Periodontology 2000 - 2021 - Hajishengallis - Polymicrobial Communities in Periodontal Disease Their Quasi Organismal

Received: 26 February 2020 | Revised: 5 March 2020 | Accepted: 28 March 2020
DOI: 10.1111/prd.12371
REVIEW ARTICLE
Polymicrobial communities in periodontal disease: Their quasi-

organismal nature and dialogue with the host
George Hajishengallis1 | Richard J. Lamont2

1
Department of Basic and Translational Sciences, Penn Dental Medicine, University of Pennsylvania, Philadelphia, USA
2
Department of Oral Immunology and Infectious Diseases, School of Dentistry, University of Louisville, Louisville, Kentucky, USA
Correspondence
George Hajishengallis, Department of Microbiology, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Email: geoh@upenn.edu
Funding information
NIH, Grant/Award Number: DE01111, DE012505, DE017921, DE023193, GM125504, DE024153, DE024716, DE026152, DE028561 and DE029436
1 | I NTRO D U C TI O N collective pathogenic potential that depends upon both the outcome
of interbacterial interactions and host susceptibility (Table 1).6 Thus,
It is now well established that, unlike classic infections of single mi- nososymbiocity (nosos [Greek for disease] potentially arising from
crobial etiology (eg, diphtheria, tetanus, typhoid fever, leprosy), peri- living together with a susceptible host) is a more accurate and con-
odontitis is not caused by a single or even a few select organisms text-dependent term than “pathogenicity”, which implies the pres-
but rather by polymicrobial communities of indigenous microbes ence of specific causative pathogens.6 It becomes apparent that the
acting in concert. In other words, periodontitis is not an infectious health- or disease-associated properties of a microbial community
condition, but rather a dysbiotic disease, that is, associated with an represent a continuum from commensalism to pathogenicity that
alteration in the abundance or influence of individual species within includes many newly recognized categories such as homeostatic
the polymicrobial community, relative to their abundance or influ- commensals, accessory pathogens, keystone pathogens, and patho-
ence in health.1,2 Periodontal dysbiosis is associated with disruption bionts2,6 (Figure 1).
of tissue homeostasis, in great part caused by microbial subversion Such polymicrobial communities within the subgingival dental
of the host immune and inflammatory response in the periodontium plaque present unique challenges to the immune system. Whereas
(Figure 1).3,4 communities of mostly eubiotic commensal organisms may contrib-
Bacteria that have accumulated into polymicrobial biofilms form ute to the training and maintenance of homeostatic immune func-
a defined structure, and attain quasi-organismal status owing to the tions (steady-state host defense), dysbiotic communities induce an
functional specialization of constituent species and coordination of immune response that is ineffective, uncontrolled, and destructive
their activities via sophisticated signaling mechanisms that maintain in a setting of disrupted homeostasis (Figure 2). In this review, we
the structure and function of the biofilm entity. 2,5 In contrast to con- describe the establishment and dynamics of subgingival microbial
ventional host-pathogen interactions in the setting of diseases with communities and discuss how the interactions among specialized
a single-infective etiology, the simple dichotomous characterization community participants determine an emergent overall function
of microbes as either commensals or pathogens is not adequate to that promotes or destabilizes periodontal tissue homeostasis. Given
describe dysbiotic endogenous communities as drivers of disease. that periodontitis requires a susceptible host (Table 1), we also ex-
Rather, the commensal or pathogenic properties of bacteria within amine the host-microbe interplay that shapes both the host immune
an organized community are not necessarily intrinsic but rather con- response and the polymicrobial community in both quantitative and
textual features. Such properties, therefore, should be considered qualitative ways. We conclude that in periodontitis, destructive in-
within the context of the community where the bacteria reside as flammation and dysbiotic communities co-develop in a reciprocally
well as the genetic and immune status of the host. In this regard, reinforced way and their interplay spirals out to become the actual
nososymbiocity is a newly coined term for a microbial community's driver of this oral disease in susceptible individuals.
© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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wileyonlinelibrary.com/journal/prd Periodontology 2000. 2021;86:210–230.
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HAJISHENGALLIS and LAMONT 211
F I G U R E 1 Functional categories among bacteria in polymicrobial communities. Inflammatory bone loss in periodontitis is induced by a
polymicrobial community, where different members have distinct and synergistic roles that promote destructive inflammation. Keystone
pathogens—which are aided by accessory pathogens in terms of nutritional and/or colonization support—initially subvert the host immune
response and contribute (along with other risk factors; see Table 1) to the emergence of a dysbiotic microbiota. Within this altered
microbiota, commensal-turned pathobionts overactivate the host response and thrive within the resulting inflammatory environment.
In contrast to an accessory pathogen, a homeostatic commensal tends to stabilize a eubiotic community, either by directly antagonizing
potentially pathogenic microbes or by inducing antimicrobial peptides that preferentially target potential pathogens [Colour figure can be
viewed at wileyonlinelibrary.com]
2 | CO M M U N IT Y I N FR A S TRU C T U R E I N of many immune effector molecules. On tooth surfaces, a layer, or

PE R I O D O NTA L H E A LTH A N D D I S E A S E pellicle, of molecules derived from saliva is rapidly deposited, and
it is to these salivary molecules that primary colonizers such as the
Within the oral cavity there are distinct microenvironments, includ- oral streptococci and actinomyces adhere. Indeed, successful oral
ing the mineralized tissues of the teeth and the epithelial surfaces colonizers often possess a multiplicity of adhesins with a variety of
of the mucosal membranes. The accumulation of heterotypic bac- specificities, a configuration which both increases the range of avail-
terial communities on these surfaces is a highly orchestrated pro- able substrates and the affinity of binding.12,13 Streptococcal ad-
cess, dependent first on a stable association with the substratum, hesins can be fimbrial components (eg, cell-surface hydrophobicity
and then on mutual interspecies binding interactions and metabolic protein A in Streptococcus gordonii and fimbria-associated protein-1
compatibility. Local environmental constraints also determine the in Streptococcus parasanguinis) and surface structural proteins, such
nature of the associated microbial communities. For example, the as the conserved antigen I/II family or the amylase-binding proteins
epithelial cells of the gingival epithelium continually turn over, and A and B.14-16 The latter example highlights a recurring theme in
hence the microbial communities have less time to develop and oral bacterial ecology, namely, an association between binding and
tend to be less complex than those on the nonshedding surfaces nutrition. Starch degradation by amylase will produce glucose and
of the teeth. Additionally, to avoid loss following host cell death, maltodextrins in close proximity to bacterial cells, which can then
many bacterial colonizers of the junctional epithelium invade the tis- be transported into the bacteria as a source of energy.17 Among
sues and internalize within epithelial cells, where they can spread the actinomyces, fimbriae are the major adhesive structures and
to adjacent cells.7-9 Polymicrobial communities can also develop in- Actinomyces oris adheres to salivary acidic proline-rich proteins and
tracellularly,10,11 a location that will protect them from the action statherin through type 1 fimbriae. Adherence may not be mediated
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212 HAJISHENGALLIS and LAMONT
TA B L E 1 Factors that modify the host response and/or the identified in these structures, for example, in the hedgehog struc-
microbiome and promote susceptibility to periodontal disease tures porphyromonads are closely associated with streptococci and
Factors References surround a central core organism, which is often Corynebacterium
matruchotii.5 Interestingly, direct observation of ex vivo plaque sam-
Geneticsa 209-212
ples does not support the widely accepted notion that the presence
Sex and genderb 213-217
218-223
of Fusobacterium nucleatum is required to function as a bridge be-
Aging
tween early and late colonizers, a concept that arose from in vitro
224-226
Obesity
coaggregation studies. 24
224,227-229
Diabetes The association between P. gingivalis and streptococci such as
230-234
Stress/depression S. gordonii has been extensively studied in vitro and in vivo, and what
29,235-237
Tobacco smoking has emerged is a picture of a complex multidimensional interaction.
Dietc 225,229,238-240
Initial detection of the streptococcal metabolite 4-amino benzoate
Alcohol consumption 241,242
by P. gingivalis increases activity of a tyrosine kinase, designated
Viral infection 243,244 P. gingivalis tyrosine kinase-1, and the ensuing protein phosphor-
a ylation-dependent signaling converges on the fimbrial adhesins
Although a genetic basis for periodontitis is strongly supported by
adult twin studies, it is uncertain whether specific individual genes designated major fimbrial protein A and minor fimbrial antigen-1. 25
determine susceptibility, as periodontitis is a polygenic disease in which While P. gingivalis thus becomes primed for attachment, pathogenic
multiple genes may contribute cumulatively to the overall disease potential at this stage is diminished, and 4-amino benzoate-treated
risk (or protection). By contrast, single genes play a causative role
P. gingivalis cells are less pathogenic in murine models of alveolar
in monogenic forms of aggressive periodontitis (eg, in patients with
leukocyte adhesion deficiency caused by mutations in the ITGB2 gene). bone loss. 25 As the two species physically associate, engagement of
b
Despite sexual dimorphisms in immune function, greater risk for the minor fimbrial antigen-1 adhesin with the streptococcal surface
destructive periodontitis in men may predominantly caused by gender- protein A/B initiates community development and also activates
based behavioral differences. the P. gingivalis low-molecular-weight tyrosine phosphatase-1. 26
c
Can modify the host response in either a protective or destructive
Porphyromonas gingivalis tyrosine kinase-1 is dephosphorylated by
manner.
the low-molecular-weight tyrosine phosphatase-1, which reverses
information flow through the phosphoprotein-dependent signal-
by the structural subunit protein, but rather by accessory proteins ing pathways and suppresses adhesin production6,27,28 (Figure 3A).
18,19
at the tip of the fimbrial shaft. Both the oral streptococci and Ultimately, community development is constrained; however, com-
actinomyces are well adapted to thrive on tooth surfaces and rapidly munities of P. gingivalis and S. gordonii cells are more pathogenic in
increase in number. In this developing polymicrobial community a vivo compared with either species alone. 29 The pathophysiology of
second major theme of oral microbial ecology rapidly emerges, that P. gingivalis also depends on the uptake of heme, which is an essen-
of interspecies communication. Streptococcus gordonii and A. oris at- tial source of iron, and S. gordonii can contribute heme acquisition.30
tach, or co-adhere, to each other through the streptococcal surface Hydrogen peroxide produced by S. gordonii oxidizes oxyhemoglobin
protein A/B binding to a glucose-, mannose-, and galactose-contain- to methemoglobin, which is followed by heme release and extraction
ing polysaccharide on the surface of the actinomyces. 20 An intricate through the actions of the lysine-specific gingipain protease and the
nutritional communication program develops in the co-adhered con- hemophore-like protein known as hemin utilization Y.31
glomerates of streptococci and actinomyces. Streptococcus gordonii As a well-adapted human oral colonizer, P. gingivalis partici-
scavenges arginine from the A. oris cell surface through the action pates in synergistic interactions with a number of other organisms
of an extracellular protease, and the arginine-containing peptides or present in oral microbial communities. Porphyromonas gingivalis
free arginine thus released are internalized and then sensed by the produces isobutyric acid, which stimulates growth of the oral spi-
arginine repressor family of transcriptional regulators. Expression of rochete Treponema denticola, and reciprocally T. denticola produces
arginine biosynthesis genes is repressed and S. gordonii develops the succinic acid, which enhances the growth of P. gingivalis.32 Contact
21-23
capacity to grow in the absence of an exogenous arginine source. with T. denticola also upregulates the expression of P. gingivalis
Communities in which early colonizers such as streptococci and adhesins and proteases, 33 and the organisms are synergistically
actinomyces predominate are generally associated with gingival pathogenic in murine models of periodontal disease.32,34 Cross-
health. However, a major corollary of the development of this plaque kingdom interactions with the pleiomorphic yeast Candida albicans
community is the provision of an attachment substratum for later have also been documented. The P. gingivalis internalin family sur-
colonizers with the potential to elevate community nososymbiocity. face protein J binds to the candidal hyphal protein known as C. al-
Indeed, image analysis of human dental plaque communities reveals bicans invasin-like protein, resulting in the upregulation of genes
spatially complex polymicrobial structures resembling “hedgehogs”, encoding components of the P. gingivalis type IX section system. 35
5
“corncobs”, and “cauliflowers”. Porphyromonads, a taxon which As the gingipain proteases and other potential virulence factors
includes the keystone pathogen Porphyromonas gingivalis, can be are secreted through the type IX section system, communities of
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F I G U R E 2 Interplay between inflammation and dysbiosis in periodontitis. A eubiotic microbial community contributes to the induction
and maintenance of homeostatic immunity, where immune activation is optimally regulated to control the health-associated microbiota
without collateral tissue damage. Inflammatory responses to a growing biofilm caused by poor oral hygiene (as it occurs in experimental
gingivitis studies) may cause incipient dysbiosis, which will further increase inflammation. Inflammation, in turn, may selectively favor the
expansion of pathobionts that can capitalize on the altered environmental conditions (eg, use inflammatory byproducts to increase their
metabolism and growth). The blooming pathobionts further exacerbate inflammation, eventually causing overt periodontitis in susceptible
individuals (eg, owing to genetic or acquired alterations; see Table 1). In susceptible hosts, inflammation is ineffective, uncontrolled,
and destructive, and engages in a positive-feedback loop with dysbiosis, each reinforcing the other [Colour figure can be viewed at
wileyonlinelibrary.com]
P. gingivalis and C. albicans may have increased nososymbiocity. 3 | I N D I G E N O U S M I C RO B I OTA A N D

In support of this, studies of subjects with chronic periodontitis H O M EOS TATI C I M M U N IT Y
have shown that the C. albicans carrier status increases dramati-
cally, together with higher isolation frequencies of P. gingivalis. 36,37 Although the mucosal immune system is faced with a bewildering
Candida albicans also interacts with the oral streptococci, and under diversity and load of bacteria, humans—and mammals in general—
host-permissive conditions these organisms can form hypervirulent are normally healthy and free of clinically significant inflammation.
mucosal biofilms.38 In great part, this can be attributed to homeostatic immunity, which
Collectively, the study of the spatial orientation and molecular restricts microbial expansion and colonization to superficial lay-
interactions in oral microbial communities shows that organisms co- ers of tissue while preventing unwarranted responses to innocu-
ordinate their behavior to optimize physical position and metabolic ous antigens39 (Figure 4). However, the indigenous microbiota also
potential. Microbes can thus become functionally specialized within contributes to the maintenance of health and provides protection
communities and their concerted activities resemble a quasi-organ- against exogenous pathogens, in part through colonization resist-
ismal state. Moreover, the degree of nososymbiocity is, to a large ance. The importance of colonization resistance becomes evident
extent, an unintended consequence of the synchronization and syn- from cases where the indigenous intestinal microbiota is disrupted
ergy of constituent organism physiological activities. or suppressed (eg, by broad-spectrum antibiotics), thereby allowing
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A C
Bi
In
Im
F I G U R E 3 Interactions among bacterial species which impact nososymbiocity. Oral bacteria interact through multiple pathways
that can be demarcated both spatially and temporally. Major threads of communication between (A) Porphyromonas gingivalis and
Streptococcus gordonii, (B) Aggregatibacter actinomycetemcomitans and S. gordonii, and (C) P. gingivalis and Streptococcus cristatus, which
either increase or decrease pathogenic potential, as indicated (see text for detailed description). Adapted with permission from ref. 2.
ApiA, Actinobacillus putative invasin A; ArcA, arginine deiminase; Cbe, chorismate binding enzyme; CdhR, community development and
hemin (transcriptional) regulator; DspB, dispersin B; fimA, fimbrial protein A; Fur, ferric uptake regulatory (protein); KatA, catalase D;
kgp, lysine-specific proteinase; LctD, lactase D; Ltp1, low-molecular-weight tyrosine phosphatase-1; Mfa, minor fimbrial antigen; RagB,
receptor antigen gene B; OxyR, oxygen resistance (positive regulator of hydrogen peroxide-inducible genes); pABA, 4-amino benzoate;
Pdk1, P. gingivalis tyrosine kinase-1; PTS, phosphotransferase system; rgpA, arginine-specific cysteine proteinase A; rgpB, arginine-specific
cysteine proteinase B; SspA/B, streptococcal surface protein A/B [Colour figure can be viewed at wileyonlinelibrary.com]
colonization by exogenous pathogens and outgrowth of indigenous colonization is required for the development of a fully competent
pathobionts with the potential for systemic dissemination and induc- immune system at the tissue, cellular, and molecular level.42-44 For
40
tion of septic shock. The mechanistic basis for colonization resist- instance, in the absence of the gut microbiota, mice have incomplete
ance involves both bacteria-bacteria and bacteria-host interactions. development of the gut-associated lymphoid tissues with relatively
Interbacterial interactions include the inhibitory action of toxic me- fewer and smaller Peyer's patches and mesenteric lymph nodes. The
tabolites, bacteriocins, antibiotics, and type VI secretion systems, commensal microbiota can regulate dendritic and other innate im-
40,41
as well as competition for space and nutrients. The indigenous mune cells in a way that promotes the differentiation of effector B
microbiota also regulates certain basic developmental features and and T cells. Particularly with regard to T cell development, the indig-
functions of the immune system in ways that prime it for vigorous enous commensal microbiota regulates the induction of T helper 17
defense against overt pathogens while maintaining tolerance to in- cells, a lineage of CD4+ T helper cells that produce interleukin 17 and
40,42
nocuous antigens, such as food proteins. interleukin 22, the combined action of which induces neutrophil re-
The use of germ-free mice and specific pathogen-free (“con- cruitment, enhances the production of mucus and antimicrobial pro-
ventional”) mice with deletions in genes controlling different bac- teins (eg, regenerating islet-derived proteins III-beta and III-gamma),
terial recognition systems, has led to an appreciation that microbial resists pathogen invasion, and promotes epithelial regeneration and
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F I G U R E 4 Significance of inflammation in host-microbe interactions. Ideally, inflammation is an integrated component of a homeostatic

process aiming to maintain host-microbe balance and immune tolerance to innocuous antigens and, if necessary, to isolate and destroy
causes of tissue injury (eg, microbial pathogens), remove necrotic cells and cellular debris, and repair tissue damage, thereby restoring
normal function. However, excessive inflammation can cause bystander tissue damage and, if not resolved, may become chronic and cause
an inflammatory disease, such as periodontitis. Inflammation is also exploited by inflammophilic pathobionts to promote their metabolism,
virulence, and adaptive fitness (see text for details on individual molecules exploited by pathobionts) [Colour figure can be viewed at
wileyonlinelibrary.com]
tissue repair.45-48 In the small intestine of mice, colonization with a immune defense or regulatory proteins (eg, lysosomal-associated
single organism, a segmented filamentous bacterium, is sufficient to membrane protein-2 or developmental endothelial locus-1, respec-
induce T helper 17 cells.49 The resident microbiota also contributes tively), greatly increase periodontal disease susceptibility in mouse
to the development of CD4+ Foxp3+ regulatory T cells, which pro- models.58-62 Under steady-state conditions, the periodontium is
duce interleukin 10 and help control host inflammatory responses, constantly patrolled by neutrophils, a network of antigen-presenting
thereby promoting tissue homeostasis.50 In this regard, metabo- cells (dendritic cells and macrophages) and a predominantly T cell-
lites (such as the short-chain fatty acids butyrate and propionate) rich infiltrate of lymphocytes.57,63 Thus, even in clinically healthy
produced by gut commensals during starch and fiber fermentation gingiva, a low level of inflammation with controlled recruitment
were shown to promote the differentiation of colonic regulatory T of neutrophils is constantly maintained to constrain bacterial out-
cells.51,52 Commensals can stimulate epithelial cells to produce an- growth or other types of insults.64,65 In contrast to T cells, a clinically
42-44
timicrobial peptides and to reinforce tight junctions. Moreover, healthy periodontium contains minimal numbers of B and plasma
exposure to certain commensal organisms or their products induces cells. Populations of gamma delta T cells and of innate lymphoid cells
metabolic and epigenetic changes in myeloid progenitor cells that can also be seen in healthy gingiva and are believed to contribute to
give rise to monocytes/macrophages in a “trained” state that enables the maintenance of tissue homeostasis.57,58,66,67
enhanced immune responses to subsequent encounters with patho- Studies in germ-free mice have shown that the recruitment of
gens.53-55 Overall, therefore, symbiotic commensals can contribute neutrophils to the periodontium does not require commensal bac-
to host-microbe homeostasis through niche protection (colonization terial colonization, which, however, further promotes this function.
resistance) and immune education in a manner that promotes ho- Specifically, the commensal microbiota selectively upregulates
meostatic immunity. the expression of the neutrophil-specific chemokine CXC motif li-
On subgingival tooth surfaces, colonizing bacteria first assem- gand-2 (but not the highly homologous CXC motif ligand-1), leading
ble into physiologically compatible communities, and the organisms to increased neutrophil recruitment to the periodontium compared
within these biofilms communicate through sophisticated signaling with the germ-free state.63 Interestingly, at least in mice, CXC motif
2,56
mechanisms. Overgrowth and overt pathogenicity are controlled ligand-1 is predominantly derived from activated endothelial cells
by the host immune and inflammatory responses and, in fact, a con- and pericytes, whereas CXC motif ligand-2 is mainly produced by
trolled state of immuno-inflammation is not only normal in healthy neutrophils.68 These two homologs perform distinct functions:
gingiva, but is required to maintain health. A well-regulated host whereas CXC motif ligand-1 promotes neutrophil crawling on the
immune response to the subgingival biofilm can thus maintain bal- endothelium and subendothelium, CXC motif ligand-2 mediates
anced host-microbe interplay and contribute to homeostasis that neutrophil transmigration through endothelial junctions.68 These
57
characterizes the healthy periodontium. Genetic deletion or in- findings are in line with the recently proposed location-depen-
hibition of either immune or regulatory cells (eg, gamma delta T dent homeostatic principle, according to which compartmental-
cells or regulatory T cells, respectively), or genetic deficiency of key ized expression of the same or related molecules enables optimal
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performance with cell type-specific actions and spatiotemporal 4 | ACC E S S O RY PATH O G E N S : U N W IT TI N G

regulation of the immune response. 69
Microbe-induced CXC motif PA RTI C I PA NT S ?
ligand-2 production requires the presence of myeloid differentia-
tion primary response gene 88,63 a signaling adaptor of most toll- In diseases with a single-infective etiology, microbial virulence may
like receptors, for example, toll-like receptor 2, toll-like receptor 4, be predicted by the capacity of the organism to express virulence
70
toll-like receptor 5, and toll-like receptor 9. The oral commensal factors, such as cytotoxins, capsular polysaccharide, or invasins. By
microbiota is also required for myeloid differentiation primary re- contrast, in diseases associated with dysbiotic microbial communi-
sponse gene 88-dependent induction of epithelial cell production ties, “virulence” may refer to any microbial trait that can elevate the
of growth arrest-specific gene 6.71 Growth arrest-specific gene 6 is collective pathogenicity or nososymbiocity of the community. In
a ligand of a group of receptor tyrosine kinases (Tyro3, Axl, and Mer, other words, whether a constituent organism behaves as a “patho-
collectively known as the TAM receptor family), which function as gen” or “commensal” may not necessarily be predicted from its abil-
homeostatic regulators in adult tissues72 including the periodon- ity, or lack thereof, to express classical “virulence factors”. Indeed, a
tium.71 Consistent with this, growth arrest-specific gene 6-deficient microbial trait or function that on its own may not contribute to dis-
mice develop microbial dysbiosis and inflammation in the gingival ease, may do so in an interactive polymicrobial community of func-
tissue.71 tionally specialized organisms. This notion is an integral part of the
In addition to bacteria, other challenges that may contribute to polymicrobial synergy and dysbiosis concept, which has challenged
the training of oral mucosal immunity include ongoing damage from the commensal-pathogen duality in favor of a more subtle, context-
57
mastication and perhaps dietary and airborne allergens/particles. dependent view of microbial pathogenic potential.1,2,56
A study investigating the mechanisms of T helper 17 induction in The term “accessory pathogen” defines a subset of microbes
the periodontium under steady-state conditions surprisingly found that, while generally perceived as symbiotic commensals, can act
that the induction of gingival T helper 17 cells was not dependent on synergistically under certain conditions to promote the virulence of
commensal bacterial colonization; indeed, the steady-state T helper disease-associated organisms (Figure 1). Although traditionally seen
17 cell population was indistinguishable between conventional and as a prototypical oral commensal, S. gordonii is now considered an
germ-free mice.73 Interestingly, the development of gingival T helper accessory pathogen, as it facilitates colonization and virulence of the
17 cells was dependent upon signals from epithelial cell-derived in- keystone periodontal pathogen P. gingivalis (as discussed above).78-
80
terleukin 6, which was induced by mechanical damage that occurs Streptococcus gordonii also enhances the pathogenicity of another
physiologically through mastication and abrasion.73 In contrast to periodontitis-associated organism, Aggregatibacter actinomyce-
homeostatic T helper 17 cells that physiologically arise in the oral temcomitans, through similarly multilayered, spatially constrained
mucosa independently of microbial triggers,73 in the setting of peri- communication mechanisms (Figure 3B). Streptococcal-derived
odontitis, pathologic T helper 17 amplification is triggered by the hydrogen peroxide is an environmental cue, to which A. actinomy-
local dysbiotic microbiota, thus suggesting divergent T helper 17 cetemcomitans responds by activation of the positive regulator of
regulation in health vs disease.74 In summary, physiological mechan- hydrogen peroxide-inducible genes, known as oxygen resistance.81
ical damage, and not commensal colonization, sets the immune tone The oxygen resistance transcriptional regulator controls expres-
of the gingiva under steady-state/homeostatic conditions. This is in sion of the gene encoding Actinobacillus putative invasin A (ApiA),
contrast to the mechanisms operating in the gut, where the micro- and higher levels of this surface protein increase resistance to
biota is responsible for steady-state control of CD4+ T cell effector complement, intracellular invasion and pro-inflammatory cytokine
function, as discussed above.42,49 production.81 The same transcriptional regulator also controls tran-
Despite host immunity and the potential benefits of the indige- scription of the gene encoding catalase A, and increased production
nous microbiota, a variety of factors can initiate the transition from of catalase A enhances degradation of hydrogen peroxide produced
a eubiotic to a dysbiotic state (Figure 2). For instance, alterations by both streptococci and neutrophils, thus protecting A. actinomy-
affecting the immuno-inflammatory status of the host could modu- cetemcomitans from oxidative damage.82 Hydrogen peroxide also
late the composition or the metatranscriptional landscape of a poly- increases the bioavailability of oxygen, allowing A. actinomycetem-
microbial community, or the ability of certain bacteria to translocate comitans to shift from a primarily fermentative to a respiratory me-
to normally sterile sites.39-41 As a community develops, changes to tabolism, an interaction termed cross-respiration, which enhances
the microenvironment, such as the availability of certain types of the growth and fitness of A. actinomycetemcomitans in vivo.83 A
nutrients, oxygen, or pH can provide physiological support for the second level of communication involves transport of streptococcal
outgrowth or overrepresentation of dysbiotic organisms.75-77 If the lactate into A. actinomycetemcomitans through the proton-driven
conditions are such that dysbiotic communities can reach a meta- lactate permease, and conversion to pyruvate by lactate dehydroge-
stable state, the potential for disease development can persist for nase.84 Pyruvate suppresses the autophosphorylation of E1, which
an extended time. Below, we review a triad of protagonists in a dys- then decreases the uptake of phosphotransferase system carbohy-
biotic community (accessory pathogens, keystone pathogens, and drates such as glucose.85 This is termed carbon resource portion-
pathobionts) and discuss their roles in inter-bacterial and host-bac- ing; and preferential utilization of lactate, even in the presence of
terial interactions. organisms that can metabolize glucose more efficiently, provides a
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competitive advantage to A. actinomycetemcomitans. Communities disproportionately large relative to their abundance, thus serving as
of A. actinomycetemcomitans and S. gordonii can become restricted the keystone of their community's structure.94 Accordingly, in the
for iron, and this induces expression of dispersin B, which is under context of microbial pathogenesis, the keystone-pathogen hypothe-
the transcriptional control of the fur transcriptional regulator.86 sis holds that certain low-abundance microbes can have a major role
Dispersin B is a beta-hexosaminidase that cleaves beta (1,6)-linked in the community structure by promoting the emergence of dysbiotic
N-acetylglucosamine polymers in the biofilm matrix, and facilitates communities that can precipitate disease64,95,96 (Figure 1). In remod-
87
the release of A. actinomycetemcomitans from biofilm communities. eling a eubiotic microbiota into a dysbiotic one, keystone pathogens
The counteracting influences of oxidative stress and metabolic syn- can mediate both quantitative (increased counts) and qualitative (the
ergy, together with the opposing constraints of retention/dispersal, emergence of newly dominant species) alterations of the microbiota.
elicit a finely balanced spatial configuration whereby A. actinomy- The qualitative alterations involve changes in microbial composition,
cetemcomitans maintains an optimal distance from streptococci in as well as the metatranscriptome and the metaproteome of the com-
dual-species communities in vivo.82 munity. Keystone pathogen-induced changes to the microbiota may
Accessory pathogenic mechanisms also operate in other mucosal involve both indirect and direct effects, the former through subver-
sites of the body. For instance, although Gardnerella vaginalis is not sion of the host immune response and the latter via interspecies in-
uropathogenic by itself, it can trigger the emergence of Escherichia teractions with other member species.64,96-99 Since the proposal that
coli from intracellular reservoirs into the lumen of the bladder, P. gingivalis may be a keystone species of the dysbiotic periodontal
where it can translocate to the kidney and cause inflammation and microbiota,64,95,96,100 a great number of keystone species have been
systemic infection.88 In a drosophila model of cholera, the action of identified in the human, plant, and soil microbiomes.101
an otherwise commensal organism, Acetobacter pasteurianus, is re-
quired for Vibrio cholerae pathogenesis.89 Moreover, in the intestine,
Bacteroides thetaiotaomicron produces fucosidases that generate 5.1 | Manipulation of complement and toll-like
fucose (from host-derived glycans), which activates a fucose sensor receptor function
of enterohemorrhagic E. coli; this sensor comprises a two-compo-
nent signal transduction system, designated FusKR, where FusK is In the oral gavage model of periodontitis,102 P. gingivalis fails to cause
the histidine sensor kinase and FusR is the response regulator. The alveolar bone loss in germ-free mice even though it can colonize this
activation of FusKR leads to the expression of genes that enhance host.96 In conventional (specific pathogen-free) mice, however, this
90
the metabolism and pathogenicity of enterohemorrhagic E. coli. oral bacterium remodels the periodontal commensal microbiota into
Consistent with the contextual nature of microbial influence on a dysbiotic community that causes bone loss, as long as the mice have
other organisms and on the host, P. gingivalis can also function as an intact complement and toll-like receptor signaling pathways.96,97
accessory pathogen in the setting of respiratory infection. Indeed, This is because the keystone-pathogen status of P. gingivalis de-
P. gingivalis, which may be aspirated into the lungs,91 promotes the pends heavily on its ability to induce subversive crosstalk between
capacity of Pseudomonas aeruginosa to invade respiratory epithelial complement component 5a receptor 1 and toll-like receptor 2 on
cells and modulates its apoptosis-inducing activity, thereby poten- leukocytes, thereby leading to selective inhibition of antimicrobial
92,93
tially enhancing its ability to establish infection. responses and promotion of destructive inflammation96,97,103-105
Given their widespread distribution and abundance, it is unlikely (Figure 5). In fact, not only does the impairment of host immunity
that oral streptococci (and other accessory pathogens such as the allow uncontrolled bacterial growth, but also the resulting inflam-
gastrointestinal Bacteroides) have specifically evolved as accessory matory environment favors the development of a subset of inflam-
pathogens. Their role is more likely that of unwitting, rather than mophilic species that can thrive on nutritional substrates derived
willing, participants. In this regard, whereas S. gordonii-derived from tissue breakdown (eg, degraded collagen as a source of amino
4-amino benzoate acts as signal for P. gingivalis to upregulate fim- acids).75,76,106 Porphyromonas gingivalis can therefore disrupt host-
brial expression and enhance its colonization, it also suppresses ex- microbe homeostasis leading to the emergence of a dysbiotic or in-
tracellular polysaccharide production by P. gingivalis and decreases flammophilic microbiota.
its virulence in the mouse abscess model. 25 It would be expected, The influence of P. gingivalis on the microbial community dis-
however, that as the biomass of P. gingivalis aggregates increases, cussed earlier is greater than expected from its low abundance,
the accessibility of streptococcal 4-amino benzoate will decrease, which was less than 0.01% of the total microbiota in the mouse
thereby resulting in increased P. gingivalis pathogenicity. periodontitis model.96 Porphyromonas gingivalis is also a quan-
titatively minor constituent in human periodontitis-associated
biofilms. Indeed, in contrast to findings from early culture-based
5 | K E YS TO N E PATH O G E N S : CO M M U N IT Y microbiological studies, most recent studies using culture-in-
S E RV I C E AT TH E H OS T ' S E X PE N S E dependent molecular methods show that P. gingivalis is a quan-
titatively minor constituent of human periodontitis-associated
The term “keystone” was introduced in the ecological litera- biofilms.107-110 However, P. gingivalis has also been detected at rel-
ture to describe species whose influence on their communities is atively high abundance in some sites.111 It is possible that dysbiosis
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F I G U R E 5 Porphyromonas gingivalis impairs innate host defenses while promoting inflammatory responses in phagocytic cells.
Porphyromonas gingivalis expresses cell-surface molecules that activate the toll-like receptor 2–toll-like receptor 1 complex (TLR2/1)
and secretes enzymes (the gingipains designated HRgpA and RgpB) that act on the complement component C5 to generate high local
concentrations of C5a, a ligand of complement component 5a receptor 1. The bacterium can thus co-activate complement component 5a
receptor 1 and toll-like receptor 2 in phagocytic cells such as neutrophils and macrophages. In both of these myeloid cell types, P. gingivalis
can bypass myeloid differentiation primary response gene 88 and thus prevent the associated bactericidal activity,97,114 which in neutrophils
is possibly mediated by downstream activation of IRAK4-dependent neutrophil granule exocytosis.115 In neutrophils, the inactivation
of myeloid differentiation primary response gene 88 involves its ubiquitination via the E3 ubiquitin ligase Smurf1 and its subsequent
proteasomal degradation. Although myeloid differentiation primary response gene 88-dependent inflammation is blocked by P. gingivalis,
this bacterium induces PI3K-dependent inflammatory cytokine in both neutrophils and macrophages.103,105 Similarly, in both cell types,
P gingivalis-induced activation of PI3K leads to inhibition of phagocytosis.97,103 In neutrophils, this activity is mediated by the ability of PI3K
to suppress RhoA guanosine triphosphatases and actin polymerization.97 Intriguingly, even within those macrophages that do manage to
phagocytose P. gingivalis bacteria, PI3K signaling suppresses phago-lysosomal maturation, thereby preventing pathogen destruction.103
These tactics compromise innate immunity while promoting inflammation that leads to the selective expansion of inflammophilic
pathobionts. Conversely, inhibition of complement component 5a receptor 1, toll-like receptor 2, or PI3K reverses dysbiotic inflammation
and periodontitis in mice.96,97 Adapted with permission from ref. 2. c5aR1, complement complement C5a receptor 1; HRgpA, hemagglutinin
arginine-specific cysteine proteinase A; IRAK4, interleukin 1 receptor-associated kinase-1; Mal, MyD88 adaptor-like; PI3K, phosphoinositide
3-kinase; RgpB; arginine-specific cysteine proteinase B; RhoA, ras homolog family member A; Smurf-1, smad ubiquitin regulatory factor-1
[Colour figure can be viewed at wileyonlinelibrary.com]
can be initiated at low P. gingivalis colonization levels, and subse- under the control of P. gingivalis gingipains that can locally generate
quently the relative abundance of P. gingivalis might increase be- C5a ligand independently of complement activation.105,113 In both
cause of elevated inflammation. human and mouse neutrophils, the P. gingivalis-induced complement
component 5a receptor 1–toll-like receptor 2 crosstalk triggers ubiq-
uitination and proteasomal degradation of a major toll-like receptor
5.2 | Subversion of neutrophils 2 signaling adaptor, myeloid differentiation primary response gene
88 (Figure 5), thereby suppressing its antimicrobial effects that can
Complement component 5a receptor 1 and toll-like receptor 2 are eradicate P. gingivalis, presumably through downstream activation
central to the ability of P. gingivalis to subvert innate immunity and this of interleukin 1 receptor-associated kinase 4-dependent neutrophil
subversion mechanism affects different phagocytic cell types. The granule exocytosis.97,114,115 However, P. gingivalis-induced degrada-
relevant mechanisms operating in neutrophils are briefly described tion of myeloid differentiation primary response gene 88 also inhibits
here. Toll-like receptor 2 is critical for P. gingivalis recognition by neu- downstream pro-inflammatory signaling; indeed, a similar but host-
trophils in vivo,112 whereas complement component 5a receptor 1 is controlled mechanism of ubiquitin-mediated myeloid differentiation
|
primary response gene 88 degradation regulates toll-like receptor- component 5a receptor 1, toll-like receptor 2, and phosphoinositide
116
induced inflammation in the periodontal tissue. 3-kinase). Thus, the protective effects seen after local pharmaco-
Given the inhibition of the myeloid differentiation primary re- logic inhibition of these molecules could additionally involve coun-
sponse gene 88 pathway, the question arose as to how P. gingivalis teraction of P. gingivalis effects on additional cell types. For instance,
rescues the nutritionally favorable (for the bacteria) inflammatory P. gingivalis was also shown to induce and exploit phosphoinositide
response. The answer came quite unexpectedly: The pharmacologic 3-kinase signaling in gingival epithelial cells, where this bacterium
blockade of complement component 5a receptor 1 or toll-like recep- inhibits apoptosis in a phosphoinositide 3-kinase-dependent manner
tor 2 in myeloid differentiation primary response gene 88-deficient in order to promote its intracellular persistence.118 Moreover, P. gin-
mice promotes bacterial killing by neutrophils, indicating that P. gingivalis instigates a subversive complement component 5a receptor
givalis evade killing via an additional, myeloid differentiation pri- 1–toll-like receptor 2 signaling in macrophages, although the under-
mary response gene 88-independent mechanism involving the two lying mechanism is different. Here, P. gingivalis-activated comple-
receptors. The dissection of this alternative pathway revealed that ment component 5a receptor 1 initiates intracellular Ca2+ signaling
another toll-like receptor 2 adaptor, Mal, induces phosphoinositide that synergistically augments the otherwise weak cyclic adenosine
3-kinase signaling, which in turn inhibits the guanosine triphospha- monophosphate responses caused by toll-like receptor 2 activation
tases Ras homolog family member A-dependent actin polymeriza- alone.104 The ensuing activation of cyclic adenosine monophos-
97
tion, and hence suppresses P. gingivalis phagocytosis. Intriguingly, phate-dependent protein kinase A inhibits nuclear factor kappa-B
the same phosphoinositide 3-kinase pathway was shown to stimu- and glycogen synthase kinase-3-beta, in turn suppressing inducible
late a robust inflammatory response, since genetic or pharmacologic nitric oxide synthase-dependent killing of P. gingivalis. Nevertheless,
ablation of Mal or phosphoinositide 3-kinase inhibits the production the induction of pro-inflammatory cytokines (such as interleukin
of pro-inflammatory cytokines by neutrophils in vitro or in vivo.97 1-beta, interleukin 6, and tumor necrosis factor) by macrophages is
Thus, P. gingivalis substitutes toll-like receptor 2–phosphoinosit- upregulated by the P. gingivalis-induced complement component 5a
ide 3-kinase in place of toll-like receptor 2–myeloid differentiation receptor 1–toll-like receptor 2 crosstalk and is also independent of
primary response gene 88 signaling to preserve the inflammatory myeloid differentiation primary response gene 88.103,105
response and at the same time uncouples inflammation from the The ability of P. gingivalis to induce toll-like receptor 2-medi-
bactericidal activities of neutrophils (Figure 5). ated inflammation by circumventing myeloid differentiation primary
The subversion of neutrophil function by P. gingivalis promotes response gene 88 in both neutrophils and macrophages is uncon-
the survival of bystander bacteria species such as F. nucleatum, ventional, given that typical toll-like receptor 2 agonists, such as
which are otherwise susceptible to neutrophil killing.97 Conversely, the lipopeptide Pam3CysSerLys4, activate toll-like receptor 2 in a
inhibition of phosphoinositide 3-kinase or any of the two upstream strictly myeloid differentiation primary response gene 88-depen-
receptors, complement component 5a receptor 1 or toll-like recep- dent way.97,103 In line with the redundant role of myeloid differentia-
tor 2, reverses the capacity of P. gingivalis to protect either itself or tion primary response gene 88 in P. gingivalis-induced inflammation,
F. nucleatum against neutrophil killing. Importantly, local inhibition this organism causes alveolar bone loss in a myeloid differentiation
of phosphoinositide 3-kinase, complement component 5a receptor primary response gene 88-independent manner, whereas the pres-
1, or toll-like receptor 2 in the periodontium of P. gingivalis-colonized ence of intact toll-like receptor 2 signaling is required.103 Equally
mice leads to elimination of P. gingivalis, reverses the increase in unconventional is the ability of P. gingivalis to exploit toll-like recep-
total microbiota counts induced earlier by P. gingivalis colonization, tor 2–phosphoinositide 3-kinase signaling to prevent phagocytosis,
and blocks periodontal inflammation and bone loss.96,97 In the same as this is in stark contrast to findings with other organisms whose
97
study , local inhibition of toll-like receptor 4 had no effect, con- phagocytosis is promoted by toll-like receptor 2 and/or phospho-
sistent with earlier findings that toll-like receptor 4-deficient neu- inositide 3-kinase signaling.119-121 Intriguingly, within those cells
trophils are phenotypically similar to wild-type neutrophils, as both which do phagocytose P. gingivalis bacteria, toll-like receptor 2–
display normal inflammatory responses to P. gingivalis while failing phosphoinositide 3-kinase signaling suppresses phago-lysosomal
to kill the organism.112 This intriguing observation is likely attributed maturation, thereby revealing another mechanistic layer whereby
to the capacity of P. gingivalis to express atypical lipid A structures this keystone pathogen can evade killing (Figure 5).103
117
that prevent toll-like receptor 4 activation. In summary, P. gingi-
valis manipulates neutrophils through distinct mechanisms, which
combine to ensure the survival of the microbial community and per- 5.4 | Interactions with dendritic cells
petuation of inflammation.
Surprisingly, whereas P. gingivalis readily exploits complement com-
ponent 5a receptor 1 to evade neutrophils and macrophages, it fails
5.3 | Subversion of macrophages to do so in dendritic cells, which utilize complement component 5a
receptor 1 to kill P. gingivalis.122 These differential effects of comple-
Of course, besides neutrophils, other cell types in the periodon- ment component 5a receptor 1 in dendritic cells and macrophages
tal environment express the implicated molecules (complement could be attributed to differential regulation of the ccyclic adenosine
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monophosphate response in these two cell types. In macrophages, of E-selectin by other periodontal bacteria.130 The combined inhibi-
activation of complement component 5a receptor 1 leads to in- tion of E-selectin and interleukin 8 expression could suppress the
creased levels of intracellular cyclic adenosine monophosphate and extravasation and directed migration of neutrophils to the gingival
hence protein kinase A activation, which is critical for suppressing crevice. Although the subversive effects of P. gingivalis on E-selectin
the nitric oxide-dependent killing of P. gingivalis.104 By contrast, in and interleukin 8 expression are transient in vivo,96 at least in prin-
dendritic cells, complement component 5a receptor 1 activation ciple they could allow adequate time for P. gingivalis and bystander
suppresses cyclic adenosine monophosphate production and thus bacteria to establish colonization while delaying the influx of neu-
the activation of protein kinase A.123 The finding that complement trophils. This could be a critical step in periodontal disease patho-
component 5a receptor 1 promotes the intracellular killing of P. gin- genesis. In this regard, a serine phosphatase B-deficient isogenic
givalis in dendritic cells while enhancing the intracellular survival of mutant of P. gingivalis (thus unable to cause local chemokine paraly-
this organism in neutrophils and macrophages is not surprising, be- sis) induces higher levels of neutrophil recruitment to the periodon-
cause the major threat to P. gingivalis in its predominant niche (ie, tium and causes reduced bone loss in rats compared with wild-type
periodontal pocket) is (primarily) represented by neutrophils, and P. gingivalis.131
(secondarily) by macrophages, rather than dendritic cells. Porphyromonas gingivalis also suppresses the expression of
Alternatively, P. gingivalis may manipulate other innate immune T-helper-1 cell-biasing chemokines (CXC motif ligands -9, -10, and
mechanisms to subvert dendritic cells. In this regard, P. gingivalis -11), even in the presence of F. nucleatum, which is a potent inducer
uses its minor fimbrial antigen-1 to interact with a C-type lectin, the of these chemokines on its own.132 The inhibitory mechanism of T
dendritic cell-specific intercellular adhesion molecule 3 grabbing helper 1-associated chemokine expression by P. gingivalis is medi-
nonintegrin, and thereby enter dendritic cells in a manner that pro- ated through suppression of the signal transducer and activator of
motes its survival while suppressing the maturation of the dendritic transcription 1-interferon regulatory factor 1 pathway in epithelial
cells.124,125 Although dendritic cell-specific intercellular adhesion cells, but also in myeloid cells (neutrophils and monocytes).132 The
molecule 3 grabbing nonintegrin directs P. gingivalis into intracel- resulting disruption of T helper 1-biasing chemokines may disrupt
lular vesicles that escape early autophagosomal recognition and the balance of protective and destructive cytokines in the periodon-
degradation, toll-like receptor 2 antagonizes autophagy evasion and tium, given that interferon-gamma can promote antimicrobial immu-
thus inhibits the intracellular persistence of this oral bacterium.126 nity133 as well mitigating osteoclast activation.134,135
Consistent with this finding, P. gingivalis displays increased viable Although many putative mechanisms for P. gingivalis immune
counts in toll-like receptor 2-deficient dendritic cells compared with subversion have been proposed, most have not been tested in vivo in
wild-type controls, thus further supporting that toll-like receptor 2 the context of experimental periodontitis. For instance, the in vitro
contributes to the intracellular killing of this pathogen.122 Taken to- capacity of P. gingivalis to degrade or inactivate antimicrobial pep-
gether, these studies suggest that dendritic cell-specific intercellular tides or the lytic action of complement could, in principle, confer in
adhesion molecule 3 grabbing nonintegrin promotes the intracellular vivo protection to bystander bacteria that are otherwise susceptible
survival of P. gingivalis in dendritic cells, whereas complement com- to these host defense mechanisms.113,136,137
ponent 5a receptor 1 and toll-like receptor 2 mediate the opposite
effect, that is, they promote the clearance of P. gingivalis.
5.6 | Interbacterial interactions
5.5 | Subversion of epithelial and endothelial cells Besides exerting community-wide influence via host modulation,
P. gingivalis may additionally modulate the commensal microbiota
Porphyromonas gingivalis may use additional mechanisms to protect through host-independent, direct effects on bacteria. Indeed, it
itself and bystander bacteria in the community. In fact, prior to the has been demonstrated that the introduction of P. gingivalis into a
eventual infiltration of neutrophils in diseased periodontal pockets health-compatible multispecies biofilm changes the pattern of mi-
heavily colonized by subgingival communities, that is, at an early crobial community gene expression98 and can even induce DNA
stage in the colonization process, P. gingivalis may be able to inhibit fragmentation and cell death to certain commensals.99 The ability
neutrophil recruitment. Indeed, this bacterium was shown to sup- of P. gingivalis to alter the composition of polymicrobial biofilms in
press the capacity of gingival epithelial cells to induce interleukin 8 vitro depends in part on the expression of the gingipain proteases.138
127
for the chemoattraction of neutrophils. This subversion effect is
known as “local chemokine paralysis” and depends on the capacity
of P. gingivalis to invade the epithelial cells127 and secrete the ser- 5.7 | The role of P. gingivalis in human periodontitis
ine phosphatase B.128 Porphyromonas gingivalis-invaded epithelial
cells are restrained from eliciting normal interleukin 8 responses, It is currently uncertain whether P. gingivalis can also act as a key-
even in the presence of bacteria such as F. nucleatum that are oth- stone pathogen in human periodontitis. However, a recent investiga-
erwise potent inducers of interleukin 8 production.127,129 Moreover, tion involving metagenomics sequencing and phylogenetic profiling of
P. gingivalis acts on endothelial cells and prevents the upregulation the microbial communities associated with human periodontitis lent
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support, albeit indirectly, to the keystone pathogen-induced polymi- species elicit host responses that do not reflect the numerically
139
crobial synergy and dysbiosis model. Direct evidence can be ob- dominant species.151 Instead, it was found that different species
tained through an interventional study in human periodontitis patients. exert different “per capita” immunostimulatory effects. The finding
If an interventional treatment that selectively targets P. gingivalis (eg, that individual members of a community disproportionately regulate
a specific vaccine or antimicrobial) leads to a significant reduction in the host innate immune response is consistent with the keystone-
P gingivalis counts, and simultaneously suppresses the entire dysbiotic pathogen concept and, moreover, suggests that knowledge of spe-
biofilm and disease development, then P. gingivalis can be considered cific keystone-like properties of individual species might provide
a human keystone pathogen (at least in a subset of patients, as P. gin- predictive insights into the function of polymicrobial communi-
givalis is not an obligatory mechanism of periodontitis; see below). In ties.151 On the other hand, the evidence that minor members in a
support of this hypothesis, nonhuman primates (which naturally harbor community can exert dominant effects challenges the notion inher-
P. gingivalis) administered with a gingipain-based vaccine displayed a ent in compositional analyses that the relative abundances of differ-
decrease in both the counts of P. gingivalis and the total subgingival ent taxa or species can have predictive value for disease pathology.
bacterial load,140 suggesting that the presence of P. gingivalis benefits In this regard, Fisher and Mehta152 used a time-series algorithm
the entire disease-associated microbial community. called Learning Interactions from MIcrobial Time Series to deduce
Porphyromonas gingivalis may also be detected, although less ecological interaction networks in the gut microbiome and identified
frequently, in the healthy human periodontium.141-145 This raises the keystone species with a disproportionate influence on the gut micro-
issue of whether there are certain triggers that can enable P. gin- biome structure. The identified species were underrepresented ac-
givalis to initiate disease. