Fitoterapia 132 (2019) 30–39

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Fitoterapia
journal homepage: www.elsevier.com/locate/fitote

Review

Polyphenols in the prevention and treatment of periodontal disease: A T

systematic review of in vivo, ex vivo and in vitro studies
⁎
Kübra Buntea, , Andreas Henselb,1, Thomas Beiklerc,1
a
Private Dental Clinic, Shanghai, China
b
University of Münster, Institute of Pharmaceutical Biology and Phytochemistry, Corrensstr. 48, 48149 Münster, Germany
c
University Medical Centre Hamburg-Eppendorf, Department of Periodontics, Preventive and Restorative Dentistry, Building O58, Martinistr. 52, 20246 Hamburg,
Germany

A R T I C LE I N FO A B S T R A C T

Keywords: Plant-derived polyphenols with antimicrobial and immunomodulatory characteristics appear to provide a
Plants variety of oral health benefits. Thus, the aim of the present study was to review the scientific literature to identify
Polyphenols these effects of polyphenols on periodontal pathogens and inflammation. A MEDLINE search from 1st January
Periodontal disease 2013 to 18th January 2018 was performed to identify studies reporting polyphenol-containing plant extracts.
Periodontitis
Reports regarding pure compounds and essential oils, as well as effects on bacteria that are not defined as
Antibacterial
Anti-inflammatory
periodontal pathogens, were excluded. Thirty-eight studies matched the selection criteria. Studies on im-
munomodulatory effects included in vitro, ex vivo, and in vivo studies (n = 23), whereas studies reporting anti-
bacterial effects against periodontal pathogens included only in vitro studies (n = 18). Three studies were in-
cluded in both groups. The antibacterial effects were characterised by inhibition of bacterial growth, adhesion to
oral cells, and enzymatic activity. Decreased secretion of pro-inflammatory and increased secretion of anti-
inflammatory cytokines were demonstrated. Higher attachment levels, lower inflammation, and bone loss were
reported by in vivo studies. Due to the high heterogeneity, it is difficult to draw clear conclusions for applic-
ability; nevertheless, polyphenols have great potential as antimicrobial and immunomodulatory substances in
the treatment and prevention of periodontal disease.

1. Introduction Non-surgical treatment of periodontitis by machine-driven or

Periodontitis is a chronic inflammatory disease initiated and per-
petuated by an intraoral dysbiosis that leads to progressive destruction
of the periodontal ligament, connective tissue, and alveolar bone; and if
left untreated, results in tooth loss [1–3]. Although the majority of
microorganisms colonizing the gingival sulcus at or below the gingival
margin are compatible with periodontal health, a subset of species may
cause or contribute to an intraoral dysbiosis, and subsequently to the
clinical signs of periodontal disease [4]. In this regard, approximately
15 to 20 bacterial species have been found to be closely associated with
periodontal disease [5]. Among these, Agregatibacter actinomycetemco-
mitans and the prominent species from the so-called “red complex” e.g.
Porphyromonas gingivalis appear to be the most virulent [6]. However,
not only bacterial invasion and virulence but also the host immune
response induced by this dysbiotic intraoral ecosystem plays a major
role in the progression of periodontal disease [7–10].
manual instrumentation aims to reduce the intraoral bacterial load.
Moreover, adjunctive antimicrobial strategies such as local and sys-
temic antibiotics or non-specific antimicrobials, e.g., chlorhexidine di-
gluconate, are used to augment the antimicrobial effects of mechanical
debridement [11]. However, numerous adverse effects, most im-
portantly an increase in bacterial resistance against antibiotics, high-
light the need for the development of novel adjunctive strategies for the
treatment and prevention of this prevalent disease [12,13].
In this regard, plant-based traditional medicine or phytother-
apeutics have become a focus of scientific and clinical interest [14].
Polyphenols are natural products, mainly produced by higher plants as
secondary metabolites with different functions ranging from defense to
growth regulation and plant colour [15,16]. An exact classification and
differentiation of these compounds is challenging due to their complex
structures; > 8000 identified compounds have been described to date,
and classification is mainly based on their respective chemical

⁎
Corresponding author at: DDS Dental Care, Office Building A, UG 05-07, No. 1799 Wuzhong Road, 201103 Shanghai, China.
E-mail addresses: kbrtncl@yahoo.com (K. Bunte), ahensel@uni-muenster.de (A. Hensel), t.beikler@uke.de (T. Beikler).
1
Co-author.

