Biomedicine & Pharmacotherapy 99 (2018) 883–893

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Biomedicine & Pharmacotherapy

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

Review

Human oral microbiota and its modulation for oral health T

a,1 a,1 a a b,⁎⁎ a,⁎
Yangheng Zhang , Xiang Wang , Houxuan Li , Can Ni , Zhibin Du , Fuhua Yan
a
Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
b
Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Brisbane, Queensland, Australia

A R T I C L E I N F O A B S T R A C T

Keywords: The oral microbiome is an important part of the human microbiome. The oral cavity contains several sig-
Oral microbiota nificantly different niches with distinct microbial communities. A wide range of microorganisms inhabit the
Composition human oral cavity, including bacteria, fungi, viruses, archaea and protozoa. These microorganisms form a
Oral diseases complex ecological community that influences oral and systemic health. The most prevalent oral diseases, dental
Systemic diseases
caries and periodontal diseases, are microbiota-associated diseases. Moreover, increasing evidences have sup-
Modulation
ported that many systemic diseases are associated with disturbances in the oral ecosystem, such as diabetes,
Probiotics
cardiovascular diseases and tumors. The current control of dental plaque-related diseases is nonspecific and is
centered on the removal of plaque by mechanical means. Due to this realization about the oral microbiome,
several new methods based on the modulation of the microbiome that aim at maintaining and reestablishing a
healthy oral ecosystem have been developed.

1. Introduction
Human are supraorganisms composed of both their own cells and
microbial cells. The number of microorganisms residing on or in the
human body is tenfold over that of the body’s own cells [1]. These
commensal microorganisms contribute to host health by resisting pa-
thogens, maintaining homeostasis and modulating the immune system
[2]. The National Institute of Health (NIH) of the United States (US)
initiated the Human Microbiome Project (HMP) to characterize the
human microbiome more completely and determine the association
between changes of microbiome and health/disease [3]. The oral mi-
crobiome is one of the important parts of the human microbiome, and it
refers specifically to the microorganisms residing in the human oral
cavity [4].
The oral cavity has been considered to possess the second most
complex microbiota in human body, only behind the colon [5]. The oral
microbiome is highly diverse, including bacteria, fungi, viruses, archaea
and protozoa. Approximately 700 species are present in the oral cavity,
and most of them are indigenous [6]. Among them, approximately 54%
have been cultivated and named, 14% are cultivated but unnamed, and
32% are known only as uncultivated phylotypes (from the Human Oral
Microbiome Database). An increasing number of studies have demon-
strated that the oral microbiota plays a vital role in the pathogenesis
and development of many oral and systemic diseases.
In this review, we describe the microbial diversity of the oral cavity,
expound microbial communities of different oral niches and present
evidences that have confirmed the relationship between oral bacterial
community shifts and oral or systemic diseases. Moreover, several
prevention and treatment methods based on oral microbiota modula-
tion are discussed.
2. Oral microbiome composition
2.1. Bacteria
Bacteria account for the main portion of oral microorganisms, and
the major knowledge of the composition of oral bacteria comes from
past culture-dependent methods. Culture-dependent techniques led to
the identification of specific microorganisms thought to have a causa-
tive role in caries and periodontitis [5]. However, these data sub-
stantially underestimated the composition of the oral microbiome. The
development of culture-independent methods, particularly targeting
16S ribosomal RNA, has expanded our awareness of the great richness
and diversity of the oral microbiome. A list of oral bacteria with a de-
scription of their characteristics and genomic information are available
from the Human Oral Microbiome Database website at www.homd.org.
The oral bacterial community is dominated by the six major phyla,
Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, Spirochaetes

⁎
Corresponding author at: 30 Zhongyang Road, Nanjing, Jiangsu, 210008, China.
⁎⁎
Corresponding author at: Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove Campus, Brisbane, QLD 4059 Australia.
E-mail addresses: zhibin.du@qut.edu.au (Z. Du), yanfh@nju.edu.cn (F. Yan).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.biopha.2018.01.146
Received 30 September 2017; Received in revised form 4 January 2018; Accepted 29 January 2018
0753-3322/ © 2018 Elsevier Masson SAS. All rights reserved.
Y. Zhang et al.
and Fusobacteria, which account for 94% of the taxa detected. The
remaining phyla, Saccharibacteria, Synergistetes, SR1, Gracilibacteria,
Chlamydia, Chloroflexi, Tenericutes, and Chlorobi, contain the re-
maining 6% of the taxa (Human Oral Microbiome Database. Available
at: http://www.homd.org).
Although our understanding of oral microorganisms has gradually
deepened in recent years, there is still a large proportion of oral bacteria
that cannot be cultivated in the laboratory. The major reason for un-
cultivable microbial species is that the conditions these microorganisms
have been accustomed to in vivo have not been reproduced completely.
Many microorganisms have unique requirements for survival, such as
specific nutrients, accurate temperature and pH, and interaction with
other microorganisms of their community [7].
2.2. Fungi
Fungi are present widely in the oral cavity. Not only as opportu-
nistic pathogens of the elderly and immune-compromised, fungi are
also members of healthy oral microbiota [8]. A detailed characteriza-
tion of oral fungi has been reported, in which up to 101 fungal species
are present in healthy subjects [9]. It was also observed that the number
of fungal species in the oral cavity of each individual ranged between 9
and 23, and the Candida species were the most frequent, followed by
Cladosporium, Aureobasidium, Saccharomyces, Aspergillus, Fusarium, and
Cryptococcus [9].
2.3. Archaea
Archaea constitutes only a minor part of the oral microbiome and is
restricted to limited species. The found species are Thermoplasmatales,
Methanobrevibacter, Methanobacterium, Methanosarcina, and
Methanosphaera, all of which are methanogens [10–12]. They can be
observed in healthy subjects, but their prevalence and numbers are
elevated in individuals with periodontitis [2].
2.4. Viruses
Most viruses in the mouth are related to diseases. Herpes simplex
virus causes primary herpetic gingivostomatitis, mucocutaneous or-
ofacial disease and recurrent lesions on the face and lips [13]. Human
papilloma virus causes many lesions in the oral cavity, including be-
nign-like oral papillomas, oral condylomas and focal epithelial hyper-
plasia [14]. Additionally, HIV infection can also indirectly cause many
oral manifestations, such as oral candidiasis, oral hairy leukoplakia,
linear gingival erythema and necrotizing ulcerative periodontitis, and
Kaposi’s sarcoma [15].
3. Location of oral microbiota
The oral ecosystem is very intricate because it has several sig-
nificantly different niches, including saliva, soft tissue surfaces of the
oral mucosa and tongue, and hard tissue surfaces of teeth [16]. Dif-
ferent surfaces attract distinct microbial communities because each
niche provides a unique ecosystem with the optimal conditions and
nutrients for its populating microbes [17,18]. Therefore, microbiomes
from the same site of different individuals were more similar than those
from different sites of the same individual [19]. It has been reported
that the profiles of 40 cultivable bacterial species have clear differences
in saliva, surfaces of oral soft tissue, and supragingival and subgingival
plaques from healthy subjects [20].
3.1. Saliva
The tissue surfaces and biofilms of the oral cavity are continuously
infiltrated with saliva. The salivary microorganisms mainly come from
the shedding of the biofilm on the surface of the oral tissue [21].
884
Biomedicine & Pharmacotherapy 99 (2018) 883–893
Therefore, the microbial profile of saliva is similar to that of the soft
tissues, but saliva and soft tissue colonization differ obviously from that
of dental plaque [22]. Approximately 3621 bacterial taxa in the saliva
of 98 healthy subjects were identified, and Firmicutes (genus Strepto-
coccus and Veillonella) and Bacteroidetes (genus Prevotella) were the
predominant phyla [23]. Some proteins in saliva could coat the surface
of the teeth and mucous membrane to promote microbial adhesion.
However, some salivary proteins also promote the desorption, aggluti-
nation and removal of microorganisms by swallowing saliva [21]. Hy-
posalivation is generally thought to contribute to the development of
oral diseases. It was found that the number of acidogenic and aciduric
microorganisms increased in subjects with hyposalivation through
analyzing the microflora in rinsing samples from healthy and hyposa-
livation subjects [24]. In addition, the salivary microbiota could be
used as potential diagnostic and prognostic markers for several specific
diseases, such as dental caries and oral cancer [22,25].
3.2. The surfaces of soft tissues
Despite unceasing shedding of superficial epithelial layers, the oral
mucosa is persistently colonized by microorganisms [21]. Compared
with other oral niches, the colonization of microorganisms on oral soft
tissue is limited [2]. The surfaces of the cheek and palate have only
monolayers of bacteria originating and desquamating regularly. In
contrast, the surface of the tongue has multilayers of biofilm-like bac-
teria. Therefore, it is thought that higher density and more diverse
microorganisms inhabit the tongue compared with other mucosal sur-
faces. The predominant microbiota on the tongue dorsa of healthy
subjects were Streptococcus salivarius, Rothia mucilaginosa, and an un-
characterized species of Eubacterium (strain FTB41) [26]. The micro-
organisms on the tongue dorsa are closely related to halitosis. The
crypts of the tongue allow anaerobic microbiota to flourish, which is an
established source of halitosis [27].
3.3. The surfaces of hard tissues
One distinctive feature of the mouth is the presence of the tooth
surface. The non-shedding surface of the tooth could provide a stable
location for the development of biofilm [21]. Dental plaque is a struc-
turally and functionally organized biofilm built on tooth surfaces.
Plaque with a variety of microbes forms in an ordered manner and
remains relatively stable over time [28]. According to the location,
dental plaque is divided into supragingival plaque (above the gum line)
and subgingival plaque (below the gum line).
The microbial community of supragingival plaque differs from that
of subgingival plaque. A study that collected supragingival plaque from
98 healthy subjects found that Firmicutes and Actinobacteria (genus
Corynebacterium and Actinomyces) dominated supragingival plaque
[23]. Supragingival plaque is associated with dental decay on occlusal
and approximal surfaces of the tooth, and these locations are the most
susceptible locations for caries [21]. Microorganisms residing in these
niches tend to produce acid and/or are resistant to an acid environment
[21].
Along with the supragingival plaque that extends down to the
subgingival area along the root, the film contains more serum and less
saliva. The environment turns more anaerobic, and the pH and tem-
perature become extreme. Based on the 16S rRNA sequence data, the
predominant subgingival microbiome consists of 347 species or phy-
lotypes that fall into 9 bacterial phyla, including Obsidian Pool OP11,
TM7, Deferribacteres, Spirochaetes, Fusobacteria, Actinobacteria,
Firmicutes, Proteobacteria, and Bacteroidetes [29].
 Table 1
Probiotics and dental caries.

