Sampaio Maia2016

CHAPTER FOUR
The Oral Microbiome in Health

and Its Implication in Oral and
Systemic Diseases
B. Sampaio-Maia*, 1, I.M. Caldas*, x, {, M.L. Pereira*,
D. Pérez-Mongiovix and R. Araujo*, jj
*Universidade do Porto, Portugal
x
Institute of Research and Advanced Training in Health Sciences and Technologies, University Institute of
Health Sciences (IUCS), CESPU, CRL, Gandra, Portugal
{
Universidade de Coimbra, Portugal
jj
Flinders University, Adelaide, SA, Australia
1
Corresponding author: E-mail: mbsmaia@gmail.com
Contents
1. Introduction 172
2. The Oral Microbiome in Health 173
2.1 Bacteria Oral Colonization 177
2.2 Archaea Oral Colonization 181
2.3 Fungal Oral Colonization 181
2.4 Protozoa Oral Colonization 183
2.5 Viral Oral Colonization 184
3. The Oral Microbiome and Oral Pathology 185
3.1 Dental Caries 185
3.2 Endodontic Infections 187
3.3 Periodontal Diseases 189
3.4 Oral Cancer 191
4. The Oral Microbiome and Systemic Pathology 193
4.1 Nonoral Infectious Diseases 193
4.2 Adverse Pregnancy Outcomes 195
4.3 Cardiovascular Disease 196
4.4 Diabetes 197
5. Conclusions 197
References 198
Abstract
The oral microbiome can alter the balance between health and disease, locally and sys-
temically. Within the oral cavity, bacteria, archaea, fungi, protozoa, and viruses may all
be found, each having a particular role, but strongly interacting with each other and
with the host, in sickness or in health. A description on how colonization occurs and
Advances in Applied Microbiology, Volume 97
© 2016 Elsevier Inc.
j
ISSN 0065-2164
http://dx.doi.org/10.1016/bs.aambs.2016.08.002 All rights reserved. 171
172 B. Sampaio-Maia et al.
how the oral microbiome dynamically evolves throughout the host’s life is given. In this
chapter the authors also address oral and nonoral conditions in which oral microorgan-
isms may play a role in the etiology and progression, presenting the up-to-date
knowledge on oral dysbiosis as well as the known underlying pathophysiologic
mechanisms involving oral microorganisms in each condition. In oral pathology, oral
microorganisms are associated with several diseases, namely dental caries, periodontal
diseases, endodontic infections, and also oral cancer. In systemic diseases, nonoral
infections, adverse pregnancy outcomes, cardiovascular diseases, and diabetes are
among the most prevalent pathologies linked with oral cavity microorganisms. The
knowledge on how colonization occurs, how oral microbiome coevolves with the
host, and how oral microorganisms interact with each other may be a key factor to
understand diseases etiology and progression.
1. INTRODUCTION
The oral cavity is the entry portal of the gastrointestinal tract, and the
microorganisms residing in it are essential components in altering the balance
between health and disease, not only locally but also systemically. Within
the oral cavity, bacteria, archaea, fungi, protozoa, and viruses may be found,
each having a particular role, but strongly interacting with each other and
with the host, in sickness or in health. Fungi interact with bacteria, exoge-
nous, or indigenous viruses interact with bacteria and with the host, and mi-
crobes are preyed upon by protozoa (Nobbs & Jenkinson, 2015). These
different taxonomic groups have coevolved to assemble the modern human
oral ecosystem.
The genetic analysis of microbial communities available within oral (and
other samples) without recurring to cultivation can be performed by next
generation sequencing (NGS) or community metagenomics. The term
“metagenomics” was initially used for description of functional and com-
plete analysis of microbial genomes contained in the samples, but later on
started to be employed as well in the context of studies focused on the
amplification of certain genes of interest (Oulas et al., 2015). NGS allows
the characterization of microbial communities by responding to queries of
who is in the sample and description of organism lineages (such as taxonomic
family and genera), what microbes are doing (performing functional compo-
sition analysis), and how the microbes interact on the oral cavity (Dewhirst
et al., 2010; Duran-Pinedo & Frias-Lopez, 2015; Oulas, et al., 2015).
Presently, NGS technology still shows limitations for description of low
taxonomic levels, presenting most results at phylum, class and family levels,
Oral Microbiome in Health and Disease 173
in some cases genus level and in very rare case at species level. In particular
scenarios, either respecting to human or environmental samples, the infor-
mation regarding low taxonomic levels can be important (Sampaio-Maia,
Sim~ oes-Silva, Pestana, Araujo, & Soares-Silva, 2016; Zaura, Nicu, Krom,
& Keijser, 2014). Nevertheless, the amount of information coming from
NGS technology is huge, and recurrently many of the reported sequences
do not match with the existing information available at the databases.
Therefore, it was established the operational taxonomic unit (OTU) for
definition and classification of closely related sequences obtained following
amplification of specific genes, such as 16S (profiling bacterial communities)
or internal transcribed spacer (profiling fungal communities); OTUs are
frequently obtained by clustering the sequences according to their similarity.
Metagenomics have been used to study and clarify specific metabolic
pathways during oral diseases and evaluate population changes associated
with infections in oral cavity (Duran-Pinedo & Frias-Lopez, 2015).
The analyses of the supragingival and subgingival calculus samples from
the teeth of prehistoric European human skeletons dating from before the
Mesolithic period (before farming) to the Medieval period denote that
oral cavity has long served as a reservoir for microbes and that the transition
from hunter gatherer to farming shifted the oral microbial community to a
less diverse microbiota, which might be contributing to chronic oral and
systemic disease in postindustrial lifestyles (Adler et al., 2013). Today, we
know that oral microbiomes can give helpful information on personal health
status and be associated with nutritional deficiencies and several chronic and
acute diseases.
Here in, we present an updated overview about the “normal” oral
microbiome, i.e., what constitutes microbial communities in health, and
describe what changes happen in oral diseases, namely in dental caries, end-
odontic infections, and periodontal disease. Also, an insight on how oral
microbiome may contribute to oral cancer is given. Furthermore, we address
the role of oral microbiome in systemic diseases, such as infection, diabetes,
cardiovascular disease as well as in adverse pregnancy outcomes (APOs).
2. THE ORAL MICROBIOME IN HEALTH

The oral cavity harbors hundreds of microbial species, presenting
complex and intricate relationships between themselves and with the host.
In a healthy adult, the oral microbiome may include bacteria, archaea, fungi,
protozoa, and viruses. Although the scientific community is beginning to

recognize that the acquisition process of the different species integrating
the “normal” and beneficial microbiome is an essential process for oral
health, it is still not fully clear how and when it occurs and how is regulated
(Zaura et al., 2014).
The primary question to be answered is, when was oral microbiome first
acquired? Although the medical community assumes that, in normal condi-
tions, intrauterine fetal development occurs in an aseptic environment, there
is clinical evidence of microbial colonization of the amniotic fluid, placenta,
umbilical cord blood, and meconium in infection-free full-term pregnancies
(Aagaard et al., 2014; Bearfield, Davenport, Sivapathasundaram, & Allaker,
2002; Jimenez et al., 2005, 2008; Stout et al., 2013). Interestingly, this intra-
uterine microbiome is more similar to the mother’s oral microbiome, usually
from the tongue and tonsils, than to the gut or skin microbiome (Aagaard
et al., 2014). The role of this intrauterine microbiome is still to be unraveled.
Zaura et al. (2014) proposed that during pregnancy, the placenta might
become an antigen-collecting site for the fetal immune system to be
“trained” in antigen tolerance, allowing a postnatal successful acquisition
of maternal microbiome. However, it is still unknown if the infant is born
with viable microorganisms within oral cavity acquired in intrauterine
environment.
Although the concept of “healthy” intrauterine colonization of the fetus
is recent, the association between periodontal disease of the mother and the
increased risk for preterm birth and low birth weight babies is known for
long time (Offenbacher et al., 1996). This issue will be discussed
under Section 2.
During birth, the first massive transmission of microorganisms to the
newborn occurs. Immediately after birth (less than 5 min), the newborn is
colonized in the different body habitats by bacterial communities very
similar to each other: the oral cavity, the nasopharyngeal cavity, the skin,
and the gut (Dominguez-Bello et al., 2010). The delivery mode, eutocic,
or dystocic may affect the type of microorganisms that the new born is first
exposed to Sampaio-Maia and Monteiro-Silva (2014). Infants born by
vaginal birth have bacterial communities similar to the mother’s vaginal
bacterial communities, predominantly Lactobacillus, Prevotella, and Sneathia
spp., while infants born by caesarean section (C-section) have bacterial
communities similar to those present in the mother’s skin, predominantly
Staphylococcus, Corynebacterium, and Propionibacterium spp (Dominguez-Bello
et al., 2010). Consequently, the delivery mode will affect the oral
microbiome of the infant; at 3 months of age, vaginally born children

showed higher taxonomic diversity than caesarean born children (Lif
Holgerson, Harnevik, Hernell, Tanner, & Johansson, 2011). Similar results
were found for gut microbiota (Backhed et al., 2015). Also, compared with
the vaginally delivered infants, the gut microbiota of infants delivered by
C-section resembles less to their mothers (Backhed et al., 2015).
After birth, the newborn comes in contact with a wide variety of mi-
croorganisms. Studies focused on phenotypic and genotypic characteristics
of oral microorganisms suggest that the mother’s oral microbiota represents
the most important source of infants’ and young children’s oral microbiota
(Klein, Florio, Pereira, Hofling, & Goncalves, 2004; Li, Ismail, Ge, Tellez,
& Sohn, 2007; Tanner et al., 2003). The proposed mechanism of the
development of fetal tolerance toward the maternal microbiome during
pregnancy may be the basis of this successful vertical transmission (Zaura
et al., 2014). Fungi were also found to be prone to vertical transmission,
namely the transmission of mother’s vaginal Candida albicans to approxi-
mately 80% of vaginally delivered newborns (Blaschke-Hellmessen,
1998; Filippidi et al., 2014).
Moreover, recent studies have shown that breast milk has a specific
microbiome that varies throughout lactation (Jeurink et al., 2013). The
milk core microbiome is thought to include the following nine genera:
Streptococcus, Staphylococcus, Serratia, Pseudomonas, Corynebacteria, Ralstonia,
Propionibacterium, Sphingomonas, and Bradyrhizobiaceae (Hunt et al., 2011).
Naturally, breastfeeding may also represent a significant source of oral mi-
croorganisms. In agreement, very high abundance of Streptococcus spp. in
both breast milk and infant saliva was found on motherechild pair (Dave
et al., 2016). Also, it was shown that the saliva microbiota differs between
breast-fed and formula-fed 3-month-old infants (Holgerson et al., 2013).
The differences found may be associated with species suppression by lacto-
bacilli indigenous to breast milk given that isolates of Lactobacillus plantarum,
Lactobacillus gasseri, and Lactobacillus vaginalis inhibited the growth of Strepto-
coccus mutans and Streptococcus sanguinis. Interestingly, a meta-analysis of cross-
sectional studies showed that breast-fed children were less affected by dental
caries than bottle-fed children, suggesting that breastfeeding can protect
against dental caries in early childhood (Avila, Pordeus, Paiva, & Martins,
2015).
Soon after birth, the process of permanent colonization of the oral cavity
begins by the adherence of the pioneer microorganisms to oral surfaces. The
pioneer microorganisms’ growth alters the environment through the
production and excretion of metabolic products, which often potentiate the

growth of other species. The production of extracellular polymers from
sucrose is an example of molecules to which other bacteria can adhere.
This process of microbial succession and increasing diversity will result in
the eventual formation of a complex and more stable microbial community
in adulthood (Sampaio-Maia & Monteiro-Silva, 2014; Zaura et al., 2014).
Thus, the early oral microbiome dictates the composition of the long-
term stable adult oral microbiome (Dave et al., 2016; Zaura et al., 2014).
The structural, metabolic, and chemical interactions between microorgan-
isms play an important role in maintaining community homeostasis by sup-
porting the critical proportions of these species in a health-compatible
microbiome (Kumar & Mason, 2015). It is thought that a more diverse
community is a more healthy community that can better respond to changes
in the environment. Conversely, microbial diversity is decreased in case of
disease (Zaura et al., 2014).
Horizontal transmission, between brothers and/or colleagues, may also
contribute to increase the oral microbiome diversity (Domejean et al.,
2010; Kohler, Lundberg, Birkhed, & Papapanou, 2003). This may be partic-
ularly relevant in children in a day care centers, contacting daily with other
children. The study of Mattos-Graner, Li, Caufield, Duncan, and Smith
(2001) showed that 29% of children aged between 12 and 30 months
attending to day care centers had two or more corresponding genotypes of
S. mutans. It is interesting to note that these children present lower maternal
S. mutans genotypes in comparison to children staying with their mothers (Li,
Wang, & Caufield, 2000; Tedjosasongko & Kozai, 2002).
In addition to the microbial route of transmission, host genetic factors may
also influence the proportion of species in genetically related individuals. In
twins, it was demonstrated that the oral microbiota is more alike than in
nonrelated persons (Corby et al., 2007; Lee et al., 2016). Despite these
intrafamiliar similarities, the oral microbiota is unique for each individual
and differs significantly from his parents and siblings from early age (Crielaard
et al., 2011). Oral microbiome appears to present a good intraindividual
stability and similarity over time (Lazarevic, Whiteson, Hernandez, Francois,
& Schrenzel, 2010; Monteiro-da-Silva, Araujo, & Sampaio-Maia, 2014; Sato
et al., 2015) and, equally important, consistent interindividual variability
(Nasidze, Li, Quinque, Tang, & Stoneking, 2009; Zaura, Keijser, Huse, &
Crielaard, 2009). These findings support the possibility of using the oral
microbiota as an individualizing factor (Leake, Pagni, Falquet, Taroni, &
Greub, 2016).
Behavioral changes (oral hygiene, smoking, and diet), systemic health

disturbances, and the inclusion of biomaterials in the oral milieu (such as
orthodontic appliances, dentures, or implants) may also induce oral micro-
biome alterations (Areias et al., 2012; Claro-Pereira et al., 2011; Gomes,
Sampaio-Maia, Vasconcelos, Fonesca, & Figueiral, 2015; Monteiro-da-
Silva, Sampaio-Maia, Pereira Mde, & Araujo, 2013; Pereira-Lopes et al.,
2013; Sampaio-Maia & Monteiro-Silva, 2014), priming a dynamic status
to oral microbiome throughout lifetime.
The exact number of species that constitute the oral microbiome is still
unknown, and most certainly, it varies among individuals. So far, more than
2000 different microbial taxa have been detected in the human oral cavity
(Keijser et al., 2008; Nobbs & Jenkinson, 2015). Recent studies evaluating
the oral microbiome using NGS have shown that most oral microorganisms
are uncultivable and that oral microbiome is much more diverse than previ-
ously thought (Huttenhower et al., 2012; Ling et al., 2010; Nasidze et al.,
2009; Zaura et al., 2009). With the advent of NGS technologies, namely
by the analysis of the sequences of conserved housekeeping genes directly
isolated from samples of saliva or oral biofilms, it was unravel the global
composition of human oral microbiome (Huttenhower et al., 2012;
Wade, 2013). In the following sections, it will be characterized the oral
microbiome regarding the different taxonomical groups: bacteria, archaea,
fungi, protozoa, and virus.
2.1 Bacteria Oral Colonization

