affecting the diversity and metabolic activity of the gut microbiota. For the above explained reasons, it is necessary to carry out simulation studies (of the oral cavity and colonic fermentation) together with human intervention studies. This integrated approach will address the study of both the microbial metabolism of polyphenols and the effect of polyphenols on growth and bacterial metabolic activity. Human intervention studies are relevant since they take into consideration individual microbiota variability and the effect of prolonged polyphenol ingestion.

Table 1. In vitro effects of polyphenols and polyphenol-rich products present in wine on most representative intestinal bacteria. Concentration

Bacteria

Results

Reference

Grape pomace Total phenolic content: 68.77  1.76 mg GAE/g (cv. Emir) 96.25  2.03 mg GAE/g (cv Kalecik karasi)

1, 2.5, 5, 10 and 20% (w/v)

All the bacteria tested were inhibited by all extract concentrations, except for Y. enterocolitica which was not inhibited by the 2.5% concentration. E. coli O157:H7 and S. aureus were the most sensitive bacteria.

Ozkan et al. (2004)

Industrial red wine Organic red wine White wine (Total phenolic content not given) ()-Epicatechin (þ)-Catechin 3-O-methyl gallic acid Gallic acid Caffeic acid 3-(4-hydroxyphenyl)-propionic acid 3-phenylpropionic acid 4-Hydroxyphenylacetic acid

1:4 dilution

Aeromonas hydrophila Bacillus cereus Enterobacter aerogenes Enterococcus faecalis Escherichia coli Escherichia coli O157:H7 Mycobacterium smegmatis Proteus vulgaris Pseudomonas aeruginosa Pseudomonas fluorescens Salmonella enteritidis Salmonella typhimurium Staphylococcus aureus Yersinia enterocolitica Salmonella ATCC 12068 P. aeruginosa ATCC 27853 E. coli ATCC 25922 Enterobacter cloacae ATCC 13047 S. aureus ATCC 25923 Bacteroides spp. Bifidobacterium spp. Clostridium spp. Escherichia coli Enterobacter spp. Enterococcus spp. Lactobacillus spp. Salmonella spp. Staphylococcus spp. Bacillus coagulans Klebsiella pneumoniae Listeria monocytogenes P. aeruginosa Vancomycin-resistant enterococci

Suppression of the growth of all pathogenic bacteria by all the wines, the effect being more prominent in the industrial red wine.

Dolara et al. (2005a)

Significant inhibition of the growth of: Clostridium perfringens by 3-O-methyl gallic acid and gallic Clostridium difficile by (þ)-catechin and ()-epicatechin Staphylococcus spp. by caffeic acid, 3-(4-hydroxyphenyl)-propionic acid, 3-phenylpropionic acid, 4-hydroxyphenylacetic acid E. coli and Salmonella spp. by 3-(4-hydroxyphenyl)propionic acid, 3-phenylpropionic acid, 4-hydroxyphenylacetic acid Lower inhibition of commensal bacteria and probiotics: Clostridium spp Bifidobacterium spp. Lactobacillus spp.

Lee et al. (2006)

Efficient destabilization of the outer membrane of Salmonella by the following acids, in particular by dihydroxylated: 3,4-dihydroxyphenylacetic acid 3-hydroxyphenylacetic acid 3-(3,4-dihydroxyphenyl)-propionic acid 3-(4-hydroxyphenyl)-propionic acid 3-phenylpropionic acid 3-(3-hydroxyphenyl)-propionic acid

Alakomi et al. (2007)

3,4-dihydroxyphenylacetic acid 3-hydroxyphenylacetic acid 3-(3,4-dihydroxyphenyl)propionic acid 3-(4-hydroxyphenyl)-propionic acid 3-phenylpropionic acid 2-hydroxyhexanoic acid 3-(3-hydroxyphenyl)-propionic acid

1.0 mg/ml, each separately

10 mM, pH 4.0 2.5 mM, pH 5.0

Salmonella enterica subsp. enterica serovar Typhimurium Salmonella enterica subsp. enterica serovar Infantis

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Product/Compound

339

Caffeic acid (þ)-Catechin Chlorogenic acid ()-Epicatechin o-Coumaric acid p-Coumaric acid Rutin Naringenin Quercetin (þ)-Catechin

2.0e25 mg/ml, each separately

()-Epicatechin

S. aureus Methicillin-resistant S. aureus P. aeruginosa Pneumococcus sp St. pyogenes Klebsiella sp. E. coli H. influenzae S. epidermidis Vancomycin-resistant E. faecalis Vancomycin-resistant E. casilliflavus L. rhamnosus E. coli S. aureus Salmonella typhimurium

0.150 mg/ml and 1.0 mg/ml

Human faeces

0.150 mg/ml and 1.0 mg/ml

Human faeces

Higher activity of fraction with DP3 than monomeric fraction at 0.25 mg/mL.

Mayer et al. (2008)

Naringenin and quercetin were the most active compounds presenting the lowest minimum inhibitory concentrations for all the four bacteria tested.

Parkar et al. (2008)

Increase in Clostridium coccoideseEubacterium rectale group, Bifidobacterium spp. and E. coli Decrease in C. histolyticum group (most notable at 150 mg/L, in all cases) Increase in Clostridium coccoideseE. rectale group (only at 150 mg/l)

Tzounis et al. (2008)

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5.99.7 mg/ml diluted 1:2, 1:20, and 1:200 ¼ 0.03e4.85 mg/ml

340

Proanthocyanidin fraction from grape seeds with different DP

Table 2. In vivo effects of the intake of polyphenols and polyphenol-rich products present in wine on most representative intestinal bacteria. Product/compound

Dose

Subject/animal

Intervention

Outcome

Reference

Monomeric flavan-3-ols Green tea extract (Polyphenon 60) (60% monomeric flavan-3-ols)

0.2% diet ¼ 6 cups tea/day

10,000 chickens

2 months

Terada et al. (1993)

Green tea extract (Polyphenon 60) (60% monomeric flavan-3-ols)

0.2% diet ¼ 6 cups tea/day

8 pigs

2 weeks

Green tea supplement

550 mg catechins, 2 times/day

30 healthy subjects

3 months

Green tea extract (Polyphenon 60) (60% monomeric flavan-3-ols)

100 mg catechins, 3 times/day

15 elderly subjects nasogastrically or gastrically fed

2 weeks

Increase in Lactobacillus Decrease in Enterobacteriaceae Decrease in ammonium and ethyl phenols Increase in volatile fatty acids, acetic and butyric acids Decrease in ammonium and ethyl phenols Increase in volatile fatty acids, acetic and butyric acids Improved intestinal regulation (38% subjects) Increase in Lactobacillus Decrease in Enterobacteriaceae and Clostridrium Decrease in faecal odor and pH Increase in organic acids

50 mg/Kg

22 rats

15 weeks

Main bacterial strains in the faeces at sacrifice were Bacteroides, Lactobacillus and Bifidobacterium spp., whereas in control-fed rats the main strains were Bacteroides, Clostridium and Propionibacterium spp.

Dolara et al. (2005b)

Proanthocyanidins Grape seed supplement (Gravinol) (38.5% procyanidins, 2.4% monomers)

0.5 g/day (0.19 g procyanidins)

9 healthy subjects

2 weeks

Yamakoshi et al. (2001)

Carob pod extract (40% tannins w/w)

1.5 g/Kg/day

6 days

Acacia angustissima extract (72% tannins)

0.7% (low-tannin diet) 2.0% (high-tannin diet)

21 babies (3e21 months old) with diarrhoea 6 rats

Increase in Bifidobacterium Decrease in Enterobacteriaceae Decrease in ammonium and ethyl phenols Reduction in the number of stools Reduction of diarrhoea

3 weeks

Increase in Gram-negative Enterobacteriaceae and Bacteroides species Decrease in Gram-positive Clostridium leptum group

Smith and Mackie (2004)

Colitis-induced rats

25 days

Increase in Lactobacillus and Bifidobacterium Decrease in E. coli and Enterobacteriaceae

Larrosa et al. (2009)

Non-flavonoid compounds Resveratrol

1 mg/Kg/day

Kanaya et al. (1995) Goto et al. (1998)

Loeb et al. (1989)

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Whole wine Wine polyphenols: 4.4% anthocyanins 0.8% flavonols 2.0% phenolic acids 1.4% catechin 1.0% epicatechin 28.0% proanthocyanidin units consisting of: 18.0% epigallocatechin 13.2% catechin 65.0% epicatechin 3.8% epicatechin gallate (mDP ¼ 6.8)

Hara et al. (1995)

341

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The knowledge of the interactions between wine polyphenols and bacteria in the oral cavity is less understood than in the gut. In spite of the fact that the mouth constitutes the first passage of food after its ingestion, scientific background related to the effect of wine polyphenols on oral bacterial microbiota is very scarce. To date, research has exclusively focused on the beneficial properties of wine components related to anticaries activity. Several preliminary studies pointed out the possible use of wine polyphenolic compounds or extracts in order to prevent the formation of dental plaque and showed the need of more exhaustive studies considering the different wine phenolic compounds and bacterial groups occurring in the oral ecosystem. Additionally, the spectrum of activities of these natural wine constituents on the oral cavity needs to be further explored. Furthermore, references to the metabolism of wine polyphenols by bacteria present in the oral ecosystem are very scarce. During their passage through the mouth, polyphenols can be degraded by oral microbiota and start to be absorbed by the mucus epithelium. This biotransformation may be affected by the capacity of the oral mucus epithelium to retain polyphenols. At the same time, other wine macrocomponents can be associated with polyphenols, interfering in their effect on oral bacterial growth. In the future, all these aspects will also require careful attention. In summary, there is scientific evidence that some polyphenols present in wine could introduce quantitative and qualitative changes in oral and gut microbiota, but further scientific investigation is still needed in relation to the biological effects of the resultant microbial metabolites to ascertain their mechanisms of action. In addition, considering that most studies have been performed with in vitro model systems, without taking into account inter-individual microbiota variability or the effect of prolonged ingestion of polyphenols on the microbiota population and its possible implication on oral and intestinal health, wine intervention studies on a large number of human subjects are necessary. A multidisciplinary approach, which considers all these aspects as a whole, is required to achieve an in-depth knowledge of this topic. Acknowledgments This work has been funded by the Spanish Ministry for Science and Innovation (AGL2009-13361-C02-00, and CSD2007-00063 Consolider Ingenio 2010 FUN-C-FOOD Projects), and the Comunidad de Madrid (ALIBIRD P2009/AGR-1469 Project). References Aas, J. A., Paster, B. J., Stokes, L. N., Olsen, I., & Dewhirst, F. E. (2005). Defining the normal bacterial flora of the oral cavity. Journal of Clinical Microbiology, 43, 5721e5732. Alakomi, H.-L., Puupponen-Pimia, R., Aura, A.-M., Helander, I. M., Nohynek, L., Oksman-Caldentey, K.-M., et al. (2007). Weakening of Salmonella with selected microbial metabolites of berry-derived phenolic compounds and organic acids. Journal of Agricultural and Food Chemistry, 55, 3905e3912.

Appeldoorn, M. M., Vincken, J.-P., Aura, A.-M., Hollman, P. C. H., & Gruppen, H. (2009). Procyanidin dimmers are metabolized by human microbiota with 2-(3,4-dihydroxyphenyl)acetic acid and 5-(3,4-didydroxyphenyl)-g-valerolactone as the major metabolites. Journal of Agricultural and Food Chemistry, 57, 1084e1092. Aura, A.-M. (2008). Microbial metabolism of dietary phenolic compounds. Phytochemistry Reviews, 7, 407e429. Blaut, M., & Clavel, T. (2007). Metabolic diversity of the gut microbiota: implications for health and disease. Journal of Nutrition, 137, 751Se755S. Bodet, C., Grenier, D., Chandad, F., Offek, I., Steinberg, D., & Weiss, E. I. (2008). Potential oral health benefits of cranberry. Critical Reviews in Food Science and Nutrition, 48, 672e680. Carroll, I. M., Threadgill, D. W., & Threadgill, D. S. (2009). The gastrointestinal microbiome: a malleable, third genome of mammals. Mammalian Genome, 20, 395e403. Clifford, M. N. (2004). Diet-derived phenols in plasma and tissues and their implication for health. Planta Medica, 70, 1103e1114. Crozier, A., Jaganath, I. B., & Clifford, M. N. (2009). Dietary phenolics: chemistry, bioavailability and effects on health. Natural Product Reports, 26, 1001e1043. Daglia, M., Papetti, A., Grisol, P., Aceti, C., Spini, V., Dacarro, C., et al. (2007). Antibacterial activity of red and white wine against oral streptococci. Journal of Agricultural and Food Chemistry, 55, 5038e5042. Da´valos, A., & Lasuncio´n, M. A. (2009). Health-promoting effects of wine phenolics. In M. V. Moreno-Arribas, & M. C. Polo (Eds.), Wine chemistry and biochemistry (pp. 571e591). New York: Springer. Dolara, P., Arrigucci, S., Cassetta, M. I., Fallani, S., & Novelli, A. (2005). Inhibitory activity of diluted wine on bacterial growth: the secret of water purification in antiquity [1]. International Journal of Antimicrobial Agents, 26, 338e340. Dolara, P., Luceri, C., De Filippo, C., Femia, A. P., Giovannelli, L., Caderni, G., et al. (2005). Red wine polyphenols influence carcinogenesis, intestinal microflora, oxidative damage and gene expression profiles of colonic mucosa in F344 rats. Mutation Research, 591, 237e246. Donovan, J. L., Manach, C., Faulks, R. M., & Kroon, P. A. (2006). Absorption and metabolism of dietary plant secondary metabolites. In A. Crozier, M. N. Clifford, & H. Ashihara (Eds.), Plant secondary metabolites. Occurrence, structure and role in the human diet (pp. 303e341). Oxford: Blackwell Publishing. Duarte, S., Gregoire, S., Singh, A. P., Vorsa, N., Schaich, K., Bowen, W. H., et al. (2006). Inhibitory effects of cranberry polyphenols on formation and acidogenicity of Streptococcus mutans biofilms. FEMS Microbiology Letters, 257, 50e56. Forester, S. C., & Waterhouse, A. L. (2009). Metabolites are key to understanding health effects of wine polyphenolics. Journal of Nutrition, 139, 1824Se1831S. Friedman, M. (2007). Overview of antibacterial, antitoxin, antiviral and antifungal activities of tea flavonoids and teas. Molecular Nutrition and Food Research, 51, 116e117. Furiga, A., Lonvaud, A., & Badet, C. (2009). In vitro study of antioxidant capacity and antibacterial activity on oral anaerobes of a grape seed extract. Food Chemistry, 113, 1037e1040. Gao, K., Xu, A., Krul, C., Venema, K., Liu, Y., Niu, Y., et al. (2006). Of the major phenolic acids formed during human microbial fermentation of tea, citrus, and soy flavonoid supplements, only 3,4-dihydroxyphenylacetic acid has antiproliferative activity. Journal of Nutrition, 136, 52e57. Gonthier, M.-P., Cheynier, V., Donovan, J. L., Manch, C., Morand, C., Mila, I., et al. (2003). Microbial aromatic metabolites formed in the gut account for a major fraction of the polyphenols excreted in urine of rats fed red wine polyphenols. Journal of Nutrition, 133, 461e467. Gonthier, M.-P., Remesy, C., Scalbert, A., Cheynier, V., Souquet, J.-M., Poutanen, K., et al. (2006). Microbial metabolism of caffeic acid

T. Requena et al. / Trends in Food Science & Technology 21 (2010) 332e344 and its esters chlorogenic and caftaric acids by human faecal microbiota in vitro. Biomedicine and Pharmacotherapy, 60, 536e540. Gonza´lez-Sarrı´as, A., Espı´n, J. C., Toma´s-Barbera´n, F. A., & Garcı´aConesa, M. T. (2009). Gene expression, cell cycle arrest and MAPK signalling regulation in Caco-2 cells exposed to ellagic acid and its metabolites, urolithins. Molecular Nutrition and Food Research, 53, 686e698. Goto, K., Kanaya, S., Nishikawa, T., Hara, H., Terada, A., Ishigami, T., et al. (1998). The influence of tea catechins on faecal flora of elderly residents in long-term facilities. Annals of Long Term Care, 6, 43e48. Groenewoud, G., & Hundt, H. K. (1986). The microbial metabolism of condensed (þ)-catechins by rat-cecal microflora. Xenobiotica, 16, 99e107. Gru¨n, C. H., van Dorsten, F. A., Jacobs, D. M., Le Belleguic, M., van Velzen, E. J. J., Bingham, M. O., et al. (2008). GC-MS methods for metabolic profiling of microbial fermentation products of dietary polyphenols in human and in vitro intervention studies. Journal of Chromatography B, 871, 212e219. Guarner, F., & Malagelada, J. R. (2003). Gut flora in health and disease. Lancet, 360, 512e519. Guggenheim, B., Guggenheim, M., Gmur, R., Giertsen, E., & Thurnheer, T. (2004). Application of the Zurich biofilm model to problems of cardiology. Caries Research, 38, 212e222. Hannig, C., Sorg, J., Spitzmu¨ller, B., Hanning, M., & Al-Ahmad, A. (2009). Polyphenolic beverages reduce initial bacterial adherence to enamel in situ. Journal of Dentistry, 37, 560e566. Hara, Y. (1997). Influence of tea catechins on the digestive tract. Journal of Cellular Biochemistry, 67, 52e58. Hara, H., Orita, N., Hatano, S., Ichikawa, H., Hara, Y., Matsumoto, N., et al. (1995). Effect of tea polyphenols on fecal flora and fecal metabolic products of pigs. Journal of Veterinary Medical Science, 57, 45e49. Hirota, S., Nishiora, T., Shimoda, T., Miura, K., Ansai, T., & Takahama, U. (2001). Quercetin glucosides are hydrolyzed to quercetin in human oral cavity to participate in peroxidasedependent scavenging of hydrogen peroxide. Food Science and Technology Research, 7, 239e245. Jacobs, D. M., Deltimple, N., van Velzen, E., van Dorsten, F. A., Bingham, M., Vaughan, E. E., et al. (2008). 1H NMR metabolite profiling of faeces as a tool to assess the impact of nutrition on the human microbiome. NMR in Biomedicine, 21, 615e626. Jenkinson, H. F., & Lamont, R. J. (2005). Oral microbial communities in sickness and in health. Trends in Microbiology, 13, 589e595. Kanaya, S., Goto, K., Hara, Y., & Hara, Y. (1995). The physiological effects of tea catechins on human volunteers. Proceedings of International Symposium of Tea Science, 314e317. Kaufman, E., & Lamster, I. B. (2000). Analysis of saliva for periodontal diagnosisda review. Journal of Clinical Periodontology, 27, 453e465. Kongstad, J., Hvidtfeldt, U. A., Gronbaek, M., Jontell, M., Stoltze, K., & Holmstrup, P. (2008). Amount and type of alcohol and periodontitis in the Copenhagen City heart study. Journal of Clinical Periodontology, 35, 1032e1039. Larrosa, M., Gonza´lez-Sarrı´as, A., Garcı´a-Conesa, M. T., Toma´sBarbera´n, F. A., & Espı´n, J. C. (2006). Urolithins, ellagic acid-derived metabolites produced by human colonic microflora, exhibit estrogenic and antiestrogenic activities. Journal of Agricultural and Food Chemistry, 54, 1611e1620. Larrosa, M., Luceri, C., Vivoli, E., Pagliuca, C., Lodovici, M., Moneti, G., et al. (2009). Polyphenol metabolites from colonic microbiota exert anti-inflammatory activity on different inflammation models. Molecular Nutrition and Food Research, 53, 1044e1054. Lee, H. C., Jenner, A. M., Low, C. S., & Lee, Y. K. (2006). Effect of tea phenolics and their aromatic fecal bacterial metabolites on

343

intestinal microbiota. Research in Microbiology, 157, 876e884. Loeb, H., Vandenplas, Y., Wursch, P., & Guesry, P. (1989). Tannin-rich carob pod for the treatment of acute-onset diarrhea. Journal of Pediatric Gastroenterology and Nutrition, 8, 480e485. Manach, C., Scalbert, A., Morand, C., Re´me´sy, C., & Jime´nez, L. (2004). Polyphenols: food sources and bioavailability. American Journal of Clinical Nutrition, 79, 727e747. Marsh, P. D., & Percival, R. S. (2006). The oral microflora- friend or foe? Can we decide? International Dental Journal, 56, 233e239. Maukonen, J., Ma¨tto¨, J., Suihko, M. L., & Saarela, M. (2008). Intraindividual diversity and similarity of salivary and faecal microbiota. Journal of Medical Microbiology, 57, 1560e1568. Mayer, R., Stecher, G., Wuerzner, R., Silva, R. C., Sultana, T., Trojer, L., et al. (2008). Proanthocyanidins: target compounds as antibacterial agents. Journal of Agricultural and Food Chemistry, 56, 6959e6966. Monagas, M., Herna´ndez-Ledesma, B., Garrido, I., Martı´nAlvarez, P. J., Go´mez-Cordove´s, C., & Bartolome´, B. (2005). Quality assessment of commercial dietary antioxidant products from Vitis vinifera L. grape seeds. Nutrition and Cancer, 53, 244e254. Monagas, M., Khan, N., Andre´s-Lacueva, C., Urpı´-Sarda´, M., Va´zquez-Agell, M., Lamuela-Ravento´s, R. M., et al. (2009). Dihydroxylated phenolic acids derived from microbial metabolism reduce lipopolysaccharide-stimulated cytokine secretion by human peripheral blood mononuclear cells. British Journal of Nutrition, 102, 201e206. Moreno-Arribas, M. V., Pozo-Bayo´n, M. A., & Polo, M. C. (2009). Peptides. In M. V. Moreno-Arribas, & M. C. Polo (Eds.), Wine chemistry and biochemistry (pp. 191e212). New York: Springer. Neveu, V., Perez-Jime´nez, J., Vos, F., Crespy, V., du Chaffaut, L., Mennen, L., et al. (2010). Phenol-explorer: an online comprehensive database on polyphenol contents in foods. (Version 1.5.2, Available at: www.phenol-explorer.eu). Database, doi: 10.1093/ database/bap024 Okubo, T., Ishihara, N., Oura, A., Serit, M., Kim, M., Yamamoto, T., et al. (1992). In vivo effects of tea polyphenols intake on human intestinal microflora and metabolism. Bioscience Biotechnology and Biochemistry, 56, 588e591. Ozkan, G., Sagdic, O., Baydar, N. G., & Kurumahmutoglu, Z. (2004). Antibacterial activities and total phenolic contents of grape pomace extracts. Journal of the Science of Food and Agriculture, 84, 807e1811. Paju, S., & Scannapieco, F. A. (2007). Oral biofilms, periodontitis, and pulmonary infections. Oral Diseases, 13, 508e512. Parisis, D. M., & Pritchard, E. T. (1983). Activation of rutin by human oral bacterial isolates to the carcinogen-mutagen quercetin. Archives of Oral Biology, 28, 583e590. Parkar, S. G., Stevenson, D. E., & Skinner, M. A. (2008). The potential influence of fruit polyphenols on colonic microflora and human gut health. International Journal of Food Microbiology, 124, 295e298. Pozo-Bayo´n, M. A., Monagas, M., Bartolome´, B., Moreno-Arribas, M. V. Wine features related to safety and consumer health: an integrated perspective. Critical Reviews in Food Science and Nutrition, in press., doi:10.1080/10408398.2010.489398. Rechner, A. R., & Kroner, C. (2005). Anthocyanins and colonic metabolites of dietary polyphenols inhibit platelet function. Thrombosis Research, 116, 327e334. Renaud, S., & de Lorgeril, M. (1992). Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet, 339, 1523e1526. Salzman, N. H., & Bevins, C. L. (2008). Negative interactions with the microbiota: IBD. Advances in Experimental Medicine and Biology., 635, 67e78. Sanz, Y., Sa´nchez, E., Marzotto, M., Calabuig, M., Torriani, S., & Dellaglio, F. (2007). Differences in faecal bacterial communities in