Test strain Dose Vehicle Frequency Sample Result Reference

Y. Zhang et al.

8
L.reuteri 1.1 × 10 CFU lozenge once daily for 10 20 healthy young women aged 20 with high reduced salivary S.mutans [135]
days S.mutans counts
B.lactis 5.3 × 109 CFU ice cream once daily for 40 24 healthy adults aged 20 reduced salivary S. mutans [136]
days
B.animalis 5.6 × 1011 CFU yogurt once daily for 8 26 healthy adolescents aged 12–16 a statistically significant reduction in salivary S.mutans [102]
weeks undergoing fixed orthodontic treatment
9
L.rhamnosus 1.5 × 10 CFU milk once daily for 21 248 healthy children aged 1–5 reduced caries with a prevented fraction of 75% [137]
months
9
L.rhamnosus 2.5 × 10 CFU milk once daily for 2 18 caries-active adolescents aged 13–17 no impact on the microbial profiles or the levels of caries- [105]
weeks associated bacteria in saliva and supragingival plaque
L.bulgaricus, S.thermophilus unclear yogurt twice daily for 2 84 healthy adolescents aged 12–18 a statistically significant reduction in S. mutans [138]
weeks
L.rhamnosus, Bifidobacterium, 1.25 × 109 microorganisms powder once daily for 14 150 healthy children aged 7–14 reduced salivary S. mutans [139]
B.coagulans days
9
L.rhamnosus 2 × 10 CFU milk once daily or 15 160 healthy subjects aged 58–84 with at least increase the numbers of root caries index reversals and mean [140]
months 2 root caries lesions electric resistance measurements values
B.animalis 5.4 × 107 CFU ice cream once daily for 10 40 healthy children aged 12–14 with no reduce salivary S.mutans and no impact on lactobacilli levels [141]
days clinically detectable caries
L.reuteri ≥1 × 108 CFU/5 drops liquid 5 drops daily for 25 19 operated cleft lip/palate children aged no statistically significant reduction in salivary S.mutans and [106]
days 4–12 lactobacilli
9
L.rhamnosus 2.34 × 10 CFU milk twice daily for 3 40 systemically healthy children aged 12–15 reduced salivary S.mutans [142]
weeks with medium to high caries risk
8
L.reuteri 1 × 10 CFU lozenge twice daily for 6 62 medical students aged 19–35 with no impact on the regrowth of salivary S.mutans [107]
weeks moderate or high counts of salivary MS
L.reuteri 1 × 108 CFU lozenges 3 tablets daily for 2 18 healthy young adults with a mean age of the salivary S.mutans counts were not significantly altered but [143]

885
weeks 26 the lactobacilli count increased significantly
L.casei 5 × 107 CFU cheese twice daily for 2 60 healthy adults aged 18–37 reduced salivary S.mutans [144]
weeks
9
S.salivarius 3.6 × 10 CFU lozenge 2 lozenges daily for 3 100 dental caries-active children aged 5–10 significantly decreased plaque scores and S.mutans counts [145]
months
B. lactis, L. acidophilus, L. casei 5.4 × 107 CFU of each strain ice cream, once daily for 7 days 40 caries free children aged 12–14 a statistically significant reduction in S.mutans counts [146]
curd
L. paracasei 1 or 2 mg/candy candy 4 times during 1.5 40 healthy subjects aged > 18 reduced salivary S.mutans [103]
days
8
L. paracasei 1 × 10 CFU cereal once daily for 9 179 children aged 4 months no impact on the frequency of dental caries, S.mutans or [109]
months Lactobacilli
B. lactis unclear yogurt once daily for 2 30 individuals aged 10–30 undergoing reduce total microbial counts in dental plaque [147]
weeks orthodontic treatment
L. paracasei 7.5 × 109 CFU milk once daily for 4 30 orthodontically treated nonsyndromic reduce the S.mutans counts and increase Lactobacilli [148]
weeks cleft lip and palate patients aged 19
L. paracasei ≥108 live microorganisms milk powder once daily for 4 40 healthy young adults aged 18–25 reduced S.mutans counts and increasedLactobacilli numbers [149]
weeks
L. reuteri 0.02 ml, 0.5 McFarland gum three times daily for 42 healthy students aged 20–30 reduced Lactobacillus count and pH of the saliva [150]
3 weeks
L. reuteri 1 × 108 CFU/5 drops drops five drops daily for 1 113 children reduced caries prevalence and gingivitis score [151]
year
B. lactis, L. acidophilus 1 × 106 CFU of each strain ice cream once daily for 7 days 60 healthy children aged 6–12 reduced salivary S.mutans [152]
B. animalis unclear curd once daily for 7 days 30 healthy children aged 12–14 reduced salivary S. mutans [153]
B. animalis 2 × 108 CFU yogurt once daily for 2 49 healthy children aged 6–12 not reduce the levels of salivary S. mutans and Lactobacilli [108]
weeks
L. paracasei 3.75 × 109 CFU milk powder once daily for 6 60 healthy teenagers aged 13–15 reduced salivary S. mutans [154]
months
L. rhamnosus 1.5 × 109 CFU milk on weekdays for 40 261 children aged 2–3 reduce caries development [155]
weeks
(continued on next page)
Biomedicine & Pharmacotherapy 99 (2018) 883–893
Y. Zhang et al. Biomedicine & Pharmacotherapy 99 (2018) 883–893

Reference 4. Oral microbiota and diseases

[156]
[157]
4.1. Dental caries

Dental caries, one of the most common oral diseases, are the pri-
mary cause of oral pain and tooth loss [30]. Dental caries result from
the complex interaction between acid-producing bacteria and fermen-
reduced salivary S. mutans and increased salivary pH

table carbohydrates [30]. The intake of high levels of carbohydrates

frequently leads to increased acid production, decreased salivary buf-
fering capacity and a low-pH environment [31]. Environmental acid-
ification is the major cause of the phenotypic and genotypic changes in
the microflora during the progression of caries [31]. Indeed, secretory
IgA from salivary and serum IgG derived from the gingival crevicular
fluid may also influence the accumulation of a cariogenic microbiota at
reduced salivary S. mutans

various stages of infection [32,33].

