Archives of Oral Biology 105 (2019) 72–80

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Archives of Oral Biology

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

Host modulation therapy using anti-inflammatory and antioxidant agents in T

periodontitis: A review to a clinical translation
⁎
Benso Sulijayaa,b,d, Naoki Takahashib,c, Kazuhisa Yamazakia,
a
Research Unit for Oral-Systemic Connection, Division of Oral Science for Health Promotion, Niigata University Graduate School of Medical and Dental Sciences, Niigata,
Japan
b
Division of Periodontology, Department of Oral Biological Science, Niigata University Faculty of Dentistry, Niigata, Japan
c
Research Center for Advanced Oral Science, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
d
Department of Periodontology, Faculty of Dentistry, Universitas Indonesia, Jakarta, Indonesia

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

Keywords: Objective: To highlight the shifting paradigm of periodontitis, describe mechanism of periodontal bone de-
Host modulation struction, and propose an updated host modulation therapy (HMT) strategy. To add further clinical relevance,
Periodontitis related studies investigating the efficacy of several HMT agents in periodontitis will be discussed.
Anti-inflammation Design: Literature searches were conducted from articles published in PubMed using keywords “periodontal
Antioxidant
disease AND periodontitis AND host modulation therapy AND anti-inflammatory AND antioxidant”, and then the
Therapy
findings were comprehensively summarized and elaborated.
Result: Accumulating evidence indicates that periodontitis is no longer defined solely as a pathogen-induced
disease; rather, it is now recognized as a consequence of uncontrolled immune response and oxidative stress
leading to periodontal tissue damage. Although periodontopathic bacteria initiate the disease, inflammation and
oxidative stress were reported to be the main causes for the severity of tissue destruction. Thus, since the concept
of periodontitis has shifted, our approach to its management needs to be adjusted to accommodate the latest
paradigm. Nowadays, the modulation of inflammation and oxidative stress is considered a target of HMT. HMT
agents, such as probiotics, anti-inflammatory drugs, anti-chemokines, lipid mediators, and bio-active fatty acids,
have been extensively investigated for their remarkable functions in modulating the immune response and
providing antioxidant effects.
Conclusion: Findings from in vitro, in vivo, and human studies frequently demonstrate positive association by the
administration of HMT in periodontitis. HMT strategy targeted on anti-inflammatory and antioxidant in peri-
odontitis might serve as an excellent therapeutic approach to reach the level of clinical benefit.

1. Introduction
The concept that dental plaque is necessary but not sufficient to
cause periodontitis progression has led to a shift in strategy for peri-
odontal therapy from anti-infective approaches to host modulation
(Bartold & Van Dyke, 2017; Van Dyke, 2008a). Besides the bacterial
challenge, several studies have revealed that uncontrolled production
of pro-inflammatory cytokines lead to major pathogenicity and tissue
destruction (Bartold & Van Dyke, 2013, 2017). The number of bacteria
does not always correlate with the severity of this destruction in clinical
studies; however, the contribution from the initiating bacteria, in-
cluding their putative factors that trigger the host’s immune response, is
indisputable (Cekici, Kantarci, Hasturk, & Van Dyke, 2014; Marsh,
2004; Sanz et al., 2017). Inflammation might also be caused by the
alteration in bacterial composition, dysbiosis, and oxidative stress
conditions (Herrero et al., 2018; Shi et al., 2015; Wang et al., 2014).
During pathogenesis, pro-inflammatory cytokines and reactive
oxygen species (ROS) may act as double-edged swords; they are re-
quired not only to keep bacteria outside the tissues but also the ex-
aggerated response of these molecules can damage the tissue (Li et al.,
2004; Schieber & Chandel, 2014; Tomofuji et al., 2009). Thus, in-
vestigations into the significance of clinical results and unwanted side
effects of using host modulation therapy (HMT) agents in periodontitis
management have been reported (Elkhouli, 2011; Preshaw et al., 2004;
Preshaw, 2018; Reddy, Geurs, & Gunsolley, 2003). In this review, we
highlighted the mechanism of periodontal bone destruction by

⁎
Corresponding author at: Research Unit for Oral-Systemic Connection, Division of Oral Science for Health Promotion, Niigata University Graduate School of
Medical and Dental Sciences 5274 Gakkocho 2-ban-cho, Chuo-ku, Niigata 951-8514, Japan.
E-mail address: kaz@dent.niigata-u.ac.jp (K. Yamazaki).

https://doi.org/10.1016/j.archoralbio.2019.07.002
Received 13 May 2019; Received in revised form 26 June 2019; Accepted 2 July 2019
0003-9969/ © 2019 Elsevier Ltd. All rights reserved.
B. Sulijaya, et al.
inflammation and ROS, and the management strategies attempting to
modulate the immune response. Moreover, based on the relevant
findings and our investigative results, we outline the current concept of
HMT. Finally, the clinical objective of this review is to guide clinicians
and researchers towards better insight into the plausible mechanisms of
inflammatory damage, a clear understanding of which will allow for
targeted HMT and will improve periodontal therapy outcomes.