https://doi.org/10.1016/j.fitote.2018.11.012
Received 13 October 2018; Received in revised form 13 November 2018; Accepted 24 November 2018
Available online 27 November 2018
0367-326X/ © 2018 Elsevier B.V. All rights reserved.
K. Bunte et al.
Fig. 1. Classification of polyphenols and typical representative compounds.
Fig. 2. Typical chemical structural features of flavonoids (A), anthocyanidins
(B), proanthocyanidins (C), cinnamic acid (D) and benzoic acid (E) derivatives.
composition [17]. Some authors have classified polyphenols into five
main groups: hydrolysable tannins, phenolic acids, polyphenolic
amides, flavonoids, and other, with their corresponding subgroups
based on chemical composition (Fig. 1) [16,18]. Flavonoids, as the most
abundant group of polyphenols, are further divided into seven sub-
groups; they share a common structure, which consists of two aromatic
rings (A and B) and three carbon atoms that bind ring A and B together,
creating an oxygenated heterocycle named ring C (Fig. 2) [19].
Oxidative stress, described as an imbalance between the production
and elimination of reactive oxygen/nitrogen species (ROS/RNS), results
in inflammation and associated health problems such as cardiovascular,
cerebrovascular, immunological, metabolic, and neurodegenerative
diseases [17]. Due to their antioxidant effects, ameliorative or pre-
ventive effects of polyphenols on several inflammatory diseases have
been reported by numerous studies [20–27]. Styshova et al., recently
published anti-diabetic activities of polyphenols derived from Zostera
seagrasses [28], and the consumption of dietary flavonoids has also
been related to a reduced risk of developing type II diabetes mellitus
[25]. Moreover, a recent systematic review indicated a reduced risk of
colorectal cancer in individuals with habitual dietary intake of flavo-
noid-rich foods [26]. Improved cardiac function, reduced diastolic
blood pressure, and more favourable cardiovascular risk factors, such as
31
Fitoterapia 132 (2019) 30–39
improved endothelial function, reduced low-density lipoprotein (LDL)
plasma concentration, and cardiac infarct size have been reported
[29,30]. In addition to these health benefits, polyphenols have been
associated with improved wound healing [31,32], inhibition of the
adhesion of pathogens to host cells [33,34], and antibacterial effects
against gastrointestinal and cariogenic pathogens [35,36].
Such characteristics turn these substances into promising targets for
the development of adjunctive preventive and therapeutic strategies not
only but also for the management of periodontal disease. Therefore, the
aims of the present study were to review the literature to identify the
antibacterial effect of plant-derived polyphenols on periodontal pa-
thogens, as well as their modulatory effect on the host immune and
inflammatory responses.
2. Materials and methods
2.1. Search strategy
An electronic database search was conducted using PubMed (access
date from 1st January 2013 to 18th January 2018). The search strategy
terms were categorised into three groups: periodontitis OR periodontal
diseases AND polyphenols OR plant extracts OR herbal medicine OR
plants AND anti-bacterial OR antiadhesive OR antivirulence OR anti-
inflammatory OR antioxidant, respectively. Search results from all re-
levant combinations of the above search terms were imported into a
citation manager program, and all duplicates were automatically re-
moved. All imported studies were screened by title and abstract.
Bibliographies of the retrieved articles were also screened for articles
relevant to the search strategy.
2.2. Inclusion criteria
The effects were classified according to their antibacterial and im-
munomodulatory actions. Studies using polyphenol-containing plant
extracts or fractions from flowers, seeds, roots, fruits, leaves, and
trunks, that have been analysed with respect to their effects on peri-
odontal pathogens were assigned to the antibacterial group.
Accordingly, studies reporting immunomodulatory effects on host cells
or tissues treated with exotoxins from periodontal pathogens were al-
located to the anti-inflammatory group. Thus, this review includes in
vitro, ex vivo, and in vivo studies that investigated the
K. Bunte et al.
immunomodulatory effects of plant-derived polyphenols and in vitro
studies that reported the antibacterial effects against periodontal pa-
thogens. Only studies published in the English language over the last
five years were taken into consideration.
2.3. Exclusion criteria
Compounds that were not directly extracted from plants, e.g., pure
compounds purchased from a provider, and essential oils emanating
from plants were omitted from the present study due to the differences
in their pharmacological activity compared to crude plant extract. As it
is known that essential oils (syn. volatile oils) act unspecific against
nearly all kinds of bacteria, mainly by destruction of cell membranes
and no specificity or selectivity has been proven until now. The use of
essential oil containing mouth wash products has already been re-
viewed and documented in the literature, therefore the present review
excludes this compound group. Reviews and studies unrelated to peri-
odontal pathogens and tissues were also excluded from the present
study. Moreover, reports describing the application of plant extracts in
combination with routine pharmacological therapy, such as chlorhex-
idine mouthrinses or antibiotics, and studies investigating the effects of
plant derived polyphenols on undefined oral multispecies biofilm were
excluded.
2.4. Data organisation
Authors, year of publication, type of study, type of plant, tested
compound from the plant extract, treatment duration, extract con-
centration, type of bacteria, type of cells and tissues, methods, and
major outcomes of each study were noted in a standard document. The
studies were categorised into two groups: studies reporting on anti-
bacterial effects on periodontal pathogens and immunomodulatory ef-
fects on host cells and tissues. The group of studies reporting im-
munomodulatory effects was further divided into three subgroups: a) in
vitro, b) ex vivo, and c) in vivo studies. The organised data were eval-
uated according to the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA) guidelines (www.prisma-
statement.org) [37].
3. Results
A total of 1408 articles were identified following an online database
search and screening of reference lists of articles. The selection process
of the search results is depicted in Fig. 3. After duplicate removal, 740
articles were further screened by title and abstract. A total of 601 ar-
ticles were excluded in the first exclusion according to the exclusion
criteria − first exclusion criteria included studies that were older than
five years, unrelated to oral and periodontal pathogens, review articles,
and non-polyphenolic compounds − and 139 full-text studies were
reevaluated for eligibility. Following the second exclusion process −
second exclusion criteria included studies regarding non-periodontal
pathogens, essential oils, and pure compounds −38 studies remained
and were included in the analysis. 18 out of the 38 remaining studies
reported on the antibacterial effects against periodontal pathogens
[38–55] and 23 out of the 38 studies reported on anti-inflammatory
effects [41,54–74]. 5 out of 23 reported in vivo [56–60]; 7 out of 23
reported ex vivo [61–67]; and 11 out of 23 reported in vitro
[41,54,55,61,64,69–75] effects. Three of these studies were included in
both groups [41,54,55].
Detailed data regarding the methods and results of each report are
summarised in Tables 1–4. Among all the included studies, six reported
on the effects of green tea extract or its active component, epigalloca-
techin-3-O-gallate (EGCG) [40,51,60,70,75,76], and three studies re-
ported on the effects of black tea extract or its active components,
theaflavins [40,41,71], Both green tea and black tea are varietals of
Camellia sinensis. Four studies highlighted the anti-inflammatory
32
Fitoterapia 132 (2019) 30–39
properties of proanthocyanidins from cranberry or cranberry juice ex-
tract [70,72–74]. Two studies reported on the anti-bacterial and anti-
inflammatory effects of blueberry extract [45,54]. Individual studies
reported the effects of Epimedium species [38], Azadirachta indica leaves
[53], Limonium brasiliense [39], Ocimum sanctum [42], Rumex acetosa