Streptococcus mutans (S. mutans) and Lactobacillus have been studied
intensively and regarded as specific pathogens in caries [34]. However,
in recent studies, S. mutans is not only present at high levels in the early
stages of caries but also in some healthy individuals [34,35]. In some
Result

patients, S. mutans and Lactobacillus were found either at low levels or

absent in several samples of dental caries [36]. All of these results in-
dicate that the initiation and progression of carious lesions cannot be
attributed to these microorganisms completely. Therefore, dental
caries, which is a bacterial disease, are caused by a complex community
60 caries free volunteers aged 20–25

rather than a single pathogen [21]. Aas et al. reported that species of
the genera Veillonella, Lactobacillus, Bifidobacterium, Propionibacterium,
61 healthy children aged 3–6

low-pH non-S. mutans streptococci, Actinomyces spp., and Atopobium spp.

also play a key role in caries progression [36]. Another study by Gross
et al. showed the levels of Selenomonas, Neisseria, and Streptococcus
mitis. Propionibacterium FMA5 in severe caries of young, permanent
teeth were significantly associated with caries progression, though they
were not found at high levels [34]. Meanwhile, some species, including
Sample

Streptococcus mitis-S. pneumoniae-S. infantis group, Corynebacterium ma-

truchotii, Streptococcus gordonii, Streptococcus cristatus, Capnocytophaga
gingivalis, Eubacterium IR009, Campylobacter rectus, and Lachnospiraceae
five drops daily for 2
once daily for 7 days

sp. C1, were significantly decreased as caries progressed [34]. In ad-

dition to acid-producing bacteria, some bacteria can produce ammonia
from arginine and urea and thus raise pH, which participates in the pH
Frequency

homeostasis of oral biofilms and may moderate initiation and pro-

weeks

gression of dental caries [37]. Teng et al. screened out 20 taxa (12 from
plaque and 8 from saliva) including S. mutans and Veillonella atypical/
Veillonella dispar/Veillonella parvula to diagnose early childhood caries
(ECC) from healthy samples with 70% accuracy and predict, with 81%
Vehicle

accuracy, future ECC onsets for samples clinically perceived as healthy

drop
curd

[38].
1 × 1010 CFU/mL 2 × 109 CFU/mL

4.2. Periodontal diseases

Gingivitis is the most common and prevalent form of periodontal

diseases among adults. Gingivitis is a reversible inflammatory disease
1.5 × 109 CFU/mL

caused by a resident bacterial plaque that forms at the gingival margin.

Eight predominant taxa found in plaque microbiota, including TM7,
Leptotrichia, Selenomonas, Streptococcus, Veillonella, Prevotella, Lautropia,
and Haemophilus, are associated with gingivitis and may serve as its
unclear
Dose

biomarkers [39,40].
If left uncontrolled, gingivitis will progress into periodontitis.
L. rhamnosus, B. infantis, L. reuteri

Periodontitis is a chronic, irreversible inflammatory disease, during

which the chronic infiltrate of immune cells induces destruction of
connective tissue, vascular proliferation and alveolar bone destruction
[41]. The shift in the composition of the microbial community leads to
alterations in the host-microbe crosstalk sufficient to mediate destruc-
Table 1 (continued)

tive inflammation and bone loss. Porphyromonas gingivalis (P. gingivalis),

L. acidophilus

Treponema denticola (T. denticola) and Tannerella forsythia (T. forsythia),

Test strain

defined historically as the “red complex”, are associated with period-

ontitis [42]. Although these bacteria may appear in low numbers in
healthy individuals, they are thought to be closely related to the

886
 Y. Zhang et al.

Table 2
Probiotics and periodontal diseases.

Test strain Dose Vehicle Frequency Sample Result Reference

10
L.casei 6.5 × 10 viable milk drink once daily for 8 weeks 50 healthy dental and medicine students reduced elastase activity and matrix metalloproteinase-3 [119]
cells with mean age 24
L.reuteri 2 × 108 CFU gum twice daily for 12 ± 1 weeks 23 healthy adults aged > 18 the ratio of “bad/good” in supragingival bacteria decreased but [158]
did not reach significance
L.reuteri 2 × 108 CFU lozenge twice daily for 21 days 30 systemically healthy individuals with reduced PI, GI, GBI, PPD and CAL, reduced A. [115]
periodontitis aged 34–50 actinomycetemcomitans, P. intermedia and P. gingivalis
9
L.casei 6.5 × 10 CFU milk drink once daily for 4 weeks 28 healthy adults aged 20–35 reduced BOP levels and GCF volume [118]
L.reuteri 2 × 108 CFU tablet 1 tablet per day for 28 days 40 systemically healthy dental students a reduction in the number of selected periodontal pathogens in the [113]
aged 20–24 with GI > 1 and no CAL subgingival microbiota, without an associated clinical impact
L.reuteri 2 × 108 CFU lozenge twice daily for 3 weeks 18 healthy females with a mean age of 38 no impact on the plaque accumulation, inflammatory reaction or [159]
the composition of the biofilm during experimental gingivitis
L.brevis 107 CFU lozenge twice daily for 14 days 20 systemically healthy individuals aged decreased PI, GI, PPD and CAL; decreased A. [117]
14–35 with CAL ≥5 mm actinomycetemcomitans and increased Lactobacilli
8
L.reuteri 2 × 10 CFU lozenge twice daily for 12 weeks 30 chronic periodontitis patients aged > 35 more P. gingivalis reduction was observed in the scaling and root [114]