2. Material and methods
Literature searches were conducted by 2 reviewers (BS and NT),
independently. Articles published in PubMed within the past 10 years
with full text written in English available were included. Keywords used
were “periodontal disease AND periodontitis AND host modulation
therapy AND anti-inflammatory AND antioxidant”. Paper selection and
data extraction were performed by aforementioned reviewers. Also,
additional articles were manually searched and included from citations
of the selected papers. We focused on the articles describing: 1) pa-
thogenesis of periodontitis and the conceptual shifting, 2) inflammation
and oxidative stress in periodontitis, 3) HMT development and its
agents, and 4) plausible HMT approach mechanism. Based on article
abstracts, irrelevant topics, and non-English written articles were ex-
cluded. Further evidence and findings reported were discussed in the
form of narrative review.
3. Results
3.1. The current concept of the pathogenesis of periodontitis
Bacteria play an undeniable role in the etiology of periodontal
disease, including gingivitis and periodontitis (Socransky & Haffajee,
1992). In fact, almost all bacterial species harbor pathogenic properties
when they are allowed to expand and when they take over the normal
microbiota. In 1965, the nonspecific plaque hypothesis was described
as the amount of the entire dental-plaque microbiota correlating with
disease status (Löe, Theilade, & Jensen, 1965). This hypothesis might be
acceptable in gingivitis; however, in periodontitis, further interaction
between bacterial by-products and the immune system are somehow
absent from this hypothesis. Another hypothesis in the late 1970s de-
scribed how the presence or increase of specific pathogenic bacteria in
sub-gingiva and their toxic products were associated with periodontitis
(Theilade, 1986). Moreover, the microbial shift hypothesis, known as
dysbiosis, reinforced the previous hypothesis, which confirms that the
change from predominantly Gram-positive aerobic bacteria to groups of
Gram-negative anaerobes (pathogenic flora) is consistent with disease
(Berezow & Darveau, 2011). In the 1990s, these hypotheses were ad-
justed to become the ecological plaque hypothesis, in which the en-
vironmental changes in the gingival sulcus mediate the growth of
Gram-negative and proteolytic species of bacteria, resulting in further
inflammation and tissue destruction (Marsh, 2004). In fact, pathogen-
esis is initiated by the oral microbial biofilm; the inflammation reacts to
the biofilm and drives the destruction of the periodontium (Sima &
Glogauer, 2014; Van Dyke, 2008b) as well as a change in microbes
(Marsh, 2004). Thus, it is assumed that periodontitis is more likely a
non-resolving inflammation that is ineffective in eliminating the in-
itiating pathogens and maintains constant inflammatory conditions
(Gaffen & Hajishengallis, 2008).
In addition to this hypothesis, an in vivo study has shown that
Porphyromonas gingivalis (P. gingivalis), one of the red complex bacteria,
failed to induce periodontal tissue breakdown and alveolar bone de-
struction in germ-free mice (Hajishengallis et al., 2011). However, in
specific pathogen-free mice, the inoculation of P. gingivalis triggered
compositional changes to oral bacteria, thus resulting in alveolar bone
loss (Hajishengallis et al., 2011). Also, surprising evidence revealed that
in advanced periodontitis lesions, the invasion of P. gingivalis reached
only the epithelial cells and did not extend to the underlying connective
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Archives of Oral Biology 105 (2019) 72–80
tissue (Guyodo et al., 2012). Considering this finding, it might be as-
sumed that bacteria and their products are simply the initiators; they do
not even have a chance to reach the underlying connective tissue where
the destruction occurs.
Related to the bacteria, dental plaque contributes only 20% of the
risk of developing periodontitis which leads to the assumption that
‘periodontal pathogens’ appear as a result of the disease rather than a
cause (Bartold & Van Dyke, 2017; Marsh, 2003). In brief, for period-
ontitis, there is convincing longitudinal data confirming that bacteria
are necessary but not sufficient for disease to develop; the uncontrolled
inflammation and immune response are responsible for bone resorption
(Kornman et al., 1991; Socransky & Haffajee, 1992; Van Dyke, 2008a,
2008b).
Another current hypothesis has been introduced with great interest,
known as the polymicrobial synergy and dysbiosis theory. This model
stresses that the host response is initially triggered by bacteria with
pathogenic potential; then, accessory bacteria assist in the colonization
and metabolic activities until later when they are outgrown by the over-
activated pathobionts leading to destructive inflammation (Darveau,
Hajishengallis, & Curtis, 2012; Hajishengallis & Lamont, 2012;
Hajishengallis, Darveau, & Curtis, 2012; Hajishengallis, 2015; Lamont
& Hajishengallis, 2015). Most likely there is no specific series of bac-
terial species that exclusively act as such; there may be individual dif-
ferences in biofilm composition and individual variation on how the
host responses to these bacterial communities. Thus, period-
ontopathogenic bacteria encompass a much wider range of bacterial
species than hitherto assumed. Moreover, host susceptibility is influ-
enced by various factors, such as genetic, epigenetic, and life style
factors (smoking, stress, and diet), as well as the presence of systemic
disease (e.g. diabetes and aging) (Hajishengallis & Lamont, 2012;
Lamont & Hajishengallis, 2015; Rinuchitra, Govindarajan, Thangavelu,
& Jayaraman, 2012). In summary, periodontitis is no longer defined as
a solely bacteria-caused disease, rather it is now seen as an uncontrolled
immune response-related disease caused by dysbiosis; therefore, its
management should include the modulation of host immunity, which
can lead to the restoration of tissue homeostasis.
3.2. Inflammation and oxidative stress in periodontitis
Biological processes including inflammation and oxidative stress at
the level of cellular state may further contribute to the clinical re-
levance of the onset and development of periodontitis (Bullon, 2014).
Inflammation and oxidative stress conditions occurring in periodontitis
and their role in the mechanism of alveolar bone destruction has been
explored by many authors (D’Aiuto et al., 2010; Liu, Lerner, & Teng,
2010; Schieber & Chandel, 2014; Tomofuji et al., 2009). Periodontal
tissue becomes inflamed after the bacterial components and metabolic
products of bacteria trigger the junctional epithelium cells to produce
cytokines, thus stimulating neurons to produce neuropeptides that
cause vasodilatation of peripheral blood vessels (Gaffen &
Hajishengallis, 2008). Following this event, an increased number of
polymorphonuclear neutrophils (PMNs), macrophages, lymphocytes,
plasma cells, and mast cells are activated and accumulated in the
connective tissue (Cekici et al., 2014). In the host response to these
bacterial components and metabolites, the innate immune response is
dominated by the phagocytic activities of macrophages and neu-
trophils, whereas plasma cells, T lymphocytes, and B lymphocytes
(IgG1 and IgG3 subclasses) are dominant in the transition to the
adaptive immune stage (Janeway & Medzhitov, 2002; Medzhitov &
Janeway, 1997). Extracted T-cells from periodontitis lesions exhibit a
reduced response to stimuli; however, this can be restored with peri-
odontal therapy (Petit et al., 2001). Later, activation of the tumor ne-
crosis factor (TNF) family and their receptors activates B-cell produc-
tion, which marks the maturation of the antibody response (Cekici
et al., 2014). Hence, both the innate and adaptive immune systems are
coordinately activated in the inflammatory response to
B. Sulijaya, et al.
periodontopathic bacteria.
In immune cells within the oral epithelium, bacterial lipopoly-
saccharide (LPS) binds to toll-like receptors 2 and 4 (TLR2 and TLR4)
(Hatakeyama et al., 2003; Pihlstrom, Michalowicz, & Johnson, 2005)
and activates the myeloid differentiation primary response protein
MYD88 as well as the toll/interleukin-1 (IL-1) receptor adaptor protein,
resulting in the production of TNF-α, IL-6 and IL-12 (Cook, Pisetsky, &
Schwartz, 2004; Kaisho & Akira, 2002; Watters, Kenny, & O’Neill,
2007). In addition, the nuclear factor κB (NF-κB) complex has been
investigated as a key transcription factor that regulates immune re-
sponses to bacteria and viruses, inflammation, developmental aspects,
and cell proliferation (Smale, 2011) through the TLR pathway
(Baldwin, 1996; Hanada & Yoshimura, 2002). In brief, the recognition
of bacteria by innate immune cells results in the production of in-
flammatory cytokines including TNF-α, IL-1β, and IL-6 (Garlet, 2010).
Thus, TNF-α is also associated with bone resorption by promoting the
production of RANKL and secretion of matrix metalloproteinases de-
grading periodontal tissue (Garlet, Martins, Fonseca, Ferreira, & Silva,
2004; Graves & Cochran, 2003; Graves, Fine, Teng, Van Dyke, &
Hajishengallis, 2008; Hadler-Olsen, Fadnes, Sylte, Uhlin-Hansen, &
Winberg, 2011). TNF-α induces immune cell migration by increasing
the adhesion of neutrophils and stimulating the production of cytokines
IL-6 (Garlet et al., 2007; Graves et al., 2008; Steeve, Marc, Sandrine,
Dominique, & Yannick, 2004) and IL-1β (Kindle, Rothe, Kriss, Osdoby,
& Collin-Osdoby, 2006; Mohammed, Ferzandi, & Hamilton, 2010;
Rajput & Ware, 2015). The mechanism of periodontal tissue destruction
mediated by inflammation through the TLR-mediated NF-κB pathway is
thus well established.
Besides, inflammasome, a multiprotein complex located in the cy-
toplasm of the cell, is responsible for the maturation of pro-in-
flammatory cytokines such as IL-1β and IL-18, also for the activation of
inflammatory cell death called pyroptosis (Olsen & Yilmaz, 2016).