(L.) [43], Murraya paniculata (L.) Jack [44], Vaccinium angustifolium Ait
[45], Glycyrrhiza uralensis [46], Phytolacca americana [47], Mammea
americana [52], Allium sativum (L.) [48], Dodonaea viscosa var. angu-
stifolia [49], blackberry [50], Stemodia maritima (L.) [56], grape seed
[57], Salvia sclarea (L.) [58], Crataeus orientalis M Bieber [59], Termi-
nalia chebula [61], Sophorae Flos [62], Magnolia officinalis (L.) [63],
Polygoni Multiflori [65], Rhododendron ferrugineum (L.) [55], Os-
manthus fragrans [66], Angelica sinensis [67], Aristotelia chilensis Maqui
[69], and Geum urbanum (L.) root [64].
3.1. Effects on periodontal pathogens
An overview of the antibacterial effects of the representative com-
pounds is depicted in Table 1. Fifteen studies reported on the effects
against P. gingivalis [38,39,41–44,46–53,55], four studies against Fu-
sobacterium(F.) nucleatum [40,45,50,53], four studies against A. acti-
nomycetemcomitans [42,48,51,54], and two studies against Prevotella
(P.) intermedia [42,51]. Reduction or complete elimination of bacterial
enzymatic activity by direct inhibition of the synthesis of proteolytic
enzymes and adhesins was reported by seven studies
[38,39,43,48–50,55].
Gingipains attribute to 85% of the total proteolytic activity of P.
gingivalis and biochemically belong to the family of cysteine-protease,
which means they are “trypsin-like” enzymes [77]. They are thiol de-
pendent and cleave carboxyl termini of amino acid chains to either
arginine or lysine [78]. There are two arginine-specific gingipains en-
coded by rgpA and rgpB genes and one lysine-specific gingipain encoded
by kgp gene [79,80]. Acting alone or in combination, gingipains are
able to interfere with the host by invading and colonizing the host cells
[81], degrading antibacterial peptides such as defensins [82,83],
modulating the complement system by either activation or deactivation
of its components [84], manipulating cytokine networks [85,86], and
inactivating protease inhibitors [87–89]. An in vitro antiadhesive ac-
tivity of Rhododendron ferrugineum L., hydroalcoholic leaf extract
(1 mg/ml) against P. gingivalis was reported by Löhr et al. [55]. This was
induced by the inhibition of Arg-gingipain activity, and was accom-
panied by significantly reduced hemagglutination. Relative gene ex-
pression of RgpA in P. gingivalis was also significantly downregulated by
the extract, while typical inflammatory genes (e.g. cyclooxygenase-2
[COX-2], interleukin-1beta [IL-1β], interleukin[IL]-5, IL-8, and tumor
necrosis factor alpha [TNF-α]) in KB cells -subline of the uniquitous
KERATIN-forming tumor cell line Henrietta Lacks- were significantly
reduced. Interestingly, the Lys-gingipain activity was unaffected by the
extract. The extract contained higher amounts of different flavonoids
and 8.7% proanthocyanidin-type tannins. De Oliveira Caleare et al.,
also observed a significant reduction (80% inhibition at 100 μg/ml
extract) in the proteolytic activity of Arg-gingipain and bacterial ad-
hesion of P. gingivalis to KB cells for a standardised hydroalcoholic Li-
monium brasiliense rhizome extract [39]. The extract did not influence
the cell viability of P. gingivalis at concentrations that significantly in-
hibited the antiadhesive activity; and was characterised by the presence
of gallic acid, EGCG, and samarangenin.
A pilot study demonstrated reduced Lys- and Arg-gingipain activity
of P. gingivalis following exposure to Dodonaea viscosa var. angustifolia
methanolic extract in sublethal concentrations [49]. Gonzalez et al.,
tested blackberry extract (BBE), which typically contains hydrolysable
and condensed tannins, at concentrations of 700 μg/ml and 1400 μg/ml
to demonstrate its antibacterial effect [50]. Their results showed a 40%
reduction in the metabolic activity of P. gingivalis and F. nucleatum
following a 24-h exposure to 700 μg/ml BBE, and an 84% reduction in
the metabolic activity of F. nucleatum following exposure to 1400 μg/ml
K. Bunte et al.
Fig. 3. Flowchart of the article search strategy, exclusion criteria, study selection, and data management process.
BBE. A more recent study with blueberry extract demonstrated an in-
hibitory effect of 29.9 ± 12.3% on the growth of F. nucleatum at a
concentration of 500 μg/ml [45].
Antibacterial effects of green tea extract (unfermented leaves from
Camelia sinensis), characterised by the lead compound EGCG, a gal-
loylated flavan-3-ol and a high amount of galloylated and unsubstituted
B-type proanthocyanidins and were demonstrated by three studies
[40,41,51]. In one study, theaflavin from black tea extract (fermented
leaves from Camelia sinensis) was shown to inhibit the growth of P.
gingivalis and Arg- and Lys-gingipain activity [41]. In an earlier study, P.
gingivalis, P. intermedia, and A. actinomycetemcomitans were shown to be
sensitive to green tea extract, with the main compound being EGCG,
with a minimum inhibitory concentration of 12.5 μg/ml, 12.5 μg/ml,
and 6.25 μg/ml, respectively [51]. Ben Lagha et al., conducted a com-
parative study on Camellia sinensis polyphenols [40] comparing black
tea extract, green tea extract, and their bioactive components theaflavin
and EGCG at 2 mg/ml, 1 mg/ml, and 0.5 mg/ml concentrations. Inter-
estingly, the antibacterial activity of green tea, which contains a higher
concentration of EGCG as compared with black tea, could be correlated
with the content of these proanthocyanidins. Moreover, their report
showed an inhibition of F. nucleatum growth, haemolytic activity, and
adhesion to oral cells. With the exception of two studies [40,53], all
tested extracts (Table 1) were shown to inhibit the growth of at least
one periodontal pathogen in a dose-dependent manner.
3.2. Effects on host inflammatory response
A total of 23 studies were included in the assessment of host in-
flammatory responses following polyphenol exposure and bacterial
toxin stimulation in vivo, ex vivo, and in vitro (Tables 2–4). Five studies
reported in vivo [56–60,76], seven studies reported ex vivo [61–67], and
11 studies reported in vitro [41,54,55,61,69–75] anti-inflammatory ef-
fects. Five of these 23 studies analysed green tea extract
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Fitoterapia 132 (2019) 30–39
[60,68,70,75,90], of which EGCG is the active compound, and four
studied cranberry proanthocyanidins (PACs) [71–74].
A reduced production of MMPs was reported by four studies
[54,64,74,75]. In one study, A. actinomycetemcomitans lipopoly-
saccharide(LPS)-induced matrix metalloproteinase(MMP)-3, −8,
and − 9 secretion from human gingival fibroblasts (HGFs) and macro-
phages was reduced following a 2-h pre-incubation with EGCG [75].
MMP-9 reduction was found by Granica et al., following incubation
with a Geum urbanum L., root extract [64]. Black tea theaflavins were
reported to inhibit interleukin secretion, especially IL-8, in oral epi-
thelial cells [71]. In addition to the anti-inflammatory effect, thea-
flavins have also been shown to induce an enhanced host defense
against periodontal pathogens via an increase in human-beta-defensin
(hBD)-1, −2, and − 4 production [71]. Gennaro et al., demonstrated
an increased level of osteoprotegerin in gingival tissues following
treatment with green tea extract [60]. Six studies reported a reduction
in IL-8 levels [55,63,64,66,73,74], and nine studies reported a reduc-
tion in interleukin-6 (IL-6) levels in periodontal tissues
[55,58,65,66,70,72–74,76]. However, Tipton et al., also showed that
incubation with cranberry proanthocyanidins (PACs) increased the se-
cretion of IL-6 from HGFs [74]. In the same study, PACs were shown to
inhibit nuclear factor kappa-light-chain-enhancer of activated B cells
(NF-κB) activation and MMP-3 secretion in HGFs. A reduction in
granulocyte colony-stimulating factor (G-CFS), growth-regulated pro-
tein alpha (GRO-α), IL-8, interferon gamma-induced protein 10 (IP-10),
monocyte chemoattractant protein 1 (MCP-1) [70], and IL-1ß stimu-
lated IL-6 production [72] was also reported; however, Bedran et al.,
found that cranberry PACs had no effect on IL-6 secretion [70].
Downregulation of COX-2 secretion was reported by two studies
[61,69], iNOS downregulation by three studies [56,64,69], and in-
hibition of receptor activator of NF-κB ligand(RANKL)-induced osteo-
clast differentiation by eight studies [54,56,60–62,65,67,74]. A total of
eight in vivo, in vitro, and ex vivo studies reported a reduction in TNF-α
K. Bunte et al. Fitoterapia 132 (2019) 30–39