887
planing + probiotic group
8
L.reuteri ≥2 × 10 viable cells tablet once daily for 30 days 20 systemically healthy subjects with improved PI, BOP and PPD [116]
initial-to-moderate chronic periodontitis
aged 44–63
L.brevis ≥1 × 109 viable cells lozenge three times daily for 14 days 34 healthy adults aged 19–29 increased production of nitric oxide in gingival crevicular fluid in [160]
the placebo group and not in the test group
8
L.reuteri 1 × 10 CFU lozenge twice daily for 3 weeks 40 systemically healthy individuals with reduced PI, GI, BOP and PD and fewer patients required surgery on [161]
chronic periodontitis aged 35–50 ≥3 sites
9
L. rhamnosus, B. animalis 2 × 10 cells for each lozenge 4 pieces per day for 4 weeks 62 healthy adults mean age 24 decreased both PI and GI and no impact on the microbial [162]
strain/day compositions of saliva
B. subtilis, B. megaterium, 5 × 107 CFU toothpaste, mouth rinse, for 8 weeks 40 systemically healthy patients with no impact on gingivitis parameters. [120]
B. pumulus toothbrush cleaner generalized gingivitis aged 18–31
L. rhamnosus 2 × 107 CFU sachet once daily for 3 months 28 systemically healthy with untreated greater reductions in PPD and a statistically significant reduction [121]
periodontitis aged > 35 in number of participants with PPD ≥6 mm
9
L. salivarius, L. reuteri 2 × 10 CFU rinse solution Twice daily for 14 days 32 systemically healthy chronic improved PI, modified GI and bleeding index [122]
periodontitis patients aged 25–59

PI: plaque index; GI: gingival index; GBI: gingival bleeding index; PPD: probing pocket depth; CAL: clinical attachment level; BOP: bleeding on probing; GCF: gingival crevicular fluid.
Biomedicine & Pharmacotherapy 99 (2018) 883–893
Y. Zhang et al.
occurrence and development of periodontitis [21]. After effective per-
iodontal treatment, the “red complex” disappears or falls below the
limit of detection [21]. The “red complex” were originally associated
with periodontal diseases by culture methods and subsequently con-
firmed with whole-genomic DNA probes. New sequencing technologies
have expanded the range of disease-associated organisms, including
Filifactor alocis, Peptostreptococcus stomatis, Prevotella, Synergistes,
Megasphaera, Selenomonas, and Desulfobulbus [43,44]. One study
showed that a change in periodontal status was accompanied by shifts
in the bacterial community of the gingival crevice [45]. Increased levels
of the Veillonella sp. Oral clone X042 and the most common member of
the subgingival bacterial community were associated with periodontal
health, whereas the number of Filifactor alocis observed was higher in
subjects with periodontal diseases [45].
In addition to bacteria, some yeasts were detected in subgingival
colonization, and C. albicans was observed to be highly associated with
the severity of chronic periodontitis [46]. Herpes viruses, including
human cytomegalovirus (HCMV), herpes simplex virus (HSV), Ep-
stein–Barr virus (EBV), and human herpes virus (HHV), have also been
described in subgingival biofilms of patients with periodontitis [47,48].
Moreover, some members of archaea could be detected in periodontal
pockets [12].
4.3. Recurrent aphthous stomatitis
Recurrent aphthous stomatitis (RAS) is the most common oral mu-
cosal disease affecting approximately 20% of the general population
[49]. The disease is characterized by recurrent, extremely painful oral
ulcers. Increasing evidences indicate that RAS is associated with dys-
biosis of mucosal and salivary microbiota [50–52]. Marchini et al.
found Prevotella was present only in the mucosal microbiota of RAS
patients but not in healthy subjects [50]. Seoudi et al. studied the
mucosal microbiota and found that the phylum Actinobacteria, espe-
cially the genus Rothia, was represented more frequently in RAS pa-
tients compared to healthy controls [51]. However, in another study,
lower levels of Streptococcaceae-comprising species were present in
ulcerated sites of patients with RAS than healthy controls. A compar-
ison of the relative abundance of each taxon revealed decreases in the
members of healthy core microbiota (e.g. Streptococcus salivarius) but
increases in rare species (e.g. Acinetobacter johnsonii) in the mucosal and
salivary microbiota of RAS patients [53].
4.4. Oral tumor
There are more and more evidences suggesting that oral microbiota
may have a role in the development of oral cancer. Oral squamous cell
carcinoma (OSCC) is the most familiar malignancy that comes from the
epidermis of the oral cavity [54]. Nagy et al. examined the oral carci-
noma and healthy mucosal surfaces of the same patient with culture-
dependent methods and found that the oral carcinoma surface harbored
a significantly increased number of aerobes and anaerobes [55]. Ap-
parent differences in the composition of the microbiota within the tu-
morous and non-tumorous mucosa have also been reported by culture-
independent 16S rRNA approaches. Streptococcus sp. oral taxon 058,
Peptostreptococcus stomatis, Streptococcus salivarius, Streptococcus gor-
donii, Gemella haemolysans, Gemella morbillorum, Johnsonella ignava and
Streptococcus parasanguinis I were highly associated with tumor sites,
whereas Granulicatella adiacens was prevalent at non-tumor sites
[56,57]. Another study showed that the counts of Capnocytophaga gin-
givalis, Prevotella melaninogenica and Streptococcus mitis (S. mitis) in-
creased in the saliva of subjects with OSCC [22]. More recently,
Schmidt et al. reported that the abundance of Firmicutes (especially
Streptococcus) and Actinobacteria (especially Rothia) was significantly
decreased in cancer samples relative to contralateral normal samples
from the same patient [58]. Lee et al. demonstrated that the oral mi-
crobiome compositions of five genera, Bacillus, Enterococcus,
888
Biomedicine & Pharmacotherapy 99 (2018) 883–893
Parvimonas, Peptostreptococcus, and Slackia, revealed significant differ-
ences between epithelial precursor lesion and cancer patients and cor-
related with their classification into two clusters [59]. These observable
differences in the oral microbiome might have the potential to serve as
a biomarker for monitoring oral cancer development, progression and
recurrence.
The role of oral microbiota in the pathogenesis of oral cancers is not
well established. Several mechanisms have been speculated. Firstly,
bacterial could provoke chronic inflammatory responses. Chronic in-
flammatory mediators produced in this process cause or facilitate cell
proliferation, mutagenesis, oncogene activation and angiogenesis.
Secondly, bacteria may influence the pathogenesis of cancers directly
via the secretion of bacterial effector proteins using type 3 or type 4
secretion systems (T3SS/T4SS), which could affect the cell prolifera-
tion, cytoskeletal rearrangements, activation of NF-KB and inhibition of
cellular apoptosis [60,61]. Thirdly, some carcinogenic substances could
be produced by bacteria, such as the bacterial conversion of ethanol to
acetaldehyde (a recognized carcinogen) [62].
4.5. Oral microbiota and systemic diseases
4.5.1. Diabetes
There is a two-way relationship between diabetes and periodontitis.
Periodontitis is regarded as one of complications of poorly controlled
diabetes [63]. Several studies have explored the effect of diabetes on
oral microbiota [64,65]. Hintao et al. reported that the supragingival
plaques of diabetic subjects had higher levels of T. denticola, Prevotella
nigrescens, Streptococcus sanguinis, Streptococcus oralis and Streptococcus
intermedius compared with those of non-diabetic subjects, but no sig-
nificant difference of the organisms levels was observed in saliva, oral
rinse or subgingival plaques between diabetic and non-diabetic subjects
[64]. In another study, there was a significant difference in the sub-
gingival microbiota between diabetic and non-diabetic subjects [65].
Diabetic subjects had higher levels of TM7, Aggregatibacter, Neisseria,
Gemella, Eikenella, Selenomonas, Actinomyces, Capnocytophaga, Fuso-
bacterium, Veillonella and Streptococcus genera and lower levels of Por-
phyromonas, Filifactor, Eubacterium, Synergistetes, Tannerella and Trepo-
nema genera compared with non-diabetic subjects. Additionally, some
phylotypes, including Fusobacterium nucleatum (F. nucleatum), Veillo-
nella parvula, V. dispar and Eikenella corrodens (E. corrodens), were found
more often in diabetic subjects than non-diabetic subjects [65].
In addition, periodontitis-associated bacteria increase the difficulty
of glycemic control. The lipopolysaccharide (LPS) produced by P. gin-
givalis (a major periodontitis pathogen) could mediate insulin resistance
and impair insulin activity through stimulating the production of some
inflammatory cytokines [66]. Additionally, bacterial infections can re-
duce insulin-mediated glucose uptake of skeletal muscle and lead to
whole-body insulin resistance [67]. Furthermore, the antimicrobial
treatment in periodontal pockets is effective to improve glycemic con-
trol in diabetics, possibly through decreasing serum level of TNF-α and
alleviated insulin resistance [68,69].
4.5.2. Cardiovascular diseases
Microbial infection is an important risk factor for cardiovascular
diseases, which has been linked to periodontal pathogens [70]. The
study by Koren et al. showed that the abundance of Veillonella and
Streptococcus in atherosclerotic plaques was associated with their
abundance in the oral cavity [71]. Some oral microbes, including P.
gingivalis, Aggregatibacter actinomycetemcomitans (A. actinomycetemco-
mitans), T. forsythia, E. corrodens, F. nucleatum, and Campylobacter rectus
were detected in atherosclerotic plaques [72,73]. Chiu reported that P.
gingivalis and S. sanguinis were present in unstable atherosclerotic pla-
ques [74]. Similarly, Ohki et al. detected A. actinomycetemcomitans, P.
gingivalis, and T. denticola in the thrombi of patients with acute myo-
cardial infarction by PCR, which indicated that oral microbiota might
be involved in plaque inflammation and instability [67]. Interestingly,
Y. Zhang et al.
some oral microbes are correlated with markers of cardiovascular dis-
eases. Streptococcus was strongly positively correlated with HDL cho-
lesterol and ApoAI (a major component of HDL), whereas Neisseria was
strongly negatively correlated with these markers. Fusobacterium
abundance was positively correlated with LDL cholesterol and total
cholesterol [71].
Several possible mechanisms have been suggested to explain the
relationship between periodontitis and cardiovascular diseases. In
general, the host response to prolonged exposure to periodontal pa-
thogens is a major factor [66]. The microorganism accesses the circu-
latory system through oral tissue and makes its way to the arteries
where it secretes LPS and inflammatory mediators, resulting in cardi-
ovascular complications, such as vascular endothelial injury, platelet
aggregation, smooth muscle proliferation and lipid deposition [5,75].
4.5.3. Tumors of distant organs
The oral microbes are also involved in the tumors of other organ
[76]. The up-regulation of cytokines and other inflammatory mediators
caused by oral microorganisms may be involved in the immune-related
mechanisms of cancer development [77]. Shiga et al. reported that
Streptococus anginosus (S. anginosus) infection might be implicated in the
occurrence and development of head and neck squamous cell carci-
noma [78]. Narikiyo et al. examined the saliva with a culture-in-
dependent molecular method and found that the oral periodontopathic
spirochete T. denticola, S. mitis, and S. anginosus were associated with
esophageal cancer [79]. Furthermore, the proportions of Neisseria
elongata and S. mitis were significantly distinct between the patients
with pancreatic cancer and healthy controls [80]. There are also data
indicating that oral streptococci may be associated with colon cancer
[81].
5. Oral microbiota modulation
In view of the role of oral microorganisms in the causation and
pathogenesis of oral and systemic diseases, it is crucial to improve oral
protection against pathogens and maintain the dynamic equilibrium of
the oral microecology. Understanding the interactions between the
microbial communities is a key to combating oral pathogens. A po-
tential pathogen might be excluded if adhesion receptors are unavail-
able and if suitable partner bacteria are not present for metabolic co-
operation, either in nutrient utilization or environmental management.
The co-existence of certain group of organisms confers a more virulence
and a higher risk for the development of oral and systemic diseases
[82,83]. On the other hand, some specific microorganism such as P.
gingivalis, define as a keystone pathogen, can change the environment to
alter proportions of other microorganisms within the ecological niche
[84].
5.1. Mechanical debridement
Current therapy is primarily geared towards reducing the number of
pathogenic microorganisms by mechanical methods. Self-performed
plaque removal, such as brushing teeth, could improve the level of
plaque control [85]. Professionally performed plaque removal, in-
cluding scaling, root planning and periodontal surgery, could reduce
the number and proportions of pathogenic bacteria and reestablish the
ecological balance of oral microbiota. Generally, the microorganisms
associated with pockets deeper than 4 mm are reduced to very low or
even undetectable levels after periodontal treatment. Periodontal pa-
thogens, such as P. gingivalis, Tannerella forsythensis (T. forsythensis), T.
denticola and Treponema socranskii, were also markedly diminished in
patients with periodontitis after mechanical debridement [86]. How-
ever, the complexity of the tooth anatomy and the limitations of the
operating area present challenges and difficulty for removing plaque
thoroughly. Mechanical means are non-specific so that beneficial bac-
teria are also removed. More importantly, the microbial richness and
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Biomedicine & Pharmacotherapy 99 (2018) 883–893
biodiversity are significantly decreased after mechanical debridement
[87], which is adverse to oral health in some senses.
5.2. Antibiotic use
Antibiotics are designed to target specific pathogenic bacteria in
animals and humans [88]. The indications for the use of antibiotics in
dentistry are limited because most oral diseases are best managed by
operative intervention and oral hygiene measures [89]. Local antibiotic
use is usually preferred to systemic administration in dentistry because
of a dramatically increased and sustained drug concentration in the
crevicular fluid, as well as a reduction of systemic undesirable side
effects [90]. Antibiotics are used as adjuncts to mechanical therapy to
treat periodontitis, particularly in cases of conventional treatment
failure and more aggressive diseases [90]. When manual treatments are
complemented with the use of local and systemic antibiotics, the oral
cavity suffers from a shift in composition and abundance of various
bacteria. Winkel et al. reported that the amoxicillin/metronidazole
group following scaling and root planning displayed significantly im-
proved periodontal parameters and reduced the levels of P. gingivalis, P.
intermedia and T. forsythensis [91]. Haffajee et al. studied the effect of
periodontal therapy on the composition of the subgingival microbiota
and found that all species of the red complex, and nine of 12 orange
complex species, were significantly reduced in the subjects receiving
systemically administered antibiotics at 12 months [92]. However, it
should be noted that antibiotic use in dental practice is characterized by
empirical prescription based on clinical and bacteriological epidemio-
logical factors, resulting in the use of a very narrow range of broad-
spectrum antibiotics for a short period. This procedure has led to the
development of antimicrobial resistance in a wide range of microbes
and to the consequent inefficacy of commonly used antibiotics [89,93].
It was reported that the number of amoxicillin-resistant oral bacteria
was significantly higher in young children with amoxicillin use than
that of children without [94]. Effective use of antibiotics may require
genomic analysis of the patient’s oral microbiome to identify the pre-
sent microbes and to determine whether they will respond to specific
treatments [75].
5.3. Probiotics and prebiotics
To overcome these limitations of traditional intervention methods,
new strategies have been developed, such as probiotics and prebiotics.
Probiotics are well-known in health promotion and have been studied
extensively. The term “probiotics” has been defined by the International
Scientific Association as “live microorganisms when administered in
adequate amounts, confer a health benefit on the host” [95]. The me-
chanism of action of probiotics in the mouth is presumed to be similar
to those observed in other parts of the body [96]. Probiotic organisms
are thought to act mainly through these paths: competition with po-
tential pathogens for nutrients or adhesion sites, killing or inhibition of
growth of pathogens through production of bacteriocins or other pro-
ducts, improvement of intestinal barrier integrity and upregulation of
mucin production, modulation of cell proliferation and apoptosis, and
stimulation and modulation of the mucosal immune system [96,97].
However, there are specific characteristics of probiotics in the oral
cavity. Oral probiotics should be able to stick to and colonize oral tissue
including hard, non-shedding surfaces and become a part of the biofilm
[96,98]. Additionally, they should not ferment sugars; otherwise, they
will decrease pH and develop caries [96].
Probiotic methods have been studied to treat caries mainly by in-
terfering with the oral colonization of cariogenic pathogens. Näse et al.
were the first to test L. rhamnosus GG for caries-inhibiting ability in vivo
and found fewer dental caries and lower S. mutans counts in the test
group [99]. In addition to L. rhamnosus, Bifidobacterium [100], Lacto-
bacillus reuteri [101], B. animalis [102], L. paracasei [103] and Lacto-
bacillus casei [104] have been verified to be able to decrease the number
Y. Zhang et al.
of cariogenic bacteria and thus prevent dental caries. In contrast, some
of the bacteria mentioned above displayed no significant impact on the
microbial profiles or the levels of caries-associated bacteria in some
studies [105–109]. Lexner et al. indicated that a short-term daily intake
of milk supplemented with L. rhamnosus LB21 did not significantly af-
fect the microbial profiles in saliva and supragingival plaque samples
collected from caries-active adolescents [105]. In another study, Bifi-
dobacterium animalis (B. animalis) administered in yogurt could not
reduce the levels of salivary S. mutans and Lactobacilli in children [108].
Similarly, it was found that daily oral administration of L.reuteri did not
seem to reduce the levels or delay the regrowth of salivary S. mutans
[106,107]. There are multiple possible reasons for discrepant results
among these studies. Firstly, the duration of probiotic therapy, the time
of follow-up, dose and the way of application (mono versus mixed
species therapy) are different. Secondly, most studies restricted to mi-
crobiological endpoints rather than caries endpoints. The presence or
levels of S. mutans in plaque and saliva as an indicator of a cariogenic
environment, but an instantaneous drop in the number of S. mutans may
not necessarily be associated with either less caries or even a reduced
caries risk [110]. Thirdly, more strain-specific analytic methods should
be employed to evaluate the number of the non-probiotic or probiotic
before and after the treatment. A recent meta-analysis of 50 rando-
mized, controlled trials demonstrated that current evidence is in-
sufficient for recommending probiotics for managing dental caries
[111]. Therefore, further studies are needed to evaluate the efficacy and
safety of probiotics for caries. The recent randomized, controlled clin-
ical studies that investigated the effect of probiotics on dental caries are
summarized in Table 1.
A growing number of studies support probiotic therapy to prevent
or treat gingivitis and periodontitis. Krasse et al. reported that the
consumption of L. reuteri-containing chewing gum could decrease gum
bleeding and reduce gingivitis [112]. L. reuteri was further evaluated by
Iniesta et al. in a case of gingivitis, and they found a reduction in the P.
gingivalis count in the subgingival microbiota but no impact on gingi-
vitis parameters [113]. For periodontitis, L. reuteri could decrease gin-
gival index, plaque index, probing pocket depth and clinical attachment
level and reduce the levels of periodontal pathogens (A. actinomyce-
temcomitans, P. intermedia and P. gingivalis) [114–116]. Similar results
were obtained for assessing the effects of L. brevis on aggressive peri-
odontitis [117]. In addition, L. casei, L. rhamnosus, L. salivarius and some
Bacillus species have also been evaluated as probiotics for periodontal
diseases, some of which have achieved improvement in periodontal
conditions [118–122]. Table 2 presents recent randomized controlled
clinical studies that investigated the effect of probiotics on periodontal
diseases.
Prebiotics are poorly digested oligosaccharides and have been de-
monstrated to be an aid to complement probiotics in the treatment of
oral diseases [97]. Prebiotics could stimulate the growth and activity of
beneficial bacteria and simultaneously inhibit the growth and activity
of potentially detrimental bacteria [97]. They could also improve the
mucosal barrier function, host immunity and enhance the production of
short-chain fatty acid [123]. Lactose, Inulin, Fructo oligosacccharides,
Galacto oligosaccharides and Xylo oligosaccharides are some common
prebiotics widely used in gut, while the studies on prebiotics used in
oral cavity are extremely limited [124]. Sugars and dietary fiber, which
are considered to be prebiotics for intestinal lactic acid bacteria, are not
suited for the oral environment. Some potential oral prebiotics such as
xylitol xylose, and arabinose could suppress the growth of Strepto-
coccus mutans, but were also utilized for the growth of some lactoba-
cilli strains [125]. Given the lack of some perfect oral prebiotics, there
are more and more studies attempting to identify new prebiotics
[125,126]. Some oral microorganisms, such as L. gasseri, L.salivarius,
L.fermentum and bifidobacteria were more prevalent in healthy oral
ecosystem [127]. Thus, a prebiotic approach assumed to promote the
growth of these microorganisms may also promote periodontal health.
Probiotics and prebiotics could be better strategies to prevent and
890
Biomedicine & Pharmacotherapy 99 (2018) 883–893
cure bacterial diseases because they can reestablish an ecological bal-
ance or regain the biodiversity of oral microbiota in its early stages
[75]. However, it is important to understand the interactions between
the oral microbiome and probiotics, as well as the exact mode of action
of oral probiotics. Furthermore, studies are needed to investigate the
efficacy and safety of probiotics in dentistry [96,111].
5.4. Other modulation methods
In addition to the above methods, some other strategies have been
investigated for oral microbiota modulation. Avirulent S. mutans pro-
duced by genetic engineering has been investigated in vitro and con-
sidered for use to control dental caries [128]. In a recent study, Ren
et al. described a compound that targets glucosyltransferases, the major
virulence factor of S. mutans, and could inhibit biofilm formation and
the cariogenicity of S. mutans in vitro and in vivo [129]. A bacter-
iophage or phage is a virus that specifically targets and destroys dis-
ease-causing bacteria by invading bacterial cells, disrupting their me-
tabolism and causing lysis [128]. The use of phages to control acid-
producing bacteria, such as Lactobacillus acidophilus (L. acidophilus), to
combat the development of dental caries has been proposed [130]. It
also has been shown that phages against Enterococcus faecalis led to a
substantial reduction in bacterial viability in infected root canals
[128,131]. Moreover, many targeted delivery systems have been de-
signed and developed to treat oral diseases, such as fibers, strips, films
and nanoparticles [132–134].The modulation of oral microbiota,
combined with these novel drugs delivery methods, will be a very
promising opportunity for treating oral diseases more efficiently.
6. Conclusions
Collectively, the oral microbial ecosystem plays an essential role in
maintaining human health. The altered oral microbiota may be in-
timately associated with both oral and systemic diseases. However,
knowledge of the role of oral microbiota in the occurrence and devel-
opment of disease is far from complete. Future research precisely
identifying the key oral microbiota in health and disease will contribute
to better development of effective tools for oral microbiota modulation.
Many emerging strategies for modulation of oral microbiota have been
explored and developed. Even so, more studies are called for to in-
vestigate the efficacy and safety of these methods.
Conflict of interest
There are no conflicts of interest.
Acknowledgements
This study was supported by the National Natural Science
Foundation Project (No. 81570982), the International Cooperation
Research and Develop Project of Nanjing Health Bureau (No.
201605083), the program B for Outstanding PhD candidate of Nanjing
University (201702B086), the Project of Invigorating Health Care
through Science, Technology and Education, Jiangsu Provincial
Medical Innovation Team (No. CXTDB2017014).
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