Likewise, IL-1β mediated by inflammasome activity has been reported
to associate with the initiation, onset, and progression of periodontitis
(Aoki‐Nonaka et al., 2019; Lukens et al., 2014; Netea, van de Veerdonk,
van der Meer, Dinarello, & Joosten, 2014; Shibata, 2018). Pathogen-
associated molecular patterns (PAMPs) are recognized by TLRs and
stimulate inflammasome-driven inflammation throughout the upregu-
lation of nucleotide-binding domain-like receptor protein 3 (NLRP3) in
an NF-κB-dependent manner, thereby cleaving pro-IL-1β into an active
form of IL-1β with the help of caspase-1 (Olsen & Yilmaz, 2016;
Yamaguchi, Kurita-Ochiai, Kobayashi, Suzuki, & Ando, 2017). Clinical
study has been reported the higher levels of inflammasome components
(e.g. NLRP3 and absent in melanoma 2 (AIM2)) in the gingival tissues
from chronic periodontitis patients than healthy controls (Park et al.,
2014). Further, an in vitro study using THP-1 cells challenged with live
P. gingivalis demonstrated higher secretion of IL-1β followed with the
activation of some inflammasomes (NRLP3 and AIM2) via the re-
cognition of TLR2/4 and AIM2-cytosolic bacterial double-stranded DNA
(dsDNA) (Park et al., 2014). These findings suggest that period-
ontopathic bacteria can modify innate immunity by affecting in-
flammasome activity; however, this in vitro study where cells are
brought in contact with whole/live bacteria might be not realistic based
on the evidence found that bacteria were not found in the deeper tis-
sues.
Oxidative stress is performed by the cells not only to produce energy
needed for physiological activity but also to destroy bacteria and their
products; this is known as defense mechanism by the cells (Bullon,
2014). The excessive endogenous production of reactive oxygen species
(ROS) is likely to contribute to periodontal tissue breakdown, as their
levels are increased in lesions (Aboodi, Goldberg, & Glogauer, 2011;
Battino, Bullon, Wilson, & Newman, 1999). In brief, when exposed to
the pathogen and its components, PMNs activate oxidative mechanisms
that kill phagocytosed bacteria and in doing so, produce ROS including
superoxide radicals, hydrogen peroxide, hydroxyl radicals, and hypo-
chlorous acid. Beside killing pathogenic bacteria, those ROS molecules
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Archives of Oral Biology 105 (2019) 72–80
also cause tissue damage via oxidation processes (Chiu, Saigh,
McCulloch, & Glogauer, 2017). An in vitro study using human gingival
fibroblast challenged with P. gingivalis LPS demonstrated higher level of
ROS followed with mitochondrial dysfunction by a reduction in mi-
tochondrial protein expression, mass, and membrane potential (Bullon
et al., 2011). On the other word, the excessive ROS production affects to
mitochondrial dysfunction thereby promoting cell apoptosis and com-
plex signaling pathways (Dirkx, Schwenk, Glatz, Luiken, & van Eys,
2011). These findings suggest that mitochondria status is also a critical
point in the initiation of inflammation and oxidative stress at the level
of cell.
The activation of matrix metalloproteinases, involved in tissue,
plasma, and bacterial proteinase activity, also reportedly increased by
oxidative stress (Murphy & Reiner, 2002; Vandooren, Van Den Steen, &
Opdenakker, 2013). Clinical investigations have found that patients
with hyperactive ROS responses are more susceptible to periodontitis
than those with normal responses (Aboodi et al., 2011; Johnstone, Koh,
Goldberg, & Glogauer, 2007). Moreover, the inhibition of antioxidant
production, by down-regulation of the nuclear factor erythroid 2-re-
lated factor 2 (NRF2) pathway in oral polymorphonuclear neutrophils,
is associated with severe periodontitis (Sima et al., 2016). Hence, the
NRF2 and NF-κB pathways are implicated to be linked in the patho-
genesis of bone destruction (Wardyn, Ponsford, & Sanderson, 2015);
NF-κB stimulates an increase in mitochondrial activity and the ex-
pression of NADPH oxidase, which are both main sources of en-
dogenous free radical ROS (Mauro et al., 2011). In addition, knocked-
down NRF2 in macrophages reduces TNF-α, inducible nitric oxide
synthase (iNOS), cyclooxygenase 2 (COX2), and IL-1β production in
response to LPS (Lin et al., 2008). Therefore, apart from the in-
flammation, periodontitis is partly triggered by over-production of ROS
through NRF2, which leads to oxidative stress and vice versa. Regulation
of ROS is important to maintain homeostasis.
In the sense of gaining the homeostasis, a supporting data have been
interestingly showed the involvement of autophagy in the pathogenesis
of periodontitis. Peripheral blood mononuclear cells from periodontitis
patients demonstrated higher expression of autophagy gene that posi-
tively correlated with high levels of mitochondrial ROS production
(Bullon et al., 2012). Additionally, in human gingival fibroblast cells
treated with P. gingivalis LPS, the protein level and gene expression of
autophagy-related protein 12 (ATG12) was increased (Bullon et al.,
2012). A reduction of mitochondrial ROS reduces autophagy activity,
while inhibition of autophagy increases cell apoptosis (Bullon, 2014).