344

T. Requena et al. / Trends in Food Science & Technology 21 (2010) 332e344

coeliac and healthy children as detected by PCR and denaturing gradient gel electrophoresis. FEMS Immunology and Medical Microbiology, 51, 562e568. Schoefer, L., Braune, A., & Blaut, M. (2004). Cloning and expression of a phloretin hydrolase gene from Eubacterium ramulus and characterization of the recombinant enzyme. Applied and Environmental Microbiology, 70, 6131e6137. Selma, M. V., Espı´n, J. C., & Toma´s-Barbera´n, F. A. (2009). Interaction between phenolics and gut microbiota: role in human health. Journal of Agricultural and Food Chemistry, 57, 6485e6501. Signoretto, C., & Canepari, P. (2009). Anticaries and antiadhesive properties of food constituents and plant extracts and implications for oral health. In Michael Wilson (Ed.), ‘Food constituents and oral health’ (pp. 240e262). Cambridge: Woodhead Publishing Limited. Smith, A. H., & Mackie, R. I. (2004). Effect of condensed tannins on bacterial diversity and metabolic activity in the rat gastrointestinal tract. Applied and Environmental Microbiology, 70, 1104e1115. Socransky, S. S., Haffajee, A. D., Smith, C., Martin, L., Haffajee, J. A., Uzel, N. G., et al. (2004). Use of checkerboard DNAeDNA hybridization to study complex microbial ecosystems. Oral Microbiology and Immunology, 19, 352e362. Stoupi, S., Williamson, G., Drynan, J. W., Barron, D., & Clifford, M. N. (2010). A comparison of the in vitro biotransformation of ()-epicatechin and procyanidin B2 by human faecal microbiota. Molecular Nutrition and Food Research, 54, 1e13. Terada, A., Hara, H., Nakajyo, S., Ichikawa, H., Hara, Y., Fukai, K., et al. (1993). Effect of supplements of tea polyphenols on the cecal flora and cecal metabolites of chicks. Microbial Ecology in Health and Disease, 6, 3e9. Thimothe, J., Bonsi, J. A., Padilla-Zakour, O. I., & Koo, H. (2007). Chemical characterization of red wine grape (Vitis vinifera and Vitis Interspecific Hybrids) and pomace phenolic extracts and their biological activity against Streptococcus mutans. Journal of Agricultural and Food Chemistry, 55, 10200e10207.

Thurnheer, T., Giertsen, E., Gmur, R., & Guggenheim, B. (2008). Cariogenicity of soluble starch in oral in vitro biofilm and experimental rat caries studies: a comparison. Journal of Applied Microbiology, 105, 829e836. Toma´s-Barbera´n, F. A., Garcı´a-Conesa, M. T., Larrosa, M., Cerda´, B., Gonza´lez-Barrio, R., Bermu´dez-Soto, M. J., et al. (2008). Bioavailability, metabolism and bioactivity of food ellagic acid and related polyphenols. In F. Daayf, & V. Lattanzio (Eds.), Recent advances in polyphenol research, Vol. 1 (pp. 263e275). Oxford: Wiley-Blackwell. Tzounis, X., Vulevic, J., Kuhnle, G. C., George, T., Leonczak, J., Gibson, G. R., et al. (2008). Flavonol monomer-induced changes to the human faecal microflora. British Journal of Nutrition, 99, 782e792. Ventura, M., O’Flaherty, S., Claesson, M. J., Turroni, F., Klaenhammer, T. R., van Sinderen, D., et al. (2009). Genome-scale analyses of health-promoting bacteria: probiogenomics. Nature Reviews Microbiology, 7, 61e71. Walle, T., Browing, A. M., Steed, L., Reed, S. G., & Walle, U. K. (2005). Flavonoid glucosides are hydrolyzed and thus activated in the oral cavity in humans. Journal of Nutrition, 135, 48e52. Walter, A., Cerdeno-Tarraga, A., & Bentley, S. (2006). Faecal matters. Nature Reviews Microbiology, 4, 572e573. Wu, C. D. (2009). Grape products and oral health. Journal of Nutrition, 139, 1818Se1823S. Wu, C. D., & Wei, G. (2009). Tea as a functional food for oral health. In M. Wilson (Ed.), Food constituents and oral health (pp. 396e417). Cambridge: Woodhead Publishing Limited. Yang, C. S., Lee, M. J., & Chen, L. (1999). Human salivary tea catechin levels and catechin esterase activities: implications in human cancer prevention studies. Cancer Epidemiology, Biomarkers & Prevention, 8, 83e89. Yamakoshi, J., Tokutake, S., Kikuchi, M., Kubota, Y., Konishi, H., & Mitsuoka, T. (2001). Effect of proanthocyanidin-rich extract from grape seeds on human fecal flora and faecal odor. Microbial Ecology in Health and Disease, 13, 25e31.