Current Concepts in The Pathogenesis of Periodontitis: From Symbiosis To Dysbiosis

Journal of Oral Microbiology
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Current concepts in the pathogenesis of

periodontitis: from symbiosis to dysbiosis
Ali A. Abdulkareem, Firas B. Al-Taweel, Ali J.B. Al-Sharqi, Sarhang S. Gul, Aram
Sha & Iain L.C. Chapple
To cite this article: Ali A. Abdulkareem, Firas B. Al-Taweel, Ali J.B. Al-Sharqi, Sarhang
S. Gul, Aram Sha & Iain L.C. Chapple (2023) Current concepts in the pathogenesis of
periodontitis: from symbiosis to dysbiosis, Journal of Oral Microbiology, 15:1, 2197779, DOI:
10.1080/20002297.2023.2197779
To link to this article: https://doi.org/10.1080/20002297.2023.2197779
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JOURNAL OF ORAL MICROBIOLOGY
2023, VOL. 15, 2197779
https://doi.org/10.1080/20002297.2023.2197779
REVIEW ARTICLE
Current concepts in the pathogenesis of periodontitis: from symbiosis to

dysbiosis
a
Ali A. Abdulkareem , Firas B. Al-Taweela, Ali J.B. Al-Sharqia, Sarhang S. Gulb, Aram Shab and Iain L.
C. Chapplec
a
Department of Periodontics, College of Dentistry, University of Baghdad, Baghdad, Iraq; bCollege of Dentistry, University of Sulaimani,
Sulaimani, Iraq; cPeriodontal Research Group, Institute of Clinical Sciences, College of Medical & Dental Sciences, University of
Birmingham, Birmingham, UK
ABSTRACT ARTICLE HISTORY

The primary etiological agent for the initiation and progression of periodontal disease is the Received 3 June 2022
dental plaque biofilm which is an organized aggregation of microorganisms residing within Revised 8 December 2022
a complex intercellular matrix. The non-specific plaque hypothesis was the first attempt to Accepted 28 March 2023
explain the role of the dental biofilm in the pathogenesis of periodontal diseases. However, the KEYWORDS
introduction of sophisticated diagnostic and laboratory assays has led to the realisation that the Dental biofilm; symbiosis;
development of periodontitis requires more than a mere increase in the biomass of dental dysbiosis; inflammation;
plaque. Indeed, multispecies biofilms exhibit complex interactions between the bacteria and periodontal disease
the host. In addition, not all resident microorganisms within the biofilm are pathogenic, since
beneficial bacteria exist that serve to maintain a symbiotic relationship between the plaque
microbiome and the host’s immune-inflammatory response, preventing the emergence of
pathogenic microorganisms and the development of dysbiosis. This review aims to highlight
the development and structure of the dental plaque biofilm and to explore current literature on
the transition from a healthy (symbiotic) to a diseased (dysbiotic) biofilm in periodontitis and
the associated immune-inflammatory responses that drive periodontal tissue destruction and
form mechanistic pathways that impact other systemic non-communicable diseases.
Introduction periodontal diseases as approximately $154.06 billion in

the US and €158.64 billion in Europe [9].
Periodontal disease is a broad term used to encompass
The dental plaque biofilm, alongside other environ
diseases and conditions of the periodontal tissues. The two
mental, lifestyle and genetic risk factors, is the main
major forms induced by dental plaque biofilm accumula
etiological agent responsible for the development and
tion are gingivitis and periodontitis. Gingivitis is an
progression of periodontitis. However, since the late
inflammatory lesion that remains confined to the gingiva,
19th century, understanding of this concept has under
but which may, in susceptible people, progress to a more gone significant advancement, sometimes with conflict
severe and destructive form, periodontitis [1]]. A causal ing evidence. The specific plaque hypothesis (SPH)
relationship between periodontitis and systemic diseases emerged which attributed dental caries to specific bac
has not yet been robustly established, however studies teria in the dental plaque biofilm, mainly Streptococcus
indicate that periodontal pathogens and consequent mutans, S. sobrinus and lactobacilli [10]. The latter
immune-inflammatory responses to them are indepen bacteria were observed to be partly indigenous in nature
dently associated with the pathogenesis of several systemic and present in both health and disease, together with
diseases such as diabetes mellitus, atherosclerotic cardio the recognition of other bacteria as potential period
vascular diseases, chronic obstructive pulmonary diseases, ontal pathogens which underpinned the SPH. This led
Alzheimer’s, chronic kidney disease, rheumatoid arthritis researchers to propose the non-specific plaque hypoth
and certain cancers [2–5]. The ulcerated pocket epithe esis which stated that it was the sheer biomass quantity
lium provides a direct portal of vascular entry for period rather than specific microorganisms that were respon
ontal pathogens, e.g. Porphyromonas gingivalis, sible for the development of periodontitis [11]. In 1994,
Aggregatibacter actinomycetemcomitans, Tannerella for Marsh suggested that ecological stress was the driver for
sythia, Eikenella corrodens, and Fusobacterium nucleatum imbalance in the oral microbiota, encouraging the out
to the systemic circulation, which may directly or indir growth of pathogenic bacteria; this was known as the
ectly affect other organ systems [6–8]. A report issued in ecological plaque hypothesis (EPH) [12]. In the late
2018 estimated the economic burden arising due to 1990s, pioneering work by Socransky and co-workers
CONTACT Ali A. Abdulkareem ali.abbas@codental.uobaghdad.edu.iq College of Dentistry, University of Baghdad, Baghdad, Iraq
© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits
unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the
posting of the Accepted Manuscript in a repository by the author(s) or with their consent.
2 A. A. ABDULKAREEM ET AL.
categorized the periodontal bacteria according to their and electrostatic interactions [23,24]. The strength of
pathogenicity by assigning distinct color-codes to clus this attachment is increased with the formation of
ters that mapped to various states of health and disease extracellular polymeric matrix (EPM) [25,26]. In
[13]. This work, with the EPH, set the basis to the addition to the biofilm matrix, attachment of bac
keystone-pathogen hypothesis, proposed by teria within the biofilm is mediated by specialized
Hajishengallis and colleagues. This hypothesis appendages called fimbriae or pili that are composed
explained the shifting of the microbiome from of subunits called fimbrillins, possessing adhesins
a symbiotic one to a biofilm characterized by dysbiosis that selectively adhere to pellicle-coated teeth or to
induced and aggravated by low abundant ‘keystone other bacteria [27]. Fimbriae are common among
pathogens’. For example, P. gingivalis elicits an many bacterial species including Streptococci,
intense/destructive host immune response [14]. The Actinomyces and P. gingivalis [28–30]. Furthermore,
aim of this narrative review was to report the current fibrils also facilitate bacterial attachment; these
literature on the transition from a health-promoting to structures are shorter and different in morphology
a diseased-forming in periodontitis and the associated and distribution from fimbriae [31]. Fibrils can be
immune-inflammatory response. found in some oral bacteria such as Prevotella inter
media, P. nigrescens, and some Streptococcal strains
[28,29,32,33]. Moreover, motile Gram-negative bac
Formation and development of the dental teria can utilize force-generating motility as
plaque biofilm a mechanism for initial attachment to the tooth
Formation of acquired pellicle surface, which counteracts repulsion forces. This
active or ‘twitching motility’ is attributed to flagella
Colonisation of organisms within the dental biofilm and type IV pili, respectively [27]. Notably, other
should be preceded by the presence of a condensed surface proteins such as autolysin [34] and capsular
layer of macromolecules at the base of the biofilm polysaccharide [35] also play a role in the attach
known as the acquired pellicle (Figure 1) [15–17]. ment of bacteria to solid surfaces.
This layer was thought to be derived principally from
salivary glycoproteins; however, a recent study impli
cated an important contribution from gingival crevi Maturation of biofilm and coaggregation of
cular fluid (GCF) in the formation of this layer [18,19]. bacteria
Maturation of the dental plaque biofilm (Figure 1)
starts with the recognition by late colonizers
Adhesion of bacteria
including F. nucleatum, Treponema denticola,
Planktonic bacteria in the oral cavity attach to spe T. forsythia, P. gingivalis, P. intermedia and
cific pellicle-associated binding sites such as acidic A. actinomycetemcomitans of polysaccharide or
proline-rich proteins and α-amylase for attachment protein-binding sites on the cell surface of primary
of early colonizers (Figure 1) [20–22]. Adhesion of colonizers [36,37]. Consequently, the relative num
bacteria at this stage is mainly dependent upon weak ber of late colonizers in the dental plaque biofilm
bonds, e.g. Lifshitz-van der Waals, Lewis acid-base increases at the expense of primary colonizing
Figure 1. Biofilm formation and development in the oral cavity. a. acquired pellicle formation; b. initial attachment of early
colonizers; c. maturation of biofilm and coaggregation of bacteria; D. dispersion of bacteria.
JOURNAL OF ORAL MICROBIOLOGY 3
bacteria such as Streptococci and Neisseria [38,39]. (composed of Capnocytophaga species) were
The tendency of paired-aggregation has been strongly associated with periodontal health.
shown in 90% of dental biofilm-associated bacteria Yellow, green, and purple complexes are the primary
[40]. However, this coaggregation is not random, colonizers and considered as a prerequisite for the
and receptor sites of each bacterial species have appearance of the orange and red complexes (sec
specificity for complementary binding to the adhe ondary colonizers). Although this pattern of coag
sion molecules of certain bacteria. For instance, gregation was the most frequent (Figure 2), rarely,
coaggregation occurs between F. nucleatum and certain complexes could be detected in the absence
S. mutans; yet, the latter lack the ability to bind of other bacteria [41].
to P. gingivalis [23]. Additionally, coaggregation
bridges are another feature of certain bacterial spe
cies which possess different receptor sites capable
Dispersion of bacteria
of binding to two or more other bacterial species.
F. nucleatum is the most well-known example of With the increase in the mass and bacterial popula
a bridging species, which mediate coaggregation of tions of the dental biofilm, solitary bacteria or bacter
aerobic and strictly anaerobic bacteria [23]. ial clusters become detached and return to
Coaggregations of bacteria in a mature dental bio a planktonic state (Figure 1) [42]. There remains no
film exhibit unique patterns, e.g. ‘corn on the cob’ consensus about a single dispersal mechanism of
structures and ‘bristle brush formations’ [36,37]. bacteria; however, two mechanisms were proposed,
The work of Socransky et al. provided an in-depth namely active and passive dispersion [43–45]. Active
understanding of the biofilm-associated bacterial com dispersion is attributed to the bacteria themselves,
munities of the subgingival microbiota [13]. The bac while passive dispersal is provoked by external forces
teria were divided into five complexes (Figure 2) which such as shear forces from salivary flow, competition
received a unique color coding [41]. P. gingivalis, with other bacteria, and mechanical debridement
T. forsythia and T. denticola belong to the red complex [42]. In general, dispersion of bacteria occurs by
of pathogens and are mainly found in subjects with three mechanisms: erosion, sloughing and seeding
periodontitis. Additionally, the orange complex patho [46,47]. While erosion and sloughing may be active
gens, Fusobacterium, Prevotella, and Campylobacter or passive, seeding is an active process limited to
species, are often related to periodontitis. The other hollow cavities within the biofilm from which large
complexes such as the yellow complex (composed of numbers of solitary cells or bacterial masses are
different Streptococcus species) and green complex rapidly detached [48,49].
Figure 2. The association among subgingival species (adapted from Socransky et al. [13,27]). Presence of 40 subgingival species
and the association among them in subgingival dental biofilm samples (n = 13,321) were analysed using checkerboard DNA-
DNA hybridization and cluster analysis and community ordination techniques, respectively. The base of the pyramid represents
the early colonizers, followed by the orange complex, which bridges the early colonizers with the red complex that dominates
the biofilm at the advanced stages of periodontitis.
Structure of the dental biofilm Microbial virulence and metabolism

Biofilms are composed of microbial cells enclosed Virulence factors are those characteristics that allow
within EPM which is derived from inhabitant micro a microorganism to cause disease by evading or sub
biota and the host [50,51]. Molecular-based sequen verting the immune response and other host defence
cing studies revealed that about 700 species systems. Virulence factors generally comprise three
contribute to the bacterial component of dental pla essential functions necessary for bacterial surface colo
que biofilms [52]. The microorganisms within bio nization of host tissues/cells (Figure 4): evading host-
film are not haphazardly arranged but functionally defense mechanisms and initiating disease symptoms
and spatially organized [53]. The type of microbiota (toxins) [62].
and the load of bacterial species detected in the dental
biofilm varies according to their location or niche
[52,54]. The number of bacteria in the supragingival
Colonization of the host tissues/cells
biofilm on an individual tooth surface can exceed 109
cells. In a periodontal pocket, counts can range from Adherence
103 bacteria in a healthy crevice to >108 bacteria in As previously discussed, the adhesive properties of
a deep pocket [55,56] (Figure 3). fimbriae are integral to biofilm formation by mediat
Mature biofilms exhibit shared structural charac ing the coaggregation of different bacterial species
teristics such as microcolonies of bacterial cells and together and facilitating their attachment to the
water channels [57]. Furthermore, steep chemical hosts’ tissues [63]. For example, P. gingivalis-fimbriae
gradients exist within dental plaque biofilm. mediate aggregation with the surface protease of
Towards the deeper part of the biofilm, it has been T. denticola [64–66] and human glyceraldehyde-
reported that nutrients, O2 and pH are lower in 3-phosphate dehydrogenase, facilitating the invasion
concentration, whereas metabolic products are highly of this bacterium into the host cells [63,67].
prevalent [58–60]. The EPM of dental plaque biofilms
consists of inorganic and organic materials derived
from the host, mainly saliva, GCF and bacterial pro Biofilms
ducts [54]. The inorganic materials include mainly The EPM of the biofilm is mainly composed of
calcium and phosphate ions, as well as small amounts macromolecules that, in addition to their protective
of other minerals such as sodium, potassium and role, maintain a close proximity between bacterial
fluoride, which play a critical role in the formation and host cells. This sustained host-bacterial interac
of dental calculus [61]. While the organic compo tion either results in promoting health or causing
nents are integral to bacterial attachment, protecting disease [50]. In addition, matrix macromolecules
individual bacteria from the immune system, provid such as adhesins and extracellular DNA participate
ing nutrients, quorum sensing, and facilitating hor in the initial attachment to salivary pellicle and to
izontal gene transfer [50] (Figure 3). coaggregation of bacteria within the biofilm [68,69].
Figure 3. Components of dental biofilm with their functions and relation of chemical gradients to the depth of dental biofilm.
DB: dental biofilm, G+ve: Gram-positive, G-ve; Gram-negative.
Figure 4. Bacterial virulence factors and metabolism.
Iron acquisition mechanisms debridement. The periodontal pocket is an appropri

The bulk of iron in the body is found in intracellular ate habitat for anaerobic, fastidious, low adherent,
complexes; however, the amount of free ionic iron is motile bacteria such as the red and orange complexes
insufficient to support the growth of bacteria [62]. [78,79]. Additionally, the subgingival domain pro
Pathogenic bacteria have developed several mechan vides mechanical protection, anaerobiosis, and nutri
isms to acquire iron from the microenvironments ents to the periodontal bacteria, including particular
[70]. These heme-acquisition pathways include growth factors such as hemin, vitamins, and hor
hemagglutinins, hemolysins, gingipains, different mones, as well as serum components from GCF [80].
outer membrane receptors (HmuR, IhtA and HusB), Proteins, peptides, and amino acids are the key
siderophore/hemophore-like proteins (HmuY and nutrient sources in GCF, and they are targets for
HusA) and intracellular heme transport, storage and the highly proteolytic red and orange complex bac
processing, e.g. PgDps [71]. Gaining access to iron teria. The key variables that enable the simultaneous
supply by the putative periodontal pathogens sup development and increase in the inflammatory reac
ports their growth, thereby contributing to shifts in tion are increased subgingival bacterial growth and
microbial ecology and an emergent dysbiosis of the altered ecology, i.e. dysbiosis. Short-chain carboxylic
biofilm [72]. acids (butyric acid, propionic acid, valeric acid,
capronic acid, and phenyl acetic acid), ammonia,
Motility and hydrogen sulfide are hazardous metabolites pro
Mobility is an evolutionary mechanism that together duced by increased metabolic activity [79].
with chemotaxis enables bacteria to seek nutrients Subsequent multiplication of the periodontal bacteria
and find favorable niches for colonization [73]. The leads to a rise in metabolic activity, bacterial number
flagella-assisted motility is the most common mole and adaptation of new bacterial species results in
cular motor utilized by periodontal pathogens includ a constantly changing ecology that lasts until the
ing spirochetes. The flagella-mediated motility and bacterial community and the host reach homeostasis.
chemotaxis-mediated motility are also considered as Such equilibrium may persist for long periods, or
virulence factors [74] and the extent as well as the even lifelong for low-periodontitis susceptible indivi
degree of motility differ among different bacterial duals (Figure 4) [79].
species. Furthermore, the location of spirochetal fla
gella varies, e.g. T. denticola is in the periplasmic
space, while other bacteria exhibit exposed flagella
Evading host-defense mechanisms
[75]. This unique periplasmic localization enhances
motility in highly viscous microenvironments, evad Capsules
ing the immune system, and provides protection Many pathogenic microorganisms, mainly Gram-
from antibodies secreted by the host specifically negative anaerobic rods, produce a capsule e.g.
against flagella proteins [76,77]. P. intermedia and P. gingivalis. The capsule serves as
an anti-phagocytosis mechanism for neutrophils and
Microbial metabolic activity and growth macrophages. In addition, encapsulated strains pos
Increased growth is another way in which periodontal sess higher virulence potential than non-capsulated
bacteria can evade natural removal and mechanical bacteria by modulating the immune system and
supporting survival of bacteria within cells [81,82]. which can be found in several pathogenic bacteria,
However, the in vivo role of the capsule in the patho such as A. actinomycetemcomitans, the PV-leucocidin
genicity of encapsulated bacteria is not well eluci in S. aureus [93] and F. necrophorum [94,95]. LPS is
dated, as most of the evidence is derived from the endotoxin of Gram-negative bacteria, containing
experimental animal models [82]. a toxic lipid portion (lipid A) that is incorporated
into the outer membrane responsible for the release
Proteases of cytokines and activation of the complement and
P. gingivalis-gingipains differentially affect neutrophil coagulation cascades [90].
chemotaxis and activation by cleaving IL-8 to a more Bacterial tissue-degrading or histolytic enzymes
active-chemokine form; hence, enhancing recruit are directly responsible for periodontal tissue destruc
ment PMNLs which contribute to periodontal tissue tion. For example, hyaluronidase ‘spreading factor’,
destruction [83]. The outer membrane vesicles chondroitin sulphatase and beta-glucuronidase
released by P. gingivalis into the microenvironment released by Streptococci, Peptostreptococci and
are also capable of destroying IL-8, offering notable Corynebacteria. Similarly, different bacterial pro
protection from host defenses [84]. In addition, teases, such as collagenases and P. gingivalis-
P. gingivalis-gingipains have the ability to attack and gingipains are known to play a crucial role in degrad
degrade C3 which gives the invading bacteria ing tissue components during infections [81] and
a substantial survival advantage [85]. degrade host defense molecules such as immunoglo
bulins and complement [96].
Intracellular residence
It is well known that periodontal pathogens remarkably
Oral microbiota from birth to adulthood
evolved to evade the immune system; one such method
is by intracellular invasion of the host’s cells. Advanced At parturition, the microorganism-free intrauterine
microscopic techniques revealed that periodontal environment transitions to the extra-uterine environ
pathogens including P. gingivalis, T. forsythia, ment with exposure to microorganisms [97]. This
A. actinomycetemcomitans, F. nucleatum, may also be influenced by the mode of birth, with
P. intermedia, and T. denticola were collectively located a more diverse oral microbiota reported in vaginally
in the buccal epithelial cells [86]. Lee et al., (2018) born children compared to those born by caesarian
demonstrated a novel mechanism of P. gingivalis for section [98], which may also lower exposure of the
intracellular invasion of gingival epithelial cells by new born to the protective commensal bacteria
exploiting the autophagy machinery of these cells [87]. acquired from the mother at birth [99]. For instance,
Similarly, for T. denticola, intracellular localization is higher numbers of taxa detected in three-month-old
the most predominant pattern associated with utilizing infants delivered vaginally relative to C-section,
cellular machinery to over-produce chymotrypsin-like which was exclusively associated with a high preva
proteinase responsible for tissue destruction in period lence of a novel species of Slackia exigua, which has
ontitis [88]. A. actinomycetemcomitans is another bac also been isolated from the subgingival biofilm of
terium which invades gingival epithelial cells mainly by periodontitis-involved teeth [100].
inducing F-actin rearrangement via FAK-signaling The evolution of microbial communities continues
downstream [89]. within the first months of an infant's life, reaching
a distinct oral microbiota derived from the mother by
Serum resistance 5 months of life [101]. However, a significant shift in the
Pathogens that cross mucosal or skin barriers but persist microbial composition of the infants’ oral cavities arises
in the extracellular environment almost always require following the eruption of the first tooth/teeth. The intro
protection from complement-mediated lysis. The lytic duction of a non-shedding tooth surface within the oral
impact of serum on Gram-negative bacteria is mediated cavity creates a novel ecological niche. This stage has
by complement and can be triggered by either the classi previously been described as ‘window of infectivity’
cal or alternative pathways (Figure 4) [90]. [102], with the principal role of S. mutans, a cariogenic
species on teeth, however S. mutans has also been
described in edentulous children, suggesting a potential
Toxins
role of the soft tissues as a reservoir for this pathogenic
Bacterial toxins are among the classical virulence species [103]. At 3 years of age, the oral microbiome
factors that have been linked with bacterial infections becomes more complex and continues to mature
[91]. Most toxins are highly specific proteins that through the various stages of tooth development, from
have evolved to influence certain components of primary, early mixed, late mixed, and the permanent
host cell signalling for the bacteria’s benefit dentition. In parallel with this, a higher prevalence of
(Figure 4) [92]. Leukotoxin is an example of an Pseudomonaceae, Enterobacteriaceae and Pasteurellaceae
exotoxin that is dedicated to damage leukocytes, and (genus Aggregatibacter), and Moraxellaceae (genera
Acinetobacter and Moraxella) species have been reported At an early stage, the hosts’ inflammatory-immune
within primary dentition. As the dentition transitions response is induced following microbial biofilm accu
from deciduous to permanent, the prevalence of mulation at and below the gingival margin. This
Veillonellaceae and Prevotella increase, whilst that of increases GCF flow which in turn delivers protective
the Carnobacteriaceae family decreases [104]. In components of the innate immune response such as
addition, the increased proportions of Bacteroidetes neutrophils, complement and cytokines [116],
(mainly the Prevotella genus), and Spirochaetes were together with host molecules such as haemoglobin,
detected with increasing age [104], with a significant which is used as a substrate for proteolytic bacteria
abundance reported in the adult population [105]. In such as P. gingivalis [117]. Although the innate
addition, puberty is characterized by hormonal response is effective against susceptible species, sub
changes that generate nutritional enrichment within version of these responses by microbial tactics, such
oral environment, resulting in increases in Gram- as subverting neutrophil function, affecting comple
negative anaerobes and spirochetes [106]. ment degradation, and inhibiting phagocytosis can be
Notably, the adult oral cavity is host to different induced by others, e.g. P. gingivalis [118]. However,
microbiomes throughout life, which are unique for those species that are at risk may exploit the potential
every oral niche and which also act as continuum that for cross-protection offered by neighbouring organ
dynamically interact with each other. Recent evidence isms within the biofilm structure, increasing their
suggests that periodontitis is not only driven by the tolerance to the inflammatory response and also
subgingival biofilm but by microbiomes from other their survival.
niches such as the dorsum of the tongue [107]. In The term ‘inflammophilic’ refers to those micro
addition, Stephen et al. (2021) demonstrated that the bial consortia associated with periodontitis that can
tongue may act as a reservoir for subgingival period endure inflammation and use inflammatory condi
ontal pathogens, e.g. Gemella morbillorum, T. denticola tions to survive and prosper [56], such as elevations
and Peptostreptococcus stomatis responsible for increas in pH [119]. Following such local environmental
ing bleeding scores and the percentage of deep period changes, bacterial competitiveness and gene expres
ontal pockets [108]. Furthermore, the severity of sion are altered and increased in different species
periodontitis was strongly associated with the total bac such as P. gingivalis [120]. During inflammation,
terial count, and also with Archaea on the tongue [109]. the volume and composition of GCF alters, form
Patients with acute tonsillitis exhibited an abundance of ing a vital source of nutrients that effect continuous
periodontal pathogens such as Prevotella, and change in the microbial composition of the dental
Fusobacterium species [110], and the prevalence of per biofilm. To clarify the importance of such nutrients
iodontitis increased in patients with peritonsillar dis within GCF, several investigations have identified
ease and recurrent tonsillitis [111]. However, the numerous nutritional inter-relationships between
composition of the subgingival biofilm did not change subgingival microbiota [121]. An example of this
following tonsillectomy [112], a finding supported by inter-bacterial dependency is the growth of
results from another cohort study, which demonstrated T. denticola that is stimulated by isobutyric acid
that tonsillectomy did not reduce the risk of period produced by P. gingivalis, whilst T. denticola pro
ontitis [113]. These apparently conflicting results may duces succinic acid, that supports the growth of
be attributed to several environmental factors that P. gingivalis [122]. This polymicrobial synergism
directly influence the bacterial composition of the oral within the dental plaque biofilm not only exists at
cavity such as the type of food, smoking, consumption the nutritional level but inter-microbial metabolic
of medications, individual immune responses [114], product and gene expression exchanges are neces
and different sampling techniques [115]. sary to sufficiently increase biomass virulence and
induce disease, which cannot be triggered by
weakly virulent individual species alone. This is
consistent with the most cotemporary plaque
Dental biofilm: the shift from health to
hypothesis, which proposes a disproportionate dys
disease
biotic influence of low abundance but virulent spe
The process of transition from periodontal health to cies on the whole microbial community, both
the advanced stages of periodontitis is associated with directly and indirectly via host immune modula
a microbial shift from the major symbiotic bacteria tion/subversion [123,124]. However, the dysbiosis
known as ‘symbionts’ to dysbiosis, with high propor theory remains open to question, as a clear associa
tions of pathogenic bacteria, the so-called ‘patho tion between any of these putative pathogens to
bionts’. This transition is influenced by several induce periodontitis in humans is lacking. This
stressors, including the host immune-inflammatory notion is supported by resistance to alveolar bone
response, individual susceptibility, and behavioural loss in a murine periodontitis model infected with
risk factors such as smoking. P. gingivalis [125].
Meta-transcriptomic studies have confirmed the proteins, and various nutrients such as hemoglobin,
role of the entire microbiota to induce dysbiosis, and amino acids [12,133]. Thus, the microbial shift
rather than a limited number of putative pathogens from health to disease is likely to involve a microbial
[126]. In addition, several species that have been succession process, in which the proportion of cur
associated with health, including Streptococci, rent species is altered by new colonizers [134].
V. parvula, P. fluorescence, were highly active in tran It has been shown that all periodontitis-associated
scribing virulence factors associated with other puta species can be detected in gingivitis and most were
tive pathogens such as P. gingivalis and T. forsythia. also detected in health [135]. In addition, depending
Furthermore, the genes isolated from these sites were on the severity of periodontitis, different ’clusters’
associated with cell motility, lipid A and peptidogly were present. For example, in a mild form of period
can biosynthesis and transport of iron, potassium and ontitis, ‘cluster A’ was represented by species of the
amino acids. Several human microbiome studies have genera Campylobacter, Corynebacterium,
confirmed a pivotal role for the dysbiosis hypothesis Fusobacterium, Leptotrichia, Prevotella, Tannerella,
in the pathogenesis of periodontitis. According to and Saccharibacteria. Whereas in severe periodonti
these studies: (i) health-associated microbiota differ tis, ‘Cluster B’ was enriched with ‘red complex’ bac
from those related to periodontitis; (ii) the microbial teria, Filifactor alocis, Treponema species, and
diversity (phylotypes) in healthy subjects is lower Fretibacterium species. The difference in the bacterial
than within periodontitis subjects; (iii) health- load of the same microbial species between period
associated species are suppressed but not lost and ontitis and healthy gingiva can be explained by the
(iv) there is merely a shift in the balance of species EPH [12], which attributes the microbial shifting
that dominate the subgingival environment rather process to pressures from the altered inflammatory
than colonization by new microbial species [127]. stress that favours the growth of pathobionts.
Periodontal health-associated microbiota can Altered nutrient concentrations may support the
remain in a state of stability over time and live in outgrowth of proteolytic and asaccharolytic bacteria
dynamic equilibrium with the host. The shift in micro within the subgingival area via secretion of inflamma
bial diversity from healthy gingiva in 1–2 weeks fol tory exudate (GCF) and by haem-acquisition. This was
lowing oral hygiene cessation has been evaluated [128]. supported by a transcriptomic study that revealed there
Bacteria that exhibited a negative correlation with was an increase in proteolysis, iron acquisition, peptide
bleeding on probing were mostly early colonizers, transport, and LPS synthesis-associated genes within
including aerobic and facultative anaerobic Gram- subgingival biofilms, which could further promote the
positive cocci and rods such as Actinomyces, Rothia inflammatory potential of the associated bacteria [136].
and Streptococcus. As gingivitis developed in response Accordingly, the term ‘inflammophilic’ pathobionts has
to microbial biofilm accumulation, other species, been applied to those subsets of species that may fail to
mostly obligate anaerobes, with positive correlations endure the new environment, but that can further
with bleeding on probing were increased in number, induce dysbiosis within the microbial community.
such as Campylobacter, Fusobacterium, Lautropia, Another important inflammatory by-product that
Leptotrichia, Porphyromonas, Selenomonas, and may promote dysbiosis is potassium ions, which were
Tannerella species [129]. However, early gingivitis is reported to be increased with increasing periodontal
still considered, in many ways, as a homeostatic con inflammation [126,137]. In addition, nitrate is con
dition and to represent stable inflammatory changes sidered another by-product that is increased during
encountered by the host. Undoubtedly, bacteria repre inflammation and further promotes dysbiosis by
sent the main aetiological agent to induce gingivitis; enhancing the anaerobic properties of
nevertheless, the host response against bacteria dictates Enterobacteriaceae. For instance, it has been found
whether disease will progress or not [130]. Indeed, that the increased level of nitrate within the period
uncontrolled or dysregulated host response patterns ontal environment of Gas6-1- mice, a deficiency in the
are the main drivers of tissue destruction [131]. growth arrest-specific gene 6, impacts by promoting
Disease-associated microbiota constitute a minor microbial dysbiosis through selective expansion of
component of the subgingival microbial community nitrate reductase-expressing proteobacteria [138].
in health and increase considerably with the develop Undoubtedly, all of these metabolic and inflamma
ment of periodontitis [132]. In healthy periodontium tory by-products appear to be environmental cues,
(and in gingivitis), inter-microbial species competi capable of remodelling the periodontal microbiota
tion seems to self-regulate, achieving microbial from a eubiotic into a dysbiotic one.
homeostasis. As inflammation proceeds and The cause-and-effect relationship between inflamma
a pocket develops, the subgingival microbiome tion and dysbiosis has been the subject of debate
becomes dominated by Gram-negative anaerobes [139,140] regarding whether inflammatory pressure can
that exploit the local microenvironment, which is create dysbiosis by shifting the proportions of inflammo
enriched with tissue breakdown products, plasma philic pathobionts and commensal symbionts, resulting
in those dysbiosis-associated bacteria further exacerbat healthy state representing Stage 0 (absence of clinical
ing inflammation [126,138]. Therefore, it seems that inflammation), the other four stages represent disease
neither the inflammatory process nor dysbiosis can be development. Stage 1 is gingivitis, in which inflam
fully established without reciprocal interactions between mation associated with the outgrowth of commensal
these processes, creating a sustained circular loop that bacteria in response to a non-specific buildup of
develops into periodontitis. dental plaque in susceptible individuals may cause
The crucial role of the hosts’ inflammatory gingival swelling and early pocket formation. Stage
response in changing microbial composition in the 2 is initial periodontitis, in which polymicrobial
subgingival environment is important to recognise. It diversity is increased with increasing inflammation
has been shown that 53 species were more abundant and dysbiosis is initiated. Stage 3 is inflammation-
in healthy sites compared to 123 species found to be induced dysbiosis exacerbation via a self-sustained
more abundant in periodontitis sites. This indicates feedforward loop, the diversity is increased, with
that the immune subversion/modulation favours more pathobionts, and symbionts tending to favor
colonization of numerous symbiotic commensals the emergence of Gram-negative species. This is
that favour pathogen growth [141]. resolvable if the inflammation is controlled, allowing
The microbial dysbiosis is not only influenced by commensal microbiota to predominate again. Finally,
inflammatory subversion and the local microbial Stage 4 is late periodontitis which in susceptible indi
environment but also by the genetic background of viduals is characterized by the emergence of polymi
individual patients/people. For instance, subjects with crobial infection with decreasing polymicrobial
leukocyte adhesion deficiency (LAD)-1 who have diversity; the associated environment is dominated
a genetic defect in CD18 or integrin-β chain-2 by anaerobic microbial species and along with
develop severe generalized periodontitis similar to uncontrollable inflammation results in advanced tis
those who have the aggressive type (currently sue destruction (Figure 5).
known as grade C periodontitis in systemically
healthy young adults) [142]. However, the microbial
compositions/proportions in subjects with LAD-1 are
Inflammatory response of the host to the
different, with less complexity compared to those
dental biofilm in periodontal disease
having the traditionally named chronic or aggressive
forms of periodontitis [134,143,144]. Microbial spe The relationship between a healthy symbiotic biofilm
cies such as A. actinomycetemcomitans, which predo and the local host response remains in static equili
minate in aggressive periodontitis patients, were brium until environmental alterations drive altera
undetectable or found in very low abundance in tions in the microbial ecology towards a destructive
LAD-1 subjects. Conversely, species such as and dysbiotic microbiota. Maintaining a healthy state
Pseudomonas aeruginosa [144,145] and Leptotrichia critically relies on the quantity, function and regula
species that were not present in either chronic or tion of the host inflammatory cells that patrol the
aggressive periodontitis, were uniquely present in local tissues, being recruited at the target site and
subjects with LAD-1. In addition, excessive produc being involved in various innate and adaptive host
tion of interleukin (IL)-17 by T helper-17 cells in responses.
LAD-1 subjects [146] is likely to induce dysbiosis in The first-line host defence systems encountered by
the microbial biofilm. the microbial biofilm, supra- or subgingivally, include
In light of how dysbiosis and the associated aggra mucosal barriers, salivary defense mechanisms, PMN
vation of periodontal tissue destruction are driven by leucocytes, GCF and antimicrobial peptides [149]. In
environmental changes, a new hypothesis, called the addition, bioactive lipids including resolvins, salivary
‘Inflammation-mediated polymicrobial-emergence mucins and agglutinins, IgA, IgG and activated com
and disease exacerbation’ (IMPEDE) model [147] plement with GCF may play a pivotal role as protec
has emerged to complement the 2018 classification tive mediators to maintain a healthy periodontium
of periodontal diseases [148]. According to this clas [150,151]. Epithelial integrity acts as an important
sification, the continuity of periodontitis from health defensive physical barrier against microbial penetra
to disease is viewed through four stages of severity, tion during inflammation. Microbial-induced cyto
complexity as well as extent and distribution. The kines are released through direct interaction of the
IMPEDE model has emerged as a possible driver of pattern recognition receptors (PRR) of the gingival
the clinical conditions that could be manifest within epithelium such as Toll-like receptor (TLR), with
each periodontitis stage. In a similar fashion to the Gram-positive and Gram-negative pathogen-
clinical classification of periodontal disease, the associated molecular patterns (PAMPS) on the bac
IMPEDE model defines five stages encountered: terial surface. This leads to the release of pro-
health, gingivitis and periodontitis that may be devel inflammatory and regulatory cytokines such as IL-6,
oped, contained or progressed. In addition to the IL-8, and IL-1α, which stimulate epithelial cells to
Figure 5. Inflammation-Mediated Polymicrobial Emergence and Dysbiotic Exacerbation (IMPEDE) model. According to this
proposed model, plaque-induced periodontitis is mainly derived from inflammation. This model consists of 5 stages: stage 1:
gingivitis, stage 2: emergence of polymicrobial diversity in early periodontitis, stage 3: inflammation mediated dysbiosis and
opportunistic infection, and stage 4: late stage of periodontitis. Adapted from Van Dyke et al., 2020 [147].
express antimicrobial peptides such as human β- adherence to the endothelial wall and subsequent
defensins, calprotectin and cathelicidin. extravasation, have been shown to induce dysbiosis
The PMNs play a leading protective role against and bone loss in mice [123,157].
invading bacteria through their antimicrobial media Neutrophils can also induce the expression of
tors, phagocytosis, degradative enzymes such as receptor activator of nuclear factor kappa-B ligand
matrix metalloproteinases (MMP), or cytotoxic sub (RANKL) on the osteoclast’s membrane, promoting
stances, e.g. reactive oxygen species [152,153]. The bone resorption [158]. In addition, neutrophils pro
PMNs become prominent as an inflammatory trigger mote Th17 cells which represent an osteoclastogenic
that continues through different stages of gingivitis T-cell subset that has been linked to bone loss [159],
and early periodontitis. However, the supremacy of as well as a B-cell activator that promotes antibody
PMNs is also evident during the burst model of production, and possible chronicity of inflammation
periodontitis, in which there is acute exacerbation of [160]. During the transition from gingivitis to the
periodontitis after a period of remission [154]. As the advanced periodontitis lesion, the antimicrobial pep
inflammation continues in response to microbial suc tides of neutrophils seem to be replaced by increased
cession, in particular within the inflammophilic dys activity of Langerhans dendritic cells and γδ-T cells,
biotic biofilm, the proteolytic trait of neutrophils which bridge the innate and adaptive host networks,
becomes as dominant as its protective responses. secreting an array of pro-inflammatory cytokines
This may lead to epithelial deformity that can provide such as IL-1, IL-6, IL-17, TNF-α and IL-23 (Figure 6).
a point of entry to microbial invasion into underlying The induced-endothelial expression of intercellular
connective tissues, which subsequently provokes tis adhesion molecule (ICAM)-1 and selectin receptors
sue destruction and bone loss [155]. by capillary activation-associated bacterial invasion
The destructive ability of neutrophils is magnified if promotes leukocyte transmigration and exudation
their activities deviate from normal, due to excessive [161]. This exists in parallel with DEL-1 reduction
or diminished recruitment, dysfunction or hyperactiv within the periodontitis lesion, enhancing leukocyte
ity, leading to exaggerated tissue breakdown [156]. In infiltration to the inflamed target site. Commensal
addition, the role of host genetics is key in maintaining bacteria, accessory and other key pathogens can
host-microbial homeostasis. Single gene deficiencies engage with their host counterpart through host-
such as deficiencies in the leukocyte function antigen, TLR and other PRRs such as the interaction between
(LFA)-1 integrin, promoting neutrophil infiltration, bacterial LPS with LPS-binding protein (CD14) [151]
and its antagonist, developmental endothelial locus and associated TLRs on the surfaces of neutrophils,
(DEL)-1, which inhibits/regulates the neutrophil’s monocytes, macrophages and mast cells. This may be
Figure 6. Neutrophils-induced inflammatory mechanisms involved in tissue destruction and bone loss. Neutrophils are recruited
in a developmental endothelial locus (Del)-1-induced pathway into the gingival epithelium that fail to encounter the dysbiotic
bacteria which invade the gingival connective tissue and interact with different host cells such as dendritic cells and γδ T cells.
Host-bacterial interaction results in production of proinflammatory cytokines such as interleukin (IL)-1, IL-6, tumor necrosis
factor (TNF)-α, IL-23, and IL-17. IL-17 has an activating influence on T helper (Th)-17 and B cells, which upon activation increase
receptor activator of nuclear factor kappa-B ligand (RANKL) expression, which is also directly activated via the recruited
extravasated neutrophils. RANKL drives the activation and maturation of osteoclast precursor to be an active osteoclast that
predisposes to bone resorption. The recruited neutrophils have a tissue degradation effect through inducing the expression of
matrix metalloproteinases (MMP) and cytotoxic substances such as reactive oxygen species (ROS). The microbial-innate-adaptive
cell interactions demonstrate some of the main mechanisms involved in the continuity of inflammation if not resolved, leading
to tissue destruction.
antagonized through the antimicrobial action of IL-37 itself, thereby exploiting it to their advantage [131].
[151]. However, these antimicrobial peptides, in asso Pathogen survival requires inflammation for nutrient
ciation with chronic inflammation may serve as danger- supply, but the host response must also be evaded or
associated molecular patterns (DAMPs) that activate modulated for bacterial survival.
inflammasomes with neutrophils, releasing superoxide For inflammophilic bacteria, the tactic of immuno
derivatives that are toxic not only against bacteria but to suppression appears unsuitable as it creates an inflam
the host itself, resulting in extensive tissue damage. On mation-free environment deprived of the essential
the other hand, within the advanced periodontitis nutrients required for bacterial colonization and persis
lesion, prostaglandin E2 production is enhanced and tence. As a principle of the keystone pathogen concept,
may activate pro-coagulant and pro-inflammatory host P. gingivalis has the ability to impair the bactericidal
responses. It is worth noting that these reactions could properties of the host response, in particular PMNs,
potentially be reversed using pro-resolving lipid media while still inducing inflammatory crosstalk [162–164],
tors such as resolvins [151]. providing a significant benefit to the whole microbial
The complement defense system comprises var community. In this situation, uncoupling bactericidal
ious proteins, mediators, effectors and complexes activity from inflammation may be achieved through
that exert antimicrobial defenses at the onset of complement, TLR signaling and cytokines manipula
acute inflammation/starting of gingivitis, and which tion by key pathogens such as P. gingivalis [140].
become dysregulated/subverted at the advanced per P. gingivalis–induced immune subversion has been
iodontitis stage. Firstly, GCF which carries comple investigated at the level of complement C5a receptor 1
ment proteins such as C3b, an opsonin, is secreted (C5aR1) and TLR2 crosstalk signaling [164,165]. The
into the gingival crevice following transmigration downstream outcome of C5aR1-TLR2 could separate
through the junctional epithelium and augments the the protective pathway of the TLR2-Myeloid differen
inflammatory response, enhancing phagocytosis and tiation primary response 88 (MYD88) from TLR2-
microbial killing by neutrophils [151]. As the inflam MyD88-Phosphoinositide 3-kinases (PI3K) pathway,
mation proceeds, the dysbiosis-associated microbiota inhibiting phagocytosis and enhancing inflammation
have the ability to uncouple the bactericidal activity [164]. Moreover, P. gingivalis may bypass MyD88, pro
of the inflammatory response from the inflammation moting anti-phagocytic/antiapoptotic TLR2-PI3K
signaling, thereby suppressing phagolysosomal activity, S536 residue of p65 sub unit of nuclear factor kappa B,
leading to intracellular persistence of pathogens [166] suppressing transcription of CXCXL8 (IL-8) [168]. In
(Figure 7). Notably, this evasion mechanism is related addition, the chemokine suppression of CXCL9,
to the gingipains, HRgpA and RgpB, whose activity can CXCL10 and CXCL11 is mediated through the invad
upregulate levels of C5a (>100 nM), that in turn mod ing P. gingivalis blocking the signal transducer and
ulates upstream of the PI3K pathway [167]. The pre activator of transcription 1 (STAT1)-interferon regu
sence of TLR2 is crucial in P. gingivalis-induced latory factor 1 (IRF1) pathway in epithelial cells and
immune subversion and inflammation regardless of neutrophils. This promotes T cell imbalance by sup
the presence of MyD88, as shown in P. gingivalis- pression of TH1-associated activities, including down
induced bone loss in mice [166]. Downstream of TLR2- regulating IL-12 and activation of TH17-associated
C5aR1 and upstream of PI3K represent potential ther activities including upregulation of pro-inflammatory
apeutic targets that can be exploited to inhibit dysbiosis IL-6 and IL-23 cytokines, thereby enhancing the
of the dental biofilm while maintaining a beneficial inflammatory response and bone loss [169] (Figure 8).
inflammatory response. The aforementioned examples of immune subver
The benefits for the whole microbial community sion/inducing inflammation help clarify the uncou
are supported by another immune subversion pling bactericidal activity of inflammation by
mechanism induced by P. gingivalis, localized chemo P. gingivalis. This is evident through chemokine
kine paralysis [140]. The suppression of chemotactic paralysis and its debilitating influence on immune
IL-8 is induced through the action of serine phospha patrolling parallel to the buildup of a dysbiotic bio
tase B (SerB) whereby P. gingivalis dephosphorylates film. Whereas, perturbation in the homeostatic
Figure 7. Porphyromonas gingivalis enhancing dysbiosis through uncoupling of inflammation from bactericidal activity of the
phagocytic cells. P. gingivalis interacts with Toll-like receptor (TLR2), and acts on complement component 5 (C5) through
P. gingivalis-associated arginine gingipains (HRgpA and RgpB) to produce C5a and C5b. C5a ligand then interacts with its
specific complement C5a receptor (C5ar1) that together are co-activated with TLR2 on the surface of phagocytic cells. The cross-
reactivity of both receptors could induce myeloid differentiation primary response 88 (MYD88)-induced inflammation or be
blocked if MyD88 is inactivated. However, the same cross-reactivity of TLR2-C5aR1 complex could bypass MyD88 and induce the
phosphoinositide 3-kinases (PI3K) pathway that may induce inflammation in phagocytic cells. In a similar manner, the activated
PI3K could inhibit bacterial phagocytosis/apoptosis and supress phagolysosomal maturation, enhancing bacterial persistence.
The latter mechanism is dependent on increased concentration of C5a beyond a threshold level (100 nM). The insurance of
bacterial survival while inducing inflammation results in increased inflammophilic pathobionts and enhances dysbiosis.
Figure 8. Porphyromonas gingivalis-induced chemokine paralysis. The activated Toll-like receptors (TLR), following interaction
with oral pathobionts such as Fusobacterium nucleatum, induce proinflammatory signaling mechanisms. The invading keystone
pathogen (P. gingivalis) can suppress interleukin (IL)-8 production through dephosphorylation of S536 residue of p65 subunit of
nuclear factor kappa B (NF-kB) by the activity of serine phosphatase B (SerB), disrupting neutrophil recruitment. Similarly, the
expression of chemokine CXCL9 (Mig), CXCL10 (IP-10), and CXCL11 (ITAC) could be inhibited through blocking the signal
transducer and activator of transcription 1 (STAT1)-interferon regulatory factor 1 (IRF1) pathway by P. gingivalis, leading to T cell
imbalance, including TH17 activation (IL-6, IL-23) and TH1 suppression (IL-12). These immune subversion mechanisms lead to
enhanced inflammatory responses and dysbiosis.
relationship between protective and destructive approaches is dedicated towards restoring symbiosis
immunity, induced by disturbance of TH1-induced by using probiotics and prebiotics [170]. Several rando
chemokines [156], could enhance the non-symbiotic mized clinical trials (RCTs) have evaluated the efficacy
environmental alterations towards a well- of using agents such as Lactobacillus reuteri,
characterized dysbiotic biofilm. From stable versus L. rhamnosus SP-1, Bifidobacterium lactis, and S. oralis
diseased sites, longitudinal meta-transcriptomic in the treatment of gingivitis and periodontitis [171–
investigation of microbial communities has shown 175]. Despite the promising results observed with using
that P. gingivalis represents the only red complex probiotics in such trials, clinical outcomes expressed as
bacterium that expresses a wide range of virulence clinical attachment gains, reduced bleeding scores, clo
factors in a proportionate manner from healthy sites, sure of periodontal pockets, and the composition of the
to be overexpressed with increasing inflammation biofilm are inconsistent. This has been attributed to
and development of dysbiosis and disease progres heterogeneity in the mode of administration, frequency,
sion. Meanwhile, other members such as T. denticola dosage, and different treatment protocols across studies.
and T. forsythia have contributed their virulence as Therefore, use of probiotics in the treatment of period
pathobionts at later stages of tissue breakdown, accel ontitis is still not recommended by the latest S3-
erating disease progression [126]. Thus, P. gingivalis treatment guidelines [176]. However, a concrete con
could promote the fitness of the whole microbial clusion cannot be drawn without conducting further
ecology in favorable nutrient rich and disease- highly standardized RCTs.
provoking inflammatory environments. However,
the keystone pathogen hypothesis is a hypothesis,
and whilst P. gingivalis is undoubtedly a key patho
Summary
gen, it cannot be a keystone organism as it is only
identified in 60% of cases of periodontitis, and bio The diversity of bacterial species and matrix macromo
film survival is not dependent upon its presence. lecules of the biofilm render the investigation of their
Current knowledge about the shift of the periodontal exact role in the pathogenesis of periodontal disease
microbiome from health to disease, together with the challenging, requiring sophisticated multispecies bio
understanding of immune-inflammatory responses to film models that are technically and financially
biofilm accumulation provide novel opportunities to demanding. Nevertheless, the available literature pro
prevent and treat periodontal disease. One of these vides insights into, and understanding of the hosts’
immunological and inflammatory responses to the Funding

accumulation of the dental biofilm on tooth surfaces
The author(s) reported there is no funding associated with
and within subjacent supra- and subgingival niches. the work featured in this article
Indeed, colonization by resident microbiota, i.e.
symbiotic biofilm formation, is evident during peri
odontal health. These bacteria are beneficial and pre ORCID
vent colonization of potentially pathogenic species. Ali A. Abdulkareem http://orcid.org/0000-0003-0102-
Once this homeostasis is compromised, dysbiosis 6715
leads to the development of periodontitis.
Whilst PMNs have a primarily protective role
against periodontal infection, they are considered as
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Current concepts in the pathogenesis of periodontitis: from symbiosis to

ABSTRACT ARTICLE HISTORY

Introduction periodontal diseases as approximately $154.06 billion in

Structure of the dental biofilm Microbial virulence and metabolism

Figure 4. Bacterial virulence factors and metabolism.

Iron acquisition mechanisms debridement. The periodontal pocket is an appropri­

immunological and inflammatory responses to the Funding

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