Altogether, this might suggest the protective role of autophagy in per-
iodontitis (e.g. eliminate metabolic debris).
These processes can lead to changes in the local environment. In the
dysbiosis theory, the influence of individual species in a polymicrobial
community could alter host-microbial interactions leading to destruc-
tive inflammation (Hajishengallis et al., 2012). In brief, non-pathogenic
bacteria known as accessory pathogens could further exacerbate in-
flammation by producing nutritional products from the end products of
tissue destruction (e.g. degraded collagen peptides and heme-containing
compounds), that help the other bacteria to flourish (Hajishengallis,
2014). Moving forward, it is worth noting that each factor contributes
to this complex mechanism wherein synergistic effects from various
factors may occur and lead to greater destruction.
3.3. Host modulation therapy
As uncontrolled products of the immune system and oxidative stress
both drive the breakdown of periodontal tissue, we propose a mod-
ification to HMT therapeutic strategies which was mainly addressed to
modulate the level of inflammation (Bartold & Dyke, 2017). We have
observed that three major components are involved in the pathogenesis
of periodontitis, including periodontal pathogen bacteria, immune re-
sponse, and periodontal tissue destruction induced by ROS.
Consequently, the possible way to modulate bacteria is by anti-bacterial
 B. Sulijaya, et al.

Table 1
Studies regarding the association between periodontitis and the use of HMT agents.
Category Author (year) Study design Treatment Main outcome

Probiotics Morales et al. (2018) (Morales et al., 2018) RCT Lactobacillus rhamnosus SP1 Lactobacillus rhamnosus SP1 administration showed similar clinical and microbiological
improvements compared to baseline
Iwasaki et al. (2016) (Iwasaki et al., 2016) RCT Heat-killed Lactobacillus plantarum L-137 Significant greater pocket depth reduction was found in test group compared to control.
(HK L-137) Daily consumption of HK L-137 decreased periodontal pocket depth in patients undergoing
SPT
Laleman et al. (2015) (Laleman et al., 2015) RCT Streptococcus oralis KJ3, Streptococcus No differences were detected of the adjunctive use of streptococci containing tablet after
uberis KJ2, Streptococcus rattus JH145 SRP
Teughels, Durukan, Ozcelik, Pauwels, Quirynen, Cenk Haytac RCT Lactobacillus reuteri Oral administration of Lactobacillus reuteri significantly enhanced the pocket depth
(2013) (Teughels, Durukan, Ozcelik, Pauwels, Quirynen, Haytac reduction, attachment gain and the reduction of P. gingivalis
et al., 2013)
Vicario et al. (2013) (Vicario et al., 2013) RCT Lactobacillus reuteri Prodentis Lactobacillus reuteri Prodentis improved the short-term clinical outcomes (plaque index,
bleeding on probing and probing depth) in patients with mild-moderate chronic
periodontitis
Mayanagi et al. (2009) (Mayanagi et al., 2009) RCT Lactobacillus salivarius WB21 Oral administration of Lactobacillus salivarius WB21 reduced the amount of
periodontopathic bacteria
Anti-chemokine Glowacki et al. (2013) (Glowacki et al., 2013) In vivo Anti-CCL22 Application anti-CCL22 in ligature-induced periodontitis in beagle dogs reduced the
inflammation and alveolar bone loss
Lipid mediators Hasturk et al. (2007) (Hasturk et al., 2007) In vivo and in Resolvin E1 In periodontitis rabbit model, Resolvin E1 significantly reduced bone loss and systemic

75
vitro CRP and IL-1β levels
Lee et al. (2016) (Lee et al., 2016) In vivo Resolvin E1 Resolvin E1 prevented bone loss in ligature induced periodontitis, reduced osteoclast
density, suppressed inflammation-related genes
Gao et al. (2013) (Gao et al., 2013) In vivo and in Resolvin E1 Resolvin E1 modulates osteoclast differentiation and bone remodeling by inducing OPG
vitro thus restore the favorable RANKL/OPG ratio
Fredman et al. (2011) (Fredman et al., 2011) In vitro Resolvin E1 Resolvin E1 (0.1-100nM) rescues the impaired phagocytic activity of localized aggressive
periodontitis-macrophages
Yamada et al. (2018) (Yamada et al., 2018) In vivo and in HYA HYA significantly improved the epithelial barrier junction on the gingival epithelial cell
vitro
Sulijaya et al. (2018) (Sulijaya et al., 2018) In vitro KetoC KetoC suppressed inflammation induced by P. gingivalis LPS through NF-κB by binding to G
protein-coupled receptor 120
Yang et al. (2017) (Yang et al., 2017) In vitro KetoC KetoC reduced pro-inflammatory cytokines via NF-κB and mitogen-activated protein
kinase/activator protein-1
Matsuda et al. (2018) (Matsuda et al., 2018) In vivo and In Resveratrol Resveratrol significantly suppressed bone loss and the expression of osteoclastogenesis-
vitro related gene in periodontal tissue
Furumoto et al. (2016) (Furumoto et al., 2016) In vitro KetoC KetoC increased antioxidant genes by upregulating the NRF2-ARE pathway
Ashour et al. (2016) (Ashour et al., 2016) RCT Cytoflavin The use of Cytoflavin showed positive impact (reduction of Russell periodontal index
45.3% and Green-Vermillion index by 39.8%)
Tamaki et al. (2014) (Tamaki et al., 2014) In vitro Resveratrol Resveratrol relieved alveolar bone resorption and activated the Sirt1/AMPK and the
NRF2/antioxidant pathways in inflamed gingival tissue.

RCT: Randomized Clinical Trial.

Archives of Oral Biology 105 (2019) 72–80
B. Sulijaya, et al.
drugs, probiotic intake and mechanical debridement. Host modulation
therapy based on anti-cytokine/chemokine and antioxidant agents are
used to modulate the over-production of the immune system (Freire &
Dyke, 2013; Preshaw, 2018; Yanine et al., 2013; Yen et al., 2008). In
addition, the anti-inflammatory drugs and gingival epithelial barrier
junction improver are used to modulate the destruction of the tissue
(Sulijaya et al., 2018; Yamada et al., 2018). On top of that, the sus-
ceptibility of the host is affecting the outcome of those approaches.
As a non-invasive therapeutic approach for periodontitis, host
modulation therapy has been investigated and explored in the last three
decades (Preshaw, 2018). It has focused on several approaches as pre-
sented in Table 1. Interestingly, many studies have tried to investigate
the benefit of using anti-inflammatory and antioxidant-targeted drugs
(Ashour et al., 2016; Fredman et al., 2011; Furumoto et al., 2016; Gao
et al., 2013; Glowacki et al., 2013; Hasturk et al., 2007; Iwasaki et al.,
2016; Laleman et al., 2015; Lee et al., 2016; Matsuda, Minagawa, Okui,
& Yamazaki, 2018; Mayanagi et al., 2009; Morales et al., 2018; Sulijaya
et al., 2018; Tamaki et al., 2014; Teughels, Durukan, Ozcelik, Pauwels,
Quirynen, Cenk Haytac, 2013; Vicario, Santos, Violant, Nart, & Giner,
2013; Yamada et al., 2018; Yang et al., 2017). In addition, nutrition has
been reviewed to possess beneficial modulation effects in adjunct to
periodontal therapy in periodontitis management (Sulijaya et al.,
2019). In the following paragraphs, several approaches including anti-
chemokine, lipid mediator, bone resorption-related factor inhibitor, and
bio-active fatty acid are discussed.
Chemokines are chemotactic cytokines that attract phagocytic cells
to the challenged site once the cells have migrated from the blood
vessel. In addition, chemokines provide messages that influence other
biological processes including proliferation, apoptosis, tumor metas-
tasis, and host defense (Zlotnik & Yoshie, 2000). CCL22 has been as-
sociated with the reduction of periodontitis severity (Glowacki et al.,
2013). The blockade of CCL22 leads to higher bone resorption, in-
flammatory cell counts, and increased levels of TNF-α and RANKL.
Moreover, it has been shown that anti-CCL22 treatment resulted in a
significant decrease in the number of Treg cells (CD4+FOXp3+) and
inflammatory bone loss through CCR4 by inhibiting the early migration
of Tregs (Araujo-Pires et al., 2015), whereas the migration of in-
flammatory cells is highly observed in the disease lesion site (Garlet
et al., 2006). This result suggests that the inhibition of CCR4-mediated
migrating inflammatory cells by anti-CCL22 treatment might be bene-
ficial to attenuate periodontitis due to its ability to prevent in-
flammatory cell migration and suppress the inflammatory cytokines
and osteoclastogenic mediators. In other words, this chemokine re-
ceptor seems to have potential as a target for HMT to reduce in-
flammatory and bone-resorptive processes. Regarding lipid mediators,
resolvins have been reported to be induced and produced endogenously
during the resolution phase of inflammation. They are synthesized from
Omega-3 fatty acids especially docosahexaenoic acid for D-series and
eicosapentaenoic acid for E-series resolvins. Both of these series have
shown anti-inflammatory and pro-resolution functions (Freire & Van
Dyke, 2013). The D-series resolvins (resolvin D2) have been shown to
suppress inflammation by reducing platelet-leukocyte adhesion and the
combination with aspirin accelerates pro-resolution activities (Serhan &
Savill, 2005).
Previous studies have also investigated the role of resolvin E1 in
inhibiting osteoclast differentiation, increasing bone formation through
osteoprotegerin (OPG) production (Gao et al., 2013), enhancing the
phagocytic activity of apoptotic PMN, and reducing ROS production. In
addition, restoring bone remodeling (as indicated by the OPG:RANKL
ratio) brings inflammation back to homeostasis (Balta, Loos, & Nicu,
2017). Local treatment with resolvin E1 solution on ligature-induced
periodontitis in a rat model showed suppression of inflammatory cell
infiltration as well as inflammation-related genes (Lee et al., 2016).