Bacteria represent the most studied and the most abundant taxonomic group
of oral microbiota. As previously mentioned the process of permanent colo-
nization of the oral cavity begins in the postpartum period. At this stage, the
most frequent colonizers of the oral cavity are Gram-positive cocci, namely
Streptococcus (Bagg, Macfarlane, Poxton, & Smith, 2006; Hegde & Munshi,
1998). Around 5 months of age, the infant’s oral microbiota differs from
maternal microbiota and consists mostly of bacteria belonging to Firmicutes,
Proteobacteria, Actinobacteria, Bacteroidetes, Fusobacteria, and Spiro-
chaetes phyla, being the most prevalent genera Streptococcus, Haemophilus,
Neisseria, and Veillonella (Cephas et al., 2011). The eruption of the first teeth
and the development of gingival crevices allows anaerobic microorganisms
to become part of the healthy oral ecology (Krom, Kidwai, & Ten Cate,
2014). It is important to note that, at this phase, infants present a greater mi-
crobial diversity but a lower microbial load than their parents (Cephas et al.,
2011). As the infant grows, the microbial communities are influenced by
natural changes of the oral habitat, as the change from the deciduous to the
permanent dentition, as well as by food ingestion, contact with other adults
and children, interaction with domestic animals, hygiene habits, and among
others (Cephas et al., 2011; Jiang et al., 2015). Thus, it is expected that the
oral microbial communities differ between childhood and adulthood.
It is thought that after the establishment of the permanent dentition, a
more stable microbiome is acquired and that persists into adulthood (Kumar
& Mason, 2015; Teles, Teles, Frias-Lopez, Paster, & Haffajee, 2013). As
mentioned previously, several factors may, however, affect this oral micro-
biome such as behavioral changes, systemic health disturbances, and oral
biomaterials (Areias et al., 2012; Claro-Pereira et al., 2011; Gomes et al.,
2015; Monteiro-da-Silva et al., 2013; Pereira-Lopes et al., 2013;
Sampaio-Maia & Monteiro-Silva, 2014).
The oral microbiota was found to be one of the most complex micro-
biome in terms of species richness of the human body (Huttenhower
et al., 2012) as well as the most stable microbiota with the highest alpha
diversity (Zhou et al., 2013). There is evidence for a core oral bacteriome,
i.e., the vast majority of humans present the same group of microorganisms
in the oral cavity. In the light of NGS, this core oral microbiome is repre-
sented by “core taxa,” “common taxa,” or “shared OTUs” among humans
and may play an important role in oral microbial ecosystem and be essential
in the balance of health and disease (Jiang et al., 2015). The major phyla,
including the most abundant bacterial species, comprise Firmicutes, Bacter-
oidetes, Proteobacteria, Actinobacteria, and Fusobacteria, being Streptococcus
the most prevalent genus within oral environment (Cephas et al., 2011;
Jiang et al., 2015; Lazarevic et al., 2010; Li, Bihan, & Methe, 2013; Xin
et al., 2013). Despite such commonalities, oral microbiome is individual spe-
cific presenting an individual profile, especially in low taxonomic groups,
such as species or lower levels.
Although oral microbiome is often studied as a whole, the oral cavity
comprises different habitats presenting divergent anatomic and physiologic
characteristics and differing in relation to oxygen tension, nutrient availabil-
ity, temperature, and host immunological factors exposure (Gizani et al.,
2009; Tanner et al., 2002). The Human Microbiome Project (HMP)
assessed bacteriome through NGS of 16S rRNA gene from buccal mucosa,
hard palate, keratinized gingiva, palatine tonsils, saliva, subgingival and
supragingival plaque, throat, and tongue dorsum from over 200 healthy in-
dividuals (Li et al., 2013). Fig. 1 depicts the high abundance core genera in
>75% samples at >10% abundance (in bold), and other major core genera in
Figure 1 The oral core bacteriome. Based in report from Li et al. (2013) from over 200
healthy individuals participating in HMP were included the genera present in >80%
samples at >1% abundance found in each oral habitat (in bold are high abundance
core genera in >75% samples at >10% abundance). Uncl., unclassified. Figure was
produced using Servier Medical Art, http://www.servier.com/Powerpoint-image-bank.
>80% samples at >1% abundance found in each oral habitat. Within these 9
oral habitats, 13 (tongue dorsum) to 19 (hard palate) bacteria phyla were
described, including 185 (tongue dorsum) to 322 (throat) genera (Zhou
et al., 2013). In comparison to the oral mucosa and saliva, teeth and tongue
present higher microbial load (Gizani et al., 2009). The Human Oral
Microbiome Database (HOMD, www.homd.org) collected 16S rRNA

gene sequences from oral microorganisms into a curated phylogeny-based
database. Currently, the HOMD includes 687 taxa in 14 phyla (plus one
Archaea phylum), as follows: Actinobacteria, Bacteroidetes, Chlamydiae,
Chlorobi, Chloroflexi, Firmicutes, Fusobacteria, Gracilibacteria (GN02),
Proteobacteria, Saccharibacteria (TM7), Spirochaetes, SR1, Synergistetes,
and WPS-2.
In the oral cavity, bacteria are organized in biofilm-structured commu-
nities, presenting highly organized stratified three-dimensionally assemblies
(Welch, Rossetti, Rieken, Dewhirst, & Borisy, 2016). The microbial com-
munities in the biofilm present a strong microbial interplay, with either
agonistic or antagonistic characteristics, leading to the regulation, matura-
tion, and remodeling of the biofilm. Within biofilm, bacteria interacts by
the process of quorum sensing, through the production of small chemical
signals, monitoring population density, and regulating gene expression
(Nobbs & Jenkinson, 2015). To further explore this intricate interplay
between oral microorganisms, we suggest the reading of the recent paper
of Nobbs and Jenkinson (2015).
Oral biofilms are present in all oral surfaces, but the biofilm of dental
surfaces is much more relevant due to the fact that all other oral surfaces
are covered in epithelial cell layers that are frequently shed. Dental plaque
was one of the first environments to be studied microscopically by
Leeuwenhoek, almost 350 years ago (Lamont, Burne, Lantz, & LeBlanc,
2006). Dental plaque is built upon an ecological succession that initiates
with the attachment of the early colonizers (mostly Streptococcus spp.) to
the saliva-coated tooth enamel. These attached microbes then serve as
receptors for other microorganisms that cannot bind directly to host surfaces.
Many studies suggested Fusobacterium nucleatum as a bridging organism due to
its capacity to bind physically to both early and late colonizers of the dental
plaque (Kolenbrander et al., 2006). A recent study linking spectral imaging
fluorescence in situ hybridization to metagenomic sequence analysis sug-
gested a new biogeography of supragingival dental plaque, consisting of a
radially arranged, nine-taxon structure organized around cells of filamentous
Corynebacterium (Welch et al., 2016). The nine taxa include Streptococcus,
Actinomyces, Haemophilus/Aggregatibacter, Porphyromonas, Neisseriaceae, Fuso-
bacterium, Leptotrichia, Capnocytophaga, and Corynebacterium. A more detailed
description about the micron scale distribution of these key elements in
the supragingival dental plaque may be consulted in the work of Welch
et al. (2016).
A study of 120 individuals from 12 worldwide locations found no signif-

icant geographical differences between their salivary microbiota, suggesting
that local diet and environment do not significantly influence the composi-
tion of the oral microbiome (Nasidze et al., 2009). However, this result
needs to be confirmed by other studies.
2.2 Archaea Oral Colonization

Archaea, also part of prokaryotic world, have long been ignored in medical
microbiology, and the knowledge about the relationship between this spe-
cific taxonomic group and the human host is still scarce. However, it is
recognized that archaea are rare and in low numbers within the human
host (Horz, 2015).
Within the oral microbiome, archaea represent a small minority, being
restricted to a small number of methanogens phylotypes (strict anaerobes
that produce methane), namely, Methanobrevibacter oralis, Methanobacterium
curvum/congolese and Methanosarcina mazeii (Lepp et al., 2004; Matarazzo,
Ribeiro, Feres, Faveri, & Mayer, 2011). Although the relationship between
archaea and the human host is still not fully understood, methanogens may
play a role in the establishment of mucosal diseases by favoring the growth of
certain bacterial groups (Matarazzo et al., 2012). Due to their metabolic
characteristics, methanogenic archaea were mainly detected in the highly
anoxic environment of subgingival biofilm (Faveri et al., 2009). In agree-
ment, archaea can be detected in healthy individuals, but its prevalence
seems to increase in subjects with periodontitis and endodontic infections
(Lepp et al., 2004; Vianna, Conrads, Gomes, & Horz, 2006). Archaea can
also be detected in ancient dental calculus and may play an important role
in the understanding of past human health and diet (Huynh, Verneau,
Levasseur, Drancourt, & Aboudharam, 2016).
2.3 Fungal Oral Colonization

Fungi represent a small minority but may play a significant role within the
oral microbiome. Although very few studies evaluate the acquisition and
maturation of the oral mycobiome as well as fungi interaction with the other
microbial players within oral cavity, it is known that bacteria and fungi
present relevant physical, chemical, and metabolic interactions that are
essential for the establishment and maintenance of a healthy oral ecology
(Krom et al., 2014).
Until recently, the only fungi group recognized as part of the normal
oral microbial population were species belonging to the genus Candida
(Scully, el-Kabir, & Samaranayake, 1994). With the improvement of the

detection technologies, other fungi were also detected in the oral environ-
ment. Although Candida genus remained the most prevalent yeast in these
studies, filamentous fungi were also detected in a very high percentage of
individuals, including Cladosporium, Aureobasidium, Saccharomycetales, Fusa-
rium, Cryptococcus, and Aspergillus among other genera (Ghannoum et al.,
2010; Monteiro-da-Silva et al., 2014, 2013). Interestingly, the individual
profile of fungal colonization was maintained over a 6-month period
(Monteiro-da-Silva et al., 2014), suggesting that at least a part of these fungi
population belongs to the group of permanent colonizers and not to the
group of oral transient microbiota.
In respect to oral fungi acquisition, few studies evaluate Candida genus
transmission suggesting that Candida spp. may be acquired by the infant
through vertical transmission from the mother’s vagina during birth
(Blaschke-Hellmessen, 1998; Filippidi et al., 2014; Payne et al., 2016), but
also acquired by nosocomial colonization or colonized objects, such as
pacifiers (Payne et al., 2016). Although during the first year of life the rate
of oral Candida colonization of the infant may vary between 40% and
82% (Kleinegger, Lockhart, Vargas, & Soll, 1996; Lay & Russel, 1977;
Odds, 1988), in older children the frequency of colonization decreases to
values ranging between 3% and 36% (Odds, 1988). These variations in
the frequency of oral Candida colonization in children may be due to
physiological factors related to age, namely the immune maturation, as
well as other factors such as environmental changes (hospital vs. home)
and diet alterations (breastfeeding vs. formula feeding) (Hannula et al.,
1999; Kadir, Uygun, & Akyuz, 2005; Kleinegger et al., 1996; van Wyk &
Steenkamp, 2011). After infancy, the prevalence of oral Candida coloniza-
tion gradually increases, being the highest in the elderly and denture wearers
(Kraneveld et al., 2012). In healthy adults, oral Candida prevalence varies
significantly in different studies, ranging from 15% up to 97% (Brambilla,
Strohmenger, & Vogel, 1992; Ghannoum et al., 2010; Hannula et al.,
1999; Kraneveld et al., 2012; Monteiro-da-Silva et al., 2014, 2013; Odds,
1988). The differences in oral Candida prevalence found among different
studies may be related to the methodology used, varying from low-sensitive
traditional culture method using selective media to high-sensitive molecular
biology approach.
Although being a forgotten player of the oral ecosystem, C. albicans is
known to adhere to oral bacteria (and vice-versa) but also to the oral
mucosa. This characteristic is not common within oral bacteria, where
most are coadhered (attached to immobilized bacteria) or coaggregated

(attached to bacteria in suspension) (Williams et al., 2013). Thus, C. albicans
might serve as a bridge between the mucosa and bacteria that normally do
not adhere to mucosal surfaces, as for example S. mutans (Krom et al.,
2014). As reviewed by Krom et al. (2014), this symbiotic mechanism may
favor bacteria in several ways: (1) avoid removal by salivary flow and swal-
lowing; (2) acquire a less susceptible profile to antibiotic treatment; and (3)
partial protection against antimicrobials delivered by dentifrices. Another
interaction described between bacteria and C. albicans is via quorum-sensing
molecules. The competence-stimulating peptide, an autoinducer peptide
required for competency and subsequent genetic transformation of strepto-
cocci, is secreted by S. mutans and is able to inhibit the transformation of
C. albicans from yeast to filamentous form (hyphae production) (Jarosz,
Deng, van der Mei, Crielaard, & Krom, 2009; Pereira-Cenci et al., 2008).
On the other hand, glucosyltransferase, produced and secreted by S. mutans,
may promote its adherence to C. albicans and the development of cospecies
biofilm (Hwang, Marsh, Gao, Waugh, & Koo, 2015). Also, C. albicans is able
to metabolize nonfermentable lactate, and thus, like Veillonella spp., can
build symbiotic interactions with lactate producing bacteria, such as
S. mutans (Krom et al., 2014). Other interkingdom interactions are reported,
for example, a symbiotic relationship with S. gordonii and Staphylococcus
aureus (Bamford et al., 2009; Schlecht et al., 2015). Taken together, these
examples illustrate that fungi may present the potential capacities to modu-
late the oral microbiome. In agreement is the study of Kraneveld et al.
(2012) showing that with the increase of oral Candida load, the salivary
microbiome diversity decreased and the composition changed
toward dominance by Bacilli (streptococci and lactobacilli) and disappear-
ance of genera within class Fusobacteria and Bacteroidia.
2.4 Protozoa Oral Colonization

In comparison to the other microbial groups colonizing the oral cavity,
protozoa represent a very small minority.
The most frequent human oral protozoa include Entamoeba gingivalis,
followed by Trichomonas tenax (Wantland & Lauer, 1970). These protozoa
are usually nonpathogenic commensals, and normally their number increases
with poor oral hygiene given that both food debris and bacteria are
nutritional sources for these protozoa (Wade, 2013). Also, the oral coloni-
zation by both E. gingivalis and T. tenax is associated with the severity of
periodontal disease (Bergquist, 2009; Bonner et al., 2014; Feki, Molet,
Haag, & Kremer, 1981; Ghabanchi, Zibaei, Afkar, & Sarbazie, 2010;
Kurnatowska, Dudko, & Kurnatowski, 2004; Pomes et al., 2000; Wantland
& Lauer, 1970).
Rarely, Leishmania sp., a flagellate protozoan, can indirectly severely
affect the human oral cavity by causing partial or total destruction of mucous
membranes (Bergquist, 2009).
2.5 Viral Oral Colonization

The human virome is highly complex, and its role on health and disease
status still needs to be clarified. Pride, Salzman, Haynes, et al. (2012) have
revealed few insights on oral virome describing a persistent community of
double-stranded DNA viruses in the saliva of healthy individuals. A large
group of the oral viruses are in fact bacteria predators. These bacteriophages
might be relevant for the regulation of microbial diversity and simulta-
neously work as reservoirs of pathogenic gene function in the human oral
environment (Pride, Salzman, Haynes, et al., 2012). Putative viruses of
Veillonella, Streptococcus, and Megasphaera were recently described and showed
how bacteria can interact and be modulated by communities of viruses
(Pride, Salzman, Haynes, et al., 2012; Pride, Salzman, & Relman, 2012).
The phage ecology and biodiversity in the subgingival crevice of healthy
subjects was also studied and compared with the communities found in
patients with moderate/severe periodontitis. Saliva and oral biofilm samples
collected in a cohort of individuals could reflect the disease status and degree
of periodontal disease based on the differences observed on the viral (bacte-
riophages) communities (Ly et al., 2014). The study concluded that viruses
could be grouped according to the tested subject, the biogeographic site, and
the oral site where the sample was collected. Interestingly, this last informa-
tion could not be obtained when bacterial communities were compared. In
addition, oral viruses could be significantly associated with the human host
sex due to host factors, such as hormones, that play a crucial role on viral
ecology and its development (Abeles et al., 2014).
Despite the current awareness of oral virome, it is known for long time
that viruses are associated with human disease and that the oral cavity is a
common route for viral entry in the human body (Andries et al., 2015;
Balique, Colson, & Raoult, 2012; Turner et al., 2011). Infections in the
oral cavity caused by virus are relatively rare. Herpes simplex virus-1 is often
acquired early in life, when the primary infection is usually subclinical, but
may take the clinical form of primary herpetic gingivostomatitis
(Kolokotronis & Doumas, 2006). Both viruses Herpes Simplex 1 or 2
agents are involved in aphthous stomatitis, although this disorder is often of

unknown etiology (Lin et al., 2005). Other virus were also reported in saliva,
oral swabs, and/or sputum samples obtained from infected patients, namely,
cytomegalovirus, enteroviruses (in particular coxsackie A e B virus), other
herpesviruses (such as varicella-zoster, EpsteineBarr and human herpes virus
6), tobacco mosaic virus (in smokers), hepatitis A, B, and C, HIV, human
papillomavirus, influenza, measles, mumps, polyomavirus, rabies, rhinovi-
ruses, rubella, dengue, and ebola virus (Corstjens, Abrams, & Malamud,
2016). Viruses may also play a role in periodontal disease, in particular
human herpes virus, human cytomegalovirus, and EpsteineBarr virus
(Nobbs & Jenkinson, 2015; Slots, 2007).
3. THE ORAL MICROBIOME AND ORAL PATHOLOGY

Oral microbiome plays an important role in the balance between
health and disease in oral cavity. Oral health appears to be associated with
a more diverse microbial community that can better respond to changes
in the environment (Krom et al., 2014). In this view, each microbial player
should have its own role in the oral ecosystem regulation and in the symbi-
otic relationship between the oral microbiome and the host.
Oral diseases of microbial origin are associated with a reduced microbial
diversity and an oral dysbiosis, i.e., an imbalance oral microbiome. Howev-
er, as critically stated by Krom et al. (2014), it is unclear whether disease is
caused by loss of diversity or whether the specific niche in pathologic tissue
represents a very selective environment resulting in a less diverse microbial
ecology.
In the following chapter, the role of oral microbiome in the most com-
mon oral infectious diseases, such as dental caries, endodontic infections, and
periodontal diseases, will be addressed. Also, the role of oral microbiome will
be explored in the development of oral cancer that currently represents the
sixth most common human cancer.
3.1 Dental Caries

Following the World Health Organization 60e90% of school children and
nearly 100% of adults worldwide have dental caries (WHO, 2012).
Although the pathophysiological mechanisms of dental caries are already
well studied and understood, there is still much to learn about the microor-
ganisms involved. The dental biofilm supports a microsystem of bacteria and
other microorganisms that have a wide variety of physiological characteris-

tics. Foremost among these is the ability to produce acid resulting from the
metabolism of carbohydrates, which leads to pH drop, responsible for the
demineralization of the tooth surface, and the consequent formation of
caries lesions (Duran-Pinedo & Frias-Lopez, 2015; Takahashi & Nyvad,
2008). In 2002, Kleinberg described the “Ecological Hypothesis” of dental
caries, which suggests that the cariogenic activity is based on the proportion
of bacteria acid or alkaline producing. According to this hypothesis, dental
caries result from changes in the natural balance of the microbiota, due to
local environmental conditions variations. For example, the increased
consumption of fermentable carbohydrates can lead to changes in biofilms
environment, such as pH reduction, which consequently induces a change
in the composition of the biofilm, favoring acidogenic and aciduric species.
Thus, knowing the aciduric and acidogenic properties of bacteria colonizing
the oral cavity may be a very relevant factor. According to the majority of
studies, S. mutans is the main responsible for dental caries, since it is often
isolated from cavities (Cephas et al., 2011; Hamada & Slade, 1980; Loesche,
1986; Takahashi & Nyvad, 2008). Yet, more recent studies stated that the
relationship between S. mutans and dental caries is not absolute, since large
amounts of S. mutans may persist on dental surfaces without causing dental
caries, which can also develop in the absence of these bacterial species (Aas
et al., 2008; Bowden, 1997). Thus, it has been suggested that other acido-
genic and aciduric microorganisms may also be responsible for the formation
of caries, as members of the genera Bifidobacterium, Propionibacterium, and
Scardovia (Takahashi & Nyvad, 2008; Tanner et al., 2011). Genomic analysis
studies have reinforced this hypothesis, demonstrating that the microbiota
associated with white enamel lesions is much more diverse than was previ-
ously thought, including species such as Actinomyces gerencseriae, Actinomyces
naeslundii, and Actinomyces israelii, as well as several species of nonemutans
streptococci, Veillonela spp., and Candida spp. (Aas et al., 2008; Becker
et al., 2002; de Carvalho, Silva, Hebling, Spolidorio, & Spolidorio, 2006;
Cephas et al., 2011; Gross et al., 2010; Ling et al., 2010; Nikawa et al.,
2003; Takahashi & Nyvad, 2008). Interesting, coinfection with S. mutans
and C. albicans resulted in enhanced development of carious lesions over
and above those caused by S. mutans alone (Falsetta et al., 2014).
In sum, since most of microorganisms associated with tooth decay
belong to normal oral microbiota, dental caries has been described as an
endogenous infection, which occurs when some members of the
commensal microbiota acquire a selective advantage over other species
by changing the homeostatic balance of the biofilm (Gross et al., 2010;

Takahashi & Nyvad, 2008).
Early childhood caries (ECC), defined as dental caries affecting children
with 71 months of age or younger, is a multifactorial disease (American
Academy on Pediatric Dentistry, 2008). Cariogenic bacteria are the major
factor, but other factors such as oral hygiene and eating habits may also be
very important for disease etiology and progression (Leong, Gussy, Barrow,
de Silva-Sanigorski, & Waters, 2013). Studies evaluating the microbiota
associated with ECC found the genera Streptococcus, Veillonella, Actinomyces,
Propionibacterium, Granulicatella, Leptotrichia, Thiomonas, Bifidobacterium, and
Atopobium, suggesting that there is not a single pathogen, but instead a
pathogenic population that correlates with the development of ECC
(Sampaio-Maia & Monteiro-Silva, 2014). Of foremost importance, the
environmental shift leading to dental caries is promoted by the acidogenic
and aciduric potential of the microorganism, meaning that the phenotype
adopted in a particular environment may be more relevant than the geno-
type (Aas et al., 2008; Kanasi et al., 2010; Li, Ge, Saxena, & Caufield,
2007; Ling et al., 2010; Sampaio-Maia & Monteiro-Silva, 2014).
As discussed previously, maternal oral microbiome may represent the
most important source of infants’ and young children’s oral microbiota
(Klein et al., 2004; Li, Ismail, et al., 2007; Tanner et al., 2003), probable
due to the development of fetal tolerance toward the maternal microbiome
during pregnancy (Zaura et al., 2014). So, the vertical transmission of cari-
ogenic bacteria may represent a risk factor for ECC. In agreement, studies
aimed to reduce maternal load of the cariogenic species S. mutans during
pregnancy demonstrated that the bacteria acquisition in the infants was
also reduced (Brambilla et al., 1998) or delayed (Nakai et al., 2010). Also,
a systematic review and meta-analysis of Avila et al. (2015) revealed that
breastfeeding can protect against dental caries in early childhood. Although
many behavioral habits may contribute to the link between bottle feeding
and ECC, the role of milk microbiome on oral health protection cannot
be excluded from this association.
3.2 Endodontic Infections

Endodontic infections refer to those that occur within the tooth pulp, root
canal system, or at the root apex (Lamont & Jenkinson, 2010). The microbial
etiology of primary endodontic infection is unique and depends on the
presence or absence of a communication channel between the endodontic
environment and the microbial source, mostly the oral cavity but also, as
suggested by some studies, the blood (i.e., the transient blood microor-
ganism) (Lamont & Jenkinson, 2010). The most frequent primary endodon-
tic infections are secondary to dental caries or traumatic pulp exposure.
Secondary endodontic infections are the ones that persist after treatment,
such as failed root canals treatments (Yun et al., 2016). Apical periodontitis
may result from the deeper evolution of microorganisms and their by-prod-
ucts into the root canal (Yun et al., 2016).
The microbiota present in primary endodontic infections may vary
depending on the oxygen tension, availability of metabolites, and renewal
of the biofilm via continuous recolonization through open communications
with the oral cavity associated with the sinus tract, full depth periodontal
pocket, and a history of trauma (Narayanan & Vaishnavi, 2010; Niazi
et al., 2016).
Primary infections have been found to include 391 bacterial taxa
belonging to 82 genera and 9 phyla (Siqueira & Rocas, 2009). In persistent
secondary infections, it is though that a more diverse bacterial community
profile is present (Tzanetakis et al., 2015), although this is not consensual
(Hong et al., 2013).
Enterococcus faecalis was frequently isolated from early-root canal infec-
tions. But, due to the introduction of molecular methods, currently is
known that E. faecalis is not the major pathogen, and other 50 to 60 taxa
are found associated with endodontic infections (Lamont & Jenkinson,
2010). The endodontic microbiome appears to vary considerable among
studies an even within each study (George et al., 2016; Rocas et al., 2016;
Yun et al., 2016). Thus, endodontic infections may not have a specific
microbiome, and the etiologic agents may be correlated with the micro-
biome of the infections source that, as described previously, may vary
considerable. Notwithstanding, the most common identified endodontic
bacteria may belong to the phyla Firmicutes, Bacteroidetes, Actinobacteria,
Fusobacteria, Proteobacteria, Spirochaetes, and Synergistes (Jhajharia,
Parolia, Shetty, & Mehta, 2015; Saito et al., 2006). In teeth with apical
abscesses, anaerobic bacteria such as Fusobacterium species are commonly
dominant (George et al., 2016; Yun et al., 2016).
In addition to bacteria, other microorganisms can be found in endodon-
tic infections. Methanogenic archaea were also associated to inflamed pulp
tissues and their participation in the endodontic infection development
has been suggested (Efenberger, Agier, Pawlowska, & Brzezinska-Blaszczyk,
2015). Fungi have often been found in the root canals of teeth in which end-
odontic treatment has failed and occasionally in primary root canal
infections. The fungal species most commonly isolated from infected root
canals is C. albicans probably due to its invasive affinity to dentin (Siqueira
& Sen, 2004).
3.3 Periodontal Diseases

Periodontal diseases are oral polymicrobial diseases caused by the
coordinated action of a complex microbial community, which results in
inflammation and destruction of the periodontium in susceptible hosts
(Yost, Duran-Pinedo, Teles, Krishnan, & Frias-Lopez, 2015). They
comprise a variety of conditions affecting the periodontium, being gingivitis
and periodontitis the most common (Duran-Pinedo & Frias-Lopez, 2015).
Gingivitis is characterized by the presence of gingival inflammation
without detectable loss of bone or clinical attachment (Alrayyes & Hart,
2011). The microorganisms involved are common constituents of the
commensal oral microbiota. Among these, we highlight Actinomyces species,
which compose much of the supragingival and subgingival plaque micro-
biota, Prevotella intermedia, Bacteroides species, and F. nucleatum, all present
both in healthy individuals and in those with periodontal disease (Bagg
et al., 2006). The contradiction of these microorganisms being present in
both health and disease periodontal tissues questions the rationality of the
theoretical underpinnings of the etiology of periodontitis, which invites
for alternative ways of thinking about periodontitis, as well as other oral
diseases (Pozhitkov et al., 2015).
The microbiota of healthy gingival sulcus is mainly composed of Gram-
positive cocci, especially Streptococcus species. The gingival sulcus has a redox
potential lower than most of the other oral habitats, and the plaque accumu-
lation determines a faster reduction of the available oxygen, enhancing the
growth of Actinomyces species and other capnophilic bacteria such as
Aggregatibacter actinomycetemcomitans (Rudiger, Carlen, Meurman, Kari, &
Olsson, 2002). Toxins released by these bacteria can induce an inflammatory
response in the gingival tissue, with consequent increase in the crevicular
fluid flow. This high flow of crevicular fluid will provide a nutrition-rich
environment essential to induce a shift in gingival sulcus microbiota over
time, leading to the growth of anaerobic bacteria such as Porphyromonas
gingivalis, P. intermedia, and spirochetes. With these changes, the gingival
inflammatory reaction progresses, causing a chronic marginal gingivitis
(Bagg et al., 2006; Rudiger et al., 2002).
Periodontitis is distinguished from gingivitis by the destruction of peri-
odontal tissues, including alveolar bone, with the consequent formation of
periodontal pockets. Periodontitis can be classified into two main classesd

chronic and aggressivedwith the latter being characterized by increased
severity and high rate of progression. It is generally accepted that periodon-
titis results from the interaction between a microbial challenge originated
from the subgingival biofilms and a deregulated host response in the peri-
odontal tissues (Curtis, Zenobia, & Darveau, 2011). It usually occurs in sites
colonized by an extensive number and variety of bacterial species (Dewhirst
et al., 2010). However, the precise role of dental plaque in periodontal dis-
ease is unclear, and several hypotheses to explain the role of microorganisms
in this pathology have emerged (Bagg et al., 2006; Loesche & Grossman,
2001).
The “specific plaque hypothesis” states that only a few species of micro-
organisms, mainly Gram-negative anaerobes, are responsible for periodontal
disease (Loesche, 1992; Loesche & Grossman, 2001). These microorganisms
do not act alone but rather associated in microbial complexes. In 1998,
Socransky, Haffajee, Cugini, Smith, and Kent stated that the complexes
most commonly associated with periodontal disease were the orange
complex, consisting of P. intermedia, Prevotella nigrescens, Peptostreptococcus
micros, and F. nucleatum, and the red complex, consisting of P. gingivalis,
Tannerella forsythia, and Treponema denticola. Meanwhile, some of these
periodontal pathogens begin to take on an increasingly important position;
recently, P. gingivalis and F. nucleatum have been associated with complex
codependent mechanisms of diverse systemic chronic diseases risk and path-
ogenesis (Atanasova & Yilmaz, 2015).
Conversely, the “nonespecific plaque hypothesis” refers that all the
bacteria have the virulence factors necessary to cause the destruction of
periodontal tissues, jointly; and even some microorganisms considered
nonpathogenic play a role. In this manner, plaque will cause disease regard-
less of its composition (Loesche & Grossman, 2001). Another hypothesis, the
“ecological plaque hypothesis,” suggests that the environmental conditions
within the periodontal pocket are responsible for the expression of microbial
virulence factors and/or the proliferation of microorganisms already present,
but in reduced numbers (Marsh, 2003). So, it would be the environmental
changes that induce the shift of the microbiota that, in turn, would predis-
pose the site for the disease. This theory helps to explain the activity of
periodontal disease, as favorable ecological conditions in a specific location
would promote the growth of periopathogenic bacteria over other
nonpathogenic microorganisms. In turn, these microorganisms would
produce virulence factors sufficient to overwhelm host defenses during a
given period, resulting in a period of periodontal destruction. This hypoth-

esis suggests that any microorganism with relevant growth and survival char-
acteristics in the periodontal environment may contribute to periodontal
disease, if it presents enough aggressive virulence factors (Bagg et al.,
2006; Kleinberg, 2002; Marsh, 2003; Wade, 2013). Recently, Yost et al.
(2015) identified metabolic changes in the microbial community associated
with the initial stages of dysbiosis, stating that regardless of the overall
composition of the community, certain metabolic signatures are consistent
with disease progression, for example, iron transport and protein secretion
activities. These authors’ results suggest that the whole community is
responsible for an increase in virulence that leads to progression.
Regardless of the hypothesis adopted, all studies agree that there is a pro-
gressive shift in microbiota composition between different stages: clinically
healthy gingiva, gingivitis, and periodontitis.
A curiosity is the fact that stress is a known risk factor for periodontal dis-
ease and some oral periopathogens such as Eikenella and Campylobacter are
especially stimulated by catecholamines (Roberts et al., 2002, 2005).
But not only bacteria are associated to periodontal diseases. The presence
of methanogenic archaea, fungi, protozoa, and virus has been correlated
with periodontitis (Bonner et al., 2014; Lepp et al., 2004; McManus
et al., 2012; Slots, 2007; Vianna et al., 2006). Methanogenic archaea, due
to its metabolic characteristics, growth in the highly anoxic environment
of subgingival biofilm, coexisting with a microbiota formed by saccharolytic
bacteria such as Capnocytophaga sp., Eubacterium nodatum, and Streptococcus con-
stellatus, and proteolytic bacteria such as P. gingivalis and T. forsythia (Faveri
et al., 2009). Thus, archaea may play a role as terminal degraders of host
components, favoring a continuous catabolic cascade within periodontal dis-
ease (Faveri et al., 2009; Matarazzo et al., 2012). The protozoa E. gingivalis
and C. albicans found in periodontal pockets have also been correlated with
periodontitis (Bonner et al., 2014; McManus et al., 2012). Viruses may also
play a role in periodontal disease, in particular human herpes virus, human
cytomegalovirus, and EpsteineBarr virus (Slots, 2007). Synergism between
specific periodontal pathogens (P. gingivalis, Prevotella spp., T. denticola, A.
actinomycetemcomitans) and herpesviruses might therefore contribute to
increased aggressiveness in disease pathogenesis (Nobbs & Jenkinson, 2015).
3.4 Oral Cancer

Another condition that must be considered when addressing the micro-
biome role in oral health is cancer. Oral cancer prevalence is rising, being
nowadays the sixth most prevalent form of cancer (Chocolatewala,

Chaturvedi, & Desale, 2010). The vast majority of oral cancers are linked
with smoking habits and alcohol consumption (Johnson, 2001). However,
15% of oral cancer patients have none of these risk factors (Chocolatewala
et al., 2010), and some authors have suggested other etiological factors,
namely genetic susceptibility, external agents, and viral infections
(Chocolatewala et al., 2010). Recently, there has been increasing evidence
suggesting the role of bacteria in oral cancer. As a matter of fact, poor oral
hygiene has been stated to potentiate the risk of oral cancer and propagation
to adjacent tissues, if microbes gain access to blood circulation or spread
locally. For example, studies in patients with tooth loss or periodontal disease
indicate an increased risk of developing tongue, gastrointestinal, or pancre-
atic cancer (Meurman, 2010; Yu et al., 2014). Moreover, several authors
described oral dysbiosis in patients with oral cancer, suggesting that some
species may be used as salivary markers for early detection of oral cancer
(Ahn, Chen, & Hayes, 2012; Hooper et al., 2007; Mager et al., 2005).
Besides, this high degree of bacterial specificity found in oral cancer may
also contribute for new prevention strategies, namely by vaccination.
There is also some evidence to support associations between both oral
fungal and viral organisms and cancer. As an example, human papillomavirus
16 infection is an established cause for the majority of oropharyngeal
squamous cell carcinomas (D’Souza et al., 2007).
Although the mechanisms underlying the link between oral microbiome
and carcinogenesis are still unknown, evidence is being gathered pointing
out to local activation of carcinogens by oral microbes. Alcohol and
smoking-related carcinogens are well-established risk factors for oral and
gastrointestinal cancer types. Oral bacteria have the capacity to convert
ethanol to acetaldehyde, which is a recognized human carcinogen (Ahn,
Chen, et al., 2012). Also, oral bacteria activate carcinogenic nitrosamines
from tobacco smoke (Ahn, Segers, & Hayes, 2012). Other proposed mech-
anism that associates oral microbiome and cancer development is the release
of proinflammatory mediators that can disturb cellular cycling, disrupt
signaling mechanisms, and act as tumor promoters (Meurman, 2010).
Besides oral cancer, oral microorganisms are being associated with
tumors in distant organs, namely gastrointestinal and pancreatic cancer
(Ahn, Chen, et al., 2012; Ahn, Segers, et al., 2012; Farrell et al., 2012;
Michaud & Izard, 2014). More recently, periodontal disease was associated
with increased risk of postmenopausal breast cancer, particularly among
former smokers who quit in the past 20 years (Freudenheim et al., 2016).
4. THE ORAL MICROBIOME AND SYSTEMIC

PATHOLOGY
The link between oral microbiome and systemic pathology is being
increasingly explored. Several mechanisms have been proposed, including
the spread of the oral infection due to transient bacteremia resulting in
bacterial colonization in extra-oral sites, systemic injury by free toxins of
oral pathogens, and systemic inflammation caused by soluble antigens of
oral pathogens (Han & Wang, 2013).
Oral microorganisms are capable of passing through oral mucous mem-
branes and periodontal pockets, spreading to different body sites and causing
systemic or focal infections. This may become a major concern when an
increased number of oral microorganisms and dysbiotic oral microbiome
exists, namely in the presence of oral infections. Nonoral infection and
APOs have been highlighted.
Also, oral pathogens may cause persistent systemic inflammation that
may be responsible for the worsening of severe systemic diseases such as
diabetes or cardiovascular disease. The successful treatment for periodontal
disease leads to reversal of systemic markers for these diseases and include
improved endothelial function (Tonetti et al., 2007), decrease in inflamma-
tory markers (Moura Foz et al., 2010; Tonetti et al., 2007), and improved
glycemic control in diabetics (Teeuw, Gerdes, & Loos, 2010), providing
strong evidence that periodontal disease is causally associated with these
systemic effects (Ahn, Chen et al., 2012).
Here, the most recent findings on the link between oral microbiome and
nonoral infectious diseases, APOs, cardiovascular diseases, and diabetes are
presented.
4.1 Nonoral Infectious Diseases

Oral microbiome may be a reservoir for opportunistic infections, not only in
oral cavity but also in distant body sites, especially in immune-compromised
hosts (Li, Kolltveit, Tronstad, & Olsen, 2000). As oral microorganisms are
able to go through oral mucous membranes and periodontal pockets to
the bloodstream, they can reach in minutes the heart, lungs, and peripheral
blood capillary system. This spreading of oral microorganisms to different
body locations is the first step to the eventual occurrence of systemic or focal
infections.
Naturally, this bacteremia implies the overtake of several protection
barriers of the oral system to allow for microbial penetration, namely, the
surface epithelium physical barrier; defensins, which are host-derived

peptide antibiotics; an electrical barrier that reflects the oxidation-reduction
potential (Eh) difference between the host cell and the microbial layer; an
immunological barrier of antibody-forming cells; and the reticuloendothe-
lial system (phagocyte barrier) (Li, Kolltveit, et al., 2000). Under normal
conditions, only a small number of microorganisms reache the bloodstream.
However, when oral mucosa trauma occurs, for example, during an invasive
dental procedure or in immunologic impaired hosts, oral microorganisms
can disseminate easily to distant locations of the human body. It is relevant
to underline that tooth brushing alone may itself disrupt a large surface area
of gingival crevicular tissue and promote bacteremia. Lockhart et al.
(2008) evaluated this process and have showed the persistence of pathogenic
species for at least 60 min after tooth brushing. Also, poor oral hygiene rises
significantly the number of oral bacteria and thus also increases the bacter-
emia prevalence and magnitude (Li, Kolltveit, et al., 2000).
The fact that bacteremia from oral origin could cause infective endocar-
ditis was suggested more than 100 years ago (Lockhart, 2012). Invasive
dental procedures, such as dental extractions, were thought to be major
factors for the development of oral bacteria-related infective endocarditis;
however, recent data suggest that poor oral hygiene and periodontal diseases
are more likely to be responsible for the vast majority of cases oral bacteria-
related infective endocarditis (Lockhart et al., 2008).
The oral cavity has also been considered a potential reservoir for
respiratory pathogens (Mojon, 2002). Aspiration of oral bacteria to the res-
piratory tract occurs daily; however, this may only be critical in the elderly,
immunocompromised, or artificial-ventilated patients. For example, tooth
brushing decreases the incidence of pneumonia and decreases mortality rates
in the elderly residing in nursing homes (Yoneyama et al., 2002). Also, oral
hygiene maintenance was suggested as an important preventive measure for
ventilator associated pneumonia (Ames, 2011). Corroborating these
reports are studies detecting oral bacteria by molecular methods in intraoper-
ative bronchial fluids of patients with pulmonary carcinoma (Hasegawa
et al., 2014), in the lungs of cystic fibrosis patients (Rogers et al., 2006) as
well as in healthy individuals (Bassis et al., 2015).
Many other reports are found in scientific literature suggesting an odon-
togenic etiology for nonoral infections (Corson, Postlethwaite, & Seymour,
2001; Li, Tronstad, & Olsen, 1999; Mills, Lofthouse, Roberts, & Karas,
2008), but most do not present a supportive genotypic analysis between
infection and oral isolates. Marques da Silva, Caugant, Josefsen, Tronstad,
and Olsen (2004) used a phenotypic and three genetic fingerprinting tech-
niques to strongly suggest that the origin of the S. constellatus responsible for a
brain abscess was the oral cavity, providing the link between oral micro-
biome as etiologic agents for nonoral infections.
4.2 Adverse Pregnancy Outcomes

As discussed previously in the chapter “Oral microbiome in health,” very
recent research introduced the novel concept of “healthy” intrauterine
colonization of the fetus (Aagaard et al., 2014; Bearfield et al., 2002;
Jimenez et al., 2005, 2008; Stout et al., 2013). However, the association
between periodontal disease of the mother and the increased risk for
preterm birth and low-birth-weight infants is known for long time
(Offenbacher et al., 1996).
APOs are a broad term including preterm labor, preterm premature
rupture of membranes, pre-eclampsia, miscarriage, intrauterine growth
retardation, low birth weight, stillbirth, and neonatal sepsis (Han &
Wang, 2013).
The most prevalent cultivable oral species in APOs is F. nucleatum, a
recognized periopathogen (Bearfield et al., 2002; Han & Wang, 2013).
F. nucleatum has been detected in a wide variety of placental and fetal tissues,
including amniotic fluid, fetal membranes, cord blood, neonatal gastric aspi-
rates, and fetal lung and stomach, associated with preterm birth, stillbirth,
and early-onset neonatal sepsis (Gonzales-Marin, Spratt, & Allaker, 2013;
Han et al., 2010, 2004; Han & Wang, 2013; Wang et al., 2013). Other peri-
odontal pathogenic microorganisms were also associated with APO, namely
P. gingivalis, P. intermedia, T. forsythia, and T. denticola, among others (Han &
Wang, 2013). The presence of periodontal pathogenic microorganisms or
their by-products in the intrauterine environment was suggested to stimulate
fetal immune and inflammatory response that may be responsible for the
increased risk for APO in pregnant women with periodontal diseases
(Offenbacher et al., 1996).
Given that an increasing number of studies report intrauterine infections
caused by bacterial species not found in the urogenital tract, such as oral
microorganisms, a hematogenous transmission has been proposed as alterna-
tive route of infection (Fardini, Chung, Dumm, Joshi, & Han, 2010; Han
et al., 2006, 2004; Han, Shen, Chung, Buhimschi, & Buhimschi, 2009).
In the pathophysiology of periodontal diseases, the increase of oral bacterial
load is accompanied by gingival inflammation and bleeding, leading to
bacteremia. These conditions may promote the hematogenous transmission
of oral microorganisms. In agreement, Fardini et al. (2010) demonstrated

that oral bacteria can translocate to the mouse placenta as a result of
bacteremia and that the placental translocation is species specific. The spec-
ificity of the species capable of translocate from oral cavity to intrauterine
environment is probably linked to the expression virulence mechanisms,
as explored by Han and Wang (2013) in their comprehensive review.
4.3 Cardiovascular Disease

Oral pathogens may also contribute for the development of noninfectious
systemic diseases. Numerous studies have suggested a higher risk of
developing a cardiovascular disease in individuals with periodontal disease
(Azarpazhooh & Tenenbaum, 2012; Kholy, Genco, & Van Dyke, 2015).
So far, the pathophysiological mechanisms proposed to tie oral microbiome
and cardiovascular disease are based on the “colonization” of atherosclerotic
plaques with oral microorganisms and systemic inflammation caused by oral
infections (Kholy et al., 2015).
Several studies reported oral microorganisms in atherosclerotic plaques,
including Streptococcus spp., Veillonella spp., P. gingivalis, A. actinomycetemcomi-
tans, T. denticola, F. nucleatum, T. forsythia, and Neisseria spp (Chiu, 1999;
Figuero et al., 2011; Ford et al., 2005; Koren et al., 2011; Libby, Ridker,
& Maseri, 2002; Ohki et al., 2012; Pucar et al., 2007). A recent study, using
16S rDNA sequencing, described 84 different bacterial taxa detected in
atheroma and vascular endothelia of patients with atherosclerotic vascular
disease and periodontal disease against only 18 different taxa detected in
patients with little or no periodontal disease (Armingohar, Jorgensen,
Kristoffersen, Abesha-Belay, & Olsen, 2014), reinforcing the suggestion of
“colonization” of atherosclerotic plaques with oral microorganisms. Thus,
the “colonization” of atherosclerotic plaques appears to have a role in plaque
inflammation and instability, contributing to endothelial dysfunction and
consequently to cardiovascular disease (He, Li, Cao, Xue, & Zhou, 2015).
Furthermore, there is evidence for two modes of invasion of the cardiovas-
cular tissues by periodontal pathogens, namely, bacteremia and phagocyte-
mediated bacterial translocation from the periodontal lesion to the vascular
tissues (Carrion et al., 2012; Kinane, Riggio, Walker, MacKenzie, &
Shearer, 2005).
Systemic inflammation caused by oral infections is other pathophysiolog-
ical mechanism proposed to contribute to the cardiovascular disease. Oral
infections, in particular periodontal diseases, are thought to indirectly induce
elevated production of inflammatory mediators in the systemic circulation,
and therefore, to accelerate atherosclerosis (Slocum, Kramer, & Genco,

2016). Corroborating this association, a recent study showed that both car-
diovascular and periodontal inflammations were reduced after lowering
inflammation in patients with statin therapy (Subramanian et al., 2013).
4.4 Diabetes
It is now becoming evident that oral microbiome dysbiosis is associated with
other systemic inflammatory diseases including diabetes (Ohlrich, Cullinan,
& Leichter, 2010). Although the biological mechanisms linking oral infec-
tions and diabetes are not fully understood, the epidemiological association
between periodontitis and diabetes is becoming relatively clear. Notwith-
standing, this seems to be a bidirectional relationship: on the one side, dia-
betes affects the subgingival environment and subsequently the subgingival
microbiome, and, on the other side, the host response to periodontal disease
may play a role in diabetes progression (Ohlrich et al., 2010).
In comparison with healthy controls, differences were found in subgin-
gival microbiome in patients with type I or II diabetes (Casarin et al., 2013;
Ebersole, Holt, Hansard, & Novak, 2008). The elevated glucose content in
subgingival microenvironment and the impaired immune system of the host
may justify these differences (Ficara, Levin, Grower, & Kramer, 1975;
Ohlrich et al., 2010). Also, diabetes induces alterations in the connective
tissue metabolism reducing the capacity of this tissue to remodel and thus
affecting the progression of periodontal disease (Willershausen-Zonnchen,
Lemmen, & Hamm, 1991). In addition, it has been proposed that the
inflamed periodontium may act as an endocrine-like source of inflammatory
mediators, which can subsequently increase insulin resistance (Preshaw,
Foster, & Taylor, 2007).
5. CONCLUSIONS
There is growing evidence showing that oral microbiome may affect
the balance between health and disease and is associated with several oral and
nonoral conditions/diseases. The investigation in this area is flourishing
and during the next years more factors related with the onset, progression,
and pathophysiology of the oral diseases will be revealed. Notwithstanding,
in this review, we highlight the up-to-date knowledge about the oral micro-
biome in health and its implication in oral and systemic diseases.
Within oral cavity, bacteria, archaea, fungi, protozoa, and viruses may all
be found, each having a particular role, but strongly interacting within each
other and with the host, in sickness or in health. The interaction of
microorganisms with the oral cavity may start even in the intrauterine
environment. The oral microbiome composition is dynamic evolving
throughout host’s life, changing during children’s growth or environmental
changes as well as responding or contributing to oral or systemic pathologies.
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CHAPTER FOUR

The Oral Microbiome in Health

2. THE ORAL MICROBIOME IN HEALTH

protozoa, and viruses. Although the scientiﬁc community is beginning to

microbiome of the infant; at 3 months of age, vaginally born children

production and excretion of metabolic products, which often potentiate the

Behavioral changes (oral hygiene, smoking, and diet), systemic health

2.1 Bacteria Oral Colonization

Microbiome Database (HOMD, www.homd.org) collected 16S rRNA

A study of 120 individuals from 12 worldwide locations found no signif-

2.2 Archaea Oral Colonization

2.3 Fungal Oral Colonization

(Scully, el-Kabir, & Samaranayake, 1994). With the improvement of the

most are coadhered (attached to immobilized bacteria) or coaggregated

2.4 Protozoa Oral Colonization

2.5 Viral Oral Colonization

agents are involved in aphthous stomatitis, although this disorder is often of

3. THE ORAL MICROBIOME AND ORAL PATHOLOGY

3.1 Dental Caries

other microorganisms that have a wide variety of physiological characteris-

by changing the homeostatic balance of the bioﬁlm (Gross et al., 2010;

3.2 Endodontic Infections

3.3 Periodontal Diseases

periodontal pockets. Periodontitis can be classiﬁed into two main classesd

given period, resulting in a period of periodontal destruction. This hypoth-

3.4 Oral Cancer

nowadays the sixth most prevalent form of cancer (Chocolatewala,

4. THE ORAL MICROBIOME AND SYSTEMIC

4.1 Nonoral Infectious Diseases

surface epithelium physical barrier; defensins, which are host-derived

4.2 Adverse Pregnancy Outcomes

of oral microorganisms. In agreement, Fardini et al. (2010) demonstrated

4.3 Cardiovascular Disease

and therefore, to accelerate atherosclerosis (Slocum, Kramer, & Genco,

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