Table 1
Antibacterial effects of plant-derived polyphenols in vitro.
Study group Plant and/or active compound/s Periodontal pathogen/s Results

Ben Lagha et al., 2018
Kariu et al., 2017
Heyman et al., 2017
De Oliveira Caleare et al.,
2017
Ben Lagha et al., 2017
Ben Lagha et al., 2017
Mallikarjun et al., 2016
Schmuch et al., 2015
Rodanant et al., 2015
Lohr et al., 2015
Ben Lagha et al., 2015
Villinski et al., 2014
Patra et al., 2014
Herrera et al., 2014
Shetty et al., 2013
Patel et al., 2013
Gonzalez et al., 2013
Araghizadeh et al., 2013
Highbush blueberry proanthocyanidins A. actinomycetemcomitans Reduction in bacterial growth
Prenyl flavonoids from Epimedium species P. gingivalis Inhibition of Arg- and Lys-gingipain and bacterial
growth
Polyphenols from Azadirachta indica leaves P. gingivalis Inhibition of P. gingivalis growth at 10 and 20 μM
F. nucleatum No effects on F. nucleatum
Flavan-3-ols and proanthocyanidins from Limonium brasiliense P. gingivalis Inhibition of Arg-gingipain and bacterial adhesion
No effects on bacterial vitality
EGCG from green tea and theaflavins from black tea F. nucleatum Inhibition of bacterial adhesion and F. nucleatum-
induced hemolysis
No effects on bacterial growth at antiadhesive
concentrations
Theaflavins from black tea P. gingivalis Inhibition of Arg- and Lys-gingipain and bacterial
adhesion
Enhanced tight junction integrity of gingival
keratinocytes
Ocimum sanctum A. actinomycetemcomitans Inhibition of A. actinomycetemcomitans growth similar
P. gingivalis to that of doxycycline
P. intermedia No significant effects on P. gingivalis or P. intermedia
Flavan-3-ols, oligomeric proanthocyanidins, and flavonoids P. gingivalis Inhibition of bacterial adhesion and P. gingivalis-
from Rumex acetosa (L.) induced hemagglutination
Inhibition of Arg-gingipain by gallolylated
proanthocyanidins
Coumarins and tetramethoxyflavone from Murraya paniculata P. gingivalis Inhibition of bacterial growth
(L.) Jack
Rhododendron ferrugineum (L.) A P. gingivalis Inhibition of bacterial adhesion and Arg- and Lys-
gingipain
Phenolic acids, flavonols, anthocyanins, flavan-3-ols, and F. nucleatum Inhibition of bacterial growth
procyanidins from Vaccinium angustifolium Ait.
Licoricidin and licorisoflavan from Glycyrrhiza uralensis P. gingivalis Inhibition of bacterial growth
Kaempferol from Phytolacca americana P. gingivalis 100% inhibition of bacterial growth at 1.8 mg/ml
Mammea americana extract P. gingivalis 96% inhibition of bacterial growth at 500 μg/ml
Allium sativum (L.) aqueous extract A. actinomycetemcomitans Inhibition of bacterial proteolytic enzymes and growth
P. gingivalis at 16.6 μl/ml
Dodonaea viscosa var. angustifolia P. gingivalis Reduction in Arg- and Lys-gingipain activity
Inhibition of total bacterial metabolic activity
Blackberry P. gingivalis Reduction in metabolic activity of both pathogens
F. nucleatum
Green tea (Camelia sinensis) A. actinomycetemcomitans Inhibition of growth of all three pathogens
P. gingivalis
P. intermedia

levels [41,54–56,58,60,65,76], whereas one study reported an increase the antibacterial and anti-inflammatory effects. These effects can also
[64]. In addition to the reduction in pro-inflammatory cytokines, an be influenced by the exposure time to the substance, which ranged from
increased secretion of IL-10, an anti-inflammatory cytokine, was re- a minimum of 20 min [49] to a maximum of 7 days [44] for the in vitro
ported by three in vivo studies [56,57,60]. studies, and from 11 [56,59] to 90 days [60] for the in vivo studies.
Clearly, an extended treatment duration and the use of higher con-
centrations can cause an overestimation of positive antibacterial and/or
4. Discussion
anti-inflammatory effects. Nonetheless, it has also been reported in the
literature that exposure to high concentrations and larger molecules can
The aim of the present study was to review the current knowledge
lead to an increased inflammatory reaction in host cells [91,92]. In
about the antibacterial effects of plant-derived polyphenols on period-
addition to these limitations, the reviewed studies only tested plank-
ontal pathogens and their effects on the modulation of the host im-
tonic bacteria. The reaction of sessile bacteria to treatment with the
mune/inflammatory response. The pooled data from these reports in-
above-mentioned polyphenols was not analysed in any of these studies;
dicated beneficial antibacterial, antiadhesive, and anti-inflammatory
however, this needs to be considered for a proper evaluation. In this
characteristics. Moreover, a positive correlation between polyphenolic
regard, the influence of polyphenols on multispecies biofilms needs to
substance exposure and inhibition of bacterial growth, adhesion, and
be studied, since the virulence and susceptibility of bacteria, as well as
proteolytic activity, as well as a reduced host inflammatory response
the effectiveness of polyphenols, may vary immensely in the natural
and enhanced host defense mechanism could be derived from these
ecosystem, i.e., the biofilm. Moreover, the studies included in the pre-
studies.
sent review are characterised by specific periodontal pathogens and cell
However, generalised conclusions for routine treatment cannot be
culture systems, which contributes to heterogenous results, even when
drawn from this review. Methodology and substance heterogeneity
the same substance is being tested. Lastly, selected studies and language
among these studies do not allow the generation of a specific treatment
bias can create a restriction, since only reports in the English language
protocol or pharmaceutical approach. Despite the fact that the methods
published within the last five years were reviewed.
were well-explained in most studies, the extraction processes differed
Based on the data presented in the present review, flavonoids,
among studies. In this regard, a variety of solvents were used for ex-
especially flavan-3-ols and proanthocyanidins, appear to be the most
traction; some studies used ethanol [40–42,45,46,48,50,52–54],
promising candidates to be used in prevention or management of per-
whereas others used aqueous solvent [55], acetone [39,43], or me-
iodontal diseases. However, this does not mean that the consumption of
thanol [38,44,47,49]. Furthermore, the type of plants and extracts and
flavonoid-enriched foods reduces the risk of progression or prevents the
the concentrations applied were different, which can greatly influence

34
 Table 2
In vivo inflammatory modulation effects of plant-derived polyphenols.
Study group Plant and/or active compound Methods Cells/tissues Results
K. Bunte et al.

Teixeira et al., Stemodia maritima L. extract 5 mg/kg body weight (bw) 1 h prior to placement of ligature and Maxillary alveolar bone of female Inhibition of alveolar bone loss
2017 once a day for the following 11 days until removal of the ligature Wister rats Decrease in TNF-α and cytokine-induced neutrophil chemoattractant
(CINC)-1 and increase in IL-10 levels in gingival tissues
Decrease in receptor activator of NF-κB (RANK), inducible nitric oxide
synthase (iNOS), IL-1β, and TNF-α mRNA expression
Ozden et al., 2017 Oligomeric proanthocyanidins 200 mg/kg bw by oral gavage, 4 groups: Mandibular molar region bone of Lower inflammatory cell number, higher connective tissue attachment
from grape seed A: Control group, B: two weeks prior to and six weeks after LPS male Sprague-Dawley rats level, and higher IL-10 and transforming growth factor beta (TGF-β)
ligature placement C: from ligation to two weeks after its removal, levels were measured in all groups, with group B having the highest IL-
D: two weeks from ligature removal 10 levels
Kostic et al., 2017 Rosmarinic acid from Salvia 200 mg/kg bw systemic administration by oral gavage twice a day Interdental papilla between the first Decrease in IL-1β, IL-6, and TNF-α levels
sclarea L. and second maxillary molars of Less inflammatory cells and more fibroblasts in the gingival tissue
Wistar rats
Hatipoglu et al., Crataeus orientalis M. Bieber 100 mg/kg bw systemic administration by oral gavage from the day Right mandibular first molars of rats Inhibition of periodontal inflammation and alveolar bone loss via
2015 of ligature placement throughout the following 11 days to ligature regulation of oxidative stress, and reduction in inflammatory cells and
removal osteoclasts in periodontal tissues
Gennaro et al., Green tea 7 mg/ml green tea ad libitum for 15, 30. 60 or 90 days after Hemi-maxilla of type I diabetic male Increase in osteoprotegerin (OPG) at 15, 60 and 90 days and increase in
2015 induction of diabetes at day 0 (n = 5 in each group) Wistar rats IL-10 at all times, increase in runt related transcription factor(RUNX)-2
and reduction in TNF-α and RANKL at 30, 60 and 90 days

35
Table 3
Ex vivo inflammatory modulation effects of plant-derived polyphenols.
Study group Plant and/or active compound Methods Cells/tissues Results

Lee et al., 2017 Terminalia chebula ethanolic extract (EETC) Medium containing dental plaque bacteria LPS (1 μg/ml) and/ Mouse-derived bone marrow Reduction in RANKL mRNA expression
or EETC (10 μg/ml) for 7 days macrophages (BMMs)
Kim et al., 2017 Sophorae Flos extract (SFE) BMMs were cultured with M-CSF (50 ng/ml) and RANKL Mouse-derived bone marrow Inhibition of RANKL-induced osteoclast differentiation via
(100 ng/ml) for 4 days to generate osteoclasts in the presence macrophages (BMMs) suppression of the NF-κB/ nuclear factor of activated T-cells,
or absence of SFE cytoplasmic 1(NFATc1) pathway
Walker et al., Magnolia officinalis (L.) extract Extract containing gum chewed by volunteers for 10 min, and Human oral epithelial cells from Reduction in IL-8 expression and oxidative stress
2016 collected cells were subsequently stimulated with LPS ex vivo 40 healthy adults
Granica et al., Pedunculagin, stachyurin, casuarynin, and gemin A, In the absence or presence of extracts/compounds at a final Human neutrophils derived from Gemin A inhibited NOS and MMP-9, IL-8, and IL-1β release,
2016 and ellagic acid derivatives from Geum urbanum L. concentration of 10 and 50 μg/ml/10 and 50 μM added 1 h blood of healthy adults but increased TNF-α secretion
root prior to stimulation with LPS (100 ng/ml)
Chin et al., 2016 2,3,5,4’-Tetrahydroxystilbene-2-O-beta-glucoside Pretreatment with 25 μM THSG followed by treatment with Human gingival fibroblasts from Suppression of NF-κB, TNF-α, IL-1β, and Il-6 release
(THSG) from Polygoni Multiflori 1 μg/ml P. gingivalis LPS for 3 h 40 healthy adults
Bin et al., 2015 Osmanthus fragrans ethanolic extract Cells were treated with increasing concentrations of extract Human periodontal ligament Inhibition of IL-6 at > 125 μg/ml and IL-8 > 62.5 μg/ml
(31.25, 62.5, 125, and 250 μg/ml) prior to P. gingivalis LPS cells obtained from 20 healthy
stimulation at a final concentration of 1 mg/ml adults
Kong et al., 2014 Angelica sinensis extract (ASE) BMMs were cultured in the presence of M-CSF (20 ng/ml) and Mouse-derived bone marrow Inhibition of RANKL-mediated osteoclast differentiation, and
RANKL (40 ng/ml) for 4 days in the presence or absence of ASE macrophages (BMMs) proto-oncogene c-Fos, protein c-Jun, and NFATc1 expression
Fitoterapia 132 (2019) 30–39
 K. Bunte et al.

Table 4
Inflammatory modulation effects of plant-derived polyphenols in vitro.
Study group Plant and/or active compound Methods Cells/tissues Results

Ben Lagha et al., Highbush blueberry proanthocyanidins Cells were pretreated for 2 h with PACs (125–31.25 μg/ml) prior to Macrophage-like cells differentiated from U937 human Inhibition of NF-κB activation
2018 (PACs) stimulation with A. actinomycetemcomitans, followed by incubation monocytes Inhibition of IL-1β, IL-6, IL8, TNF-α, MMP-3,
for 24 h in the presence or absence of PACs and with or without and MMP-9 secretion
bacterial stimulation
Morin and Grenier EGCG from green tea and green tea 2-h stimulation with LPS followed by incubation with green tea 1:10 macrophage-like cells differentiated from U937 Reduction in MMP-3, −8, and − 9 secretion
2017 extract extract or EGCG human monocytes and primary human gingival by both green tea extract and EGCG at non-
fibroblast cell line HGF-1 cytotoxic concentrations
Lee et al., 2017 Terminalia chebula ethanolic extract Cells were exposed to serum-free medium containing LPS (1 μg/ RAW264.7 murine macrophage cells, immortalized Inhibition of prostaglandin E2 (PGE2), COX-
(EETC) ml) and/or EETC (10 mg/ml) for 24 h human oral keratinocytes (IHOK), immortalized human 2, and RANKL expression and osteoclast
gingival fibroblasts (IGF), and YD38 human gingival formation
epithelial cells
Cespedes et al., Quercetin, gallic acid, luteolin, and Cells were incubated in media with or without LPS (1.0 mg/ml), RAW264.7 murine macrophage cells Downregulation of iNOS and COX-2
2017 myricetin from Aristotelia chilensis and the samples (plant extracts, fractions, or pure com- pounds)
(Elaeocarpaceae), Maqui were subsequently applied and incubated for 12 h
Ben Lagha et al., Theaflavins from black tea Theaflavin preparation was applied at 31.25, 62.5, 125, and Macrophage-like cells differentiated from U937 human Reduction in IL-1β, TNF-α, IL-6, IL-8, MMP-
2017 250 mg/ml, and cells were subsequently stimulated with P. monocytes 3, -8, and -9

36
gingivalis and incubated for 4 h Inhibition of the NF-κB signaling pathway
Lombardo Bedran EGCG from green tea and A type- AC-PACs at 25 and 50 μg/ml, EGCG at 1 and 5 μg/ml Immortalized human gingival epithelial cell line OBA-9 Reduced secretion of GRO-α, G-CSF, IL-6, IL-
et al., 2015 cranberry proanthocyanidins (AC-PACs) and primary human gingival fibroblast cell line HGF-1 8, IP-10, and MCP-1 with both EGCG and
AC-PACs
Lombardo Bedran Theaflavin and theaflavin-3,3′-digallate 2-h pretreatment with black tea extract (100 and 200 μg/ml), Immortalized human oral epithelial cell line OBA-9 Reduction in IL-8 secretion with all tested
et al., 2015 from black tea and black tea extract theaflavin, theaflavin-3,3′-digallate, or EGCG (10 and 50 μg/ml) compounds
prior to A. actinomycetemcomitans LPS stimulation Increased hBD-1, hBD-2, and hBD-4
secretion following treatment with black tea
extract and theaflavin-3,3′-digallate
Lohr et al., 2015 Isoquercitrin and tannins from KB cells were incubated for 24 h prior to exposure to P. gingivalis KB cells derived from human oral epidermoid Inhibition of IL-1ß, IL-6, IL-8, and TNF-α
Rhododendron ferrugineum L. aqueous carcinoma expression
extract
Tipton et al., 2014 Proanthocyanidins (PACs) from cranberry Cells were incubated with IL-1β in the presence or absence of Smulow-Glickman (S-G) human gingival epithelial cells Inhibition of NF-κB activation, and activator
cranberry PACs for 6 days protein 1(AP-1)- and IL-1β-stimulated IL-6
expression
Tipton et al., 2013 Proanthocyanidins (PACs) from cranberry Cells were incubated with IL-17 in the presence or absence of Normal human gingival fibroblasts and Smulow- Reduction in IL-17-stimulated IL-6 and IL-8
cranberry PACs for 6 days Glickman (S-G) human gingival epithelial cells production
Tipton et al., 2013 Proanthocyanidins (PACs) from cranberry Aggressive periodontitis fibroblasts were incubated with PACs, Aggressive periodontitis and normal human gingival Increased IL-6 production in aggressive
with or without F. nucleatum or P. gingivalis LPS, for up to 6 days fibroblasts periodontitis HGFs
Reduction of IL-6 and MMP-3 production,
and inhibition of NF-κB in normal HGFs
Fitoterapia 132 (2019) 30–39
K. Bunte et al.
onset of periodontal disease. The hydrophilic compounds (e.g. flavonoid
glycosides, proanthocyanidins, and anthocyanidins) are hardly ab-
sorbed following oral ingestion, unless they are transported by specific
carrier systems [93,94]. Most polyphenols are relatively hydrophilic
compounds due to the presence of polar hydroxyl groups in the aro-
matic parts of the molecules. Modification of these compounds (e.g.
methylation of hydroxyl groups or prenylation) results in an increase in
lipophilicity, which leads to an increased cell membrane permeability
and a higher absorption rate. When polyphenols become bioavailable in
the respective pharmacokinetic compartment, a cascade of reactions is
initiated that results in a decreased oxidation rate of lipids or proteins
within cells [95]; this process is mainly mediated by hydroxylation of
the B-ring [15]. However, a high hydroxylation grade leads to higher
polarity of the molecules, and thus a reduced bioavailability in inflamed
tissues. For this reason, in vitro investigations of polyphenols do not
necessarily reflect the pharmacodynamic reality; which is why struc-
tural differences of polyphenols play a crucial role in their biological
activities [16]. On the other hand, when used locally, e.g., as a mouth
rinse or gel, a favourable immunomodulatory and antibacterial effect
can be achieved irrespective of tissue concentrations. Dabholkar et al.,
compared 0.12% chlorhexidine digluconate mouth rinse, a commercial
mouth rinse containing extracts from Terminalia bellirica, Piper betle and
Salvadora persica and another commercial mouth rinse containing Pu-
nica granatum (pomegranate) and Camellia sinensis leaf extracts for their
antimicrobial effect against oral biofilm-forming bacteria in vitro. All
three mouth rinses showed an antibacterial effect in varying con-
centrations; however, there were statistically significant differences
between chlorhexidine digluconate and both herbal mouth rinses [12].
These findings indicate that chlorhexidine remains to be superior to the
herbal mouth rinses, and thus may be considered the gold standard for
short-term use; however, a polyphenol-containing mouth rinse may be
useful for long-term control of the microbial and inflammatory situa-
tion avoiding the adverse effects of chlorhexidine digluconate.
Local delivery devices containing high concentrations of poly-
phenols, especially flavonoids may be another way of implementing
these substances in the management or prevention of periodontitis. In
this regard, a 4-week controlled, randomised, split-mouth, single-eva-
luator, masked study tested a green tea catechin gel for local applica-
tion in patients with chronic periodontitis, reporting a highly statisti-
cally significant reduction (p < .001) in pocket-probing depth and
inflammation as compared with baseline [96]. When incorporated into
a controlled delivery device, one could further envision a clinically and
cost-effective local therapy. Moreover, preventive measures and addi-
tional supportive therapy are beneficial and can be more efficient in
terms of cost savings than mechanical debridement alone [97]. It is
therefore necessary to identify substances that are not yet deployed and
could serve the adult dentate population to facilitate substantial ag-
gregate improvements in periodontal health at an acceptable cost.
5. Conclusions
Despite the variety of substances and concentrations applied and the
heterogeneous methodology used in the reviewed studies, the anti-
bacterial and anti-inflammatory effects of plant-derived polyphenols
are readily identifiable. The positive findings regarding the inhibition of
periodontal pathogen activities and the reduction in the host in-
flammatory and immune responses following the use of polyphenols
warrant further studies aiming to identify the substances that can pre-
vent tissue breakdown or suppress periodontal pathogens and reverse
the intraoral dysbiosis.
Declarations of interest
None.
37
Fitoterapia 132 (2019) 30–39
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Acknowledgments
The first author would like to acknowledge the contributions and
comments by Dr. Ricarda Hess and Dr. Susanne Bierbaum from the
University of Dresden, Germany.
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