Resolvin E1 also reduced PMN infiltration by about 50% (Arita,
Bianchini et al., 2005; Arita, Yoshida et al., 2005) and down-regulated
leukocyte rolling by about 40% (Dona et al., 2008). In an experimental
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Archives of Oral Biology 105 (2019) 72–80
periodontitis rabbit model using ligatures inoculated with P. gingivalis,
resolvin E1 not only suppressed bone loss but also restored the systemic
C-reactive protein (CRP) and IL-1β levels (Hasturk et al., 2007). Re-
solvin E1 also recovered the impaired phagocytosis activity of macro-
phages collected from humans with localized aggressive periodontitis
(Fredman et al., 2011). Furthermore, Chemokine-like receptor 1
(ChemR23) and BLT1 (a leukotriene receptor) have been investigated
as receptors of resolvin E1 that mediate its inflammation-related action
on monocytes, macrophages, dendritic cells, osteoblasts, and osteo-
clasts (Arita, Bianchini et al., 2005; Arita, Yoshida et al., 2005; Arita
et al., 2007; El Kebir, Gjorstrup, & Filep, 2012; Freire, Dalli, Serhan, &
Van Dyke, 2017). ChemR23 acts as a chemoattractant and as an adi-
pokine (Bondue, Wittamer, & Parmentier, 2011), whereas BLT1 is
highly associated with leukotriene B4 (LTB4), a pro-inflammatory
mediator (Arita et al., 2007). Therefore, it is proposed that via binding
to ChemR23, resolvin E1 induces phagocytosis of apoptotic PMNs and
inhibits inflammation. Also, by binding to BLT1, resolvin E1 competes
with LTB4 thus attenuating the inflammatory signal. Finally, with no
unwanted side effects having been reported, these consistent results
bring about the possibility of this compound to be applied in humans.
Hence, to the best of our knowledge, no clinical studies on humans have
evaluated the effect of this compound on periodontitis.
Resveratrol, an inhibitor of bone resorption-related factors, has been
shown to have cardioprotective and anti-inflammatory effects
(Minagawa et al., 2015), antioxidant properties (Orihuela-Campos
et al., 2015), and the capacity to inhibit osteoclast differentiation
(Matsuda et al., 2018). In a ligature-induced periodontitis rat model,
the administration of Resveratrol induced production of Sirt1/AMPK
and NFR2 proteins, thus inhibiting the NF-κB/mitogen-activated pro-
tein kinase (MAPK) pathway, resulting in the improvement of systemic
inflammation and oxidative stress (Tamaki et al., 2014). In human
gingival epithelial cells, Resveratrol suppresses IL-1β, IL-8, and mono-
cyte chemoattractant-1 (MCP-1) in a Sirt1-independent manner
(Minagawa et al., 2015). Aside from that, it promotes heme oxygenase 1
(HO-1), an antioxidant enzyme, through the upregulation of NRF2
pathway. Thus, mediated by carbon monoxide (CO), HO-1 can suppress
oxidative stress by down-regulating iNOS, an oxidant gene (Datta,
Koukouritaki, Hopp, & Lianos, 1999; Thirunavukkarasu et al., 2007).
Summarizing these findings, it is accepted that Resveratrol has multi-
functional and beneficial effects as an HMT targeted to inflammatory
genes, osteoclast differentiation, and oxidant-related genes.
Several studies have been performed to investigate the effect of
polyunsaturated fatty acids (PUFAs) on periodontitis. Omega-3 (ω-3),
one of the PUFAs, showed anti-inflammatory activity by reducing the
synthesis of IL-1β and TNF-α in in vitro studies (Caughey, Mantzioris,
Gibson, Cleland, & James, 1996; Meydani et al., 1991). In clinical
studies, supplementation with omega-3 (ω-3) for 21 days failed to re-
duce levels of gingivitis (Campan, 1997). In contrast, a clinical trial
study using ω-3 as an adjunctive therapy to scaling and root planing
(SRP) in periodontitis subjects, showed significant reduction on gin-
gival index, probing depth, and gain in clinical attachment level com-
pared to control (Deore et al., 2014). Furthermore, several studies
found positive improvement on periodontal parameters by using a
combination of PUFAs with aspirin (El-Sharkawy et al., 2010; Naqvi
et al., 2014). However, prolonged bleeding time that may be a result
from impaired blood vessels or decreased number of thrombocytes was
reported as a systemic adverse effect of ω-3 dietary supplementation
(Dyerberg & Bang, 1979). Several investigations later disproved the
association between prolonged bleeding time and high dietary doses of
ω-3 (Eritsland, Arnesen, Seljeflot, & Høstmark, 1995; Wachira, Larson,
& Harris, 2014). Therefore, the adjunctive use of ω-3 in periodontal
therapy affects hemostasis without increasing the risk of bleeding.
Recently, another PUFA generated by Lactobacillus plantarum has
been widely investigated due to its potential effects. The PUFAs KetoC
and HYA have been shown to have beneficial effects in the context of
inflammatory disease, especially for periodontitis. KetoC was shown to
B. Sulijaya, et al.
have an anti-inflammatory effect on TNF-α production through the NF-
κB/G protein-coupled receptor-120 pathway by treating macrophages
with LPS derived from P. gingivalis (Sulijaya et al., 2018); moreover, it
was also reported that this suppression effect was mediated by MAPK/
activator protein-1 (Yang et al., 2017). KetoC also showed some po-
tential antioxidant properties by up-regulating the HO-1 and NQO1
genes through the NRF2 pathway in HepG2 cells (Furumoto et al.,
2016), macrophages (Sulijaya et al. unpublished data), and epithelial
cells (Yokoji et al. unpublished data). Regarding osteoclastogenesis,
KetoC has no significant effect on osteoclast differentiation-related
genes, e.g. RANKL and OPG (Sulijaya et al. unpublished data). Mean-
while, HYA is reported to have a protective role in epithelial cells by
inducing E-cadherin (E-cad), a gingival epithelial barrier junction
component (Yamada et al., 2018). Bringing these results together, it
may be assumed that gut metabolites suppress inflammatory cytokines
and induce oxidant genes in addition to improving the epithelial barrier
junction, thus resolving inflammation and oxidative stress.
Concerning the disadvantages of HMT agents, several studies have
been performed. For example, even though consumption of oral pro-
biotics is generally safe (Chatterjee, Bhattacharya, & Kandwal, 2011),
cases of probiotics-related bacteremia, Lactobacillus endocarditis, and
secondary liver abscesses have been reported from Lactobacillus rham-
nosus (Meurman & Stamatova, 2007). Targeted inhibition of pros-
taglandins and leukotrienes by corticosteroids has shown a variety of
side effects including osteoporosis, peptic ulceration, inhibition of
adrenal cortex function, hypertension, and impaired wound healing
(Alani & Seymour, 2014). Bisphosphonates, which are often used to
treat osteoporosis and other bone-resorptive related diseases, have been
shown to potentially induce osteonecrosis (Otomo-Corgel, 2012). As
mentioned earlier, PUFAs, and especially ω-3, have been reported to
increase bleeding time, but this side effect has since been disproven
(Eritsland et al., 1995; Wachira et al., 2014).
Furthermore, the use of low dose doxycycline (SDD; 20 mg, sub anti-
microbial dose) twice a day for a minimum of 3 months has been in-
dicated to be safe and can improve clinical outcomes; however, anti-
biotic resistance has gained global concern recently and therefore the
use of antibiotics should be limited (Caton et al., 2000; Jepsen &
Jepsen, 2016; Preshaw et al., 2004; Sgolastra, Petrucci, Gatto,
Giannoni, & Monaco, 2011; Sulijaya, Takahashi, Yamazaki, &
Yamazaki, 2019). With respect to this, resolvin E1 might be potentially
beneficial for periodontal therapy. No clinical studies have yet been
performed to analyze the efficacy of gut metabolites (KetoC and HYA)
in periodontitis subjects; so far, investigations are still progressing in in
vitro and in vivo studies. However, the prospect of these agents as food
supplements is expected to be valuable without giving any harmful side
effects.
4. Conclusions
In summary, the host system itself is perhaps the best system for
coming to a non-destructive equilibrium with the biofilm; not by taking
drugs or the likes, but fortifying the host immune response by natural
ways, which is improvement of immune fitness by a healthy life style
(e.g. not smoking, sufficient dietary precursors of resolving, anti-oxi-
dant vitamins, maintaining proper body weight, etc.). Furthermore,
increasing evidence supports the substantive effectiveness of HMT
agents in periodontitis through in vitro, in vivo, and human studies.
Though HMT in combination with periodontal therapy improves peri-
odontal parameters, systemic effects caused by HMT agent should
continue to be monitored especially in immunocompromised patients.
A better understanding of how HMT agents work, and their targets will
be beneficial in periodontal therapy. Rationally, to treat periodontitis, a
chronic inflammatory disease in response to commensals and patho-
bionts, the inflammation and oxidative stress induced tissue destruction
could be managed in part by modulating the host immune response
with adjunctive use of a bioactive compound with protective functions,
77
Archives of Oral Biology 105 (2019) 72–80
e.g. anti-inflammatory and anti-oxidative properties. However, limited
studies have investigated HMT in humans and the possible side effects
of HMT agents need to be further clarified. In this sense, future clinical
investigations are required to support the remarkable role of HMT
agents in the management of periodontitis.
5. Contributors
All authors have read and approved the final article.
Acknowledgements
This work was financially supported in part by Japan Society for the
Promotion of Science (JSPS) Grants-in-Aid for Scientific Research
(KAKENHI) (Grant numbers 15H02578 (to K.Y.) and 16H05554 (to T.
N.)), located in Japan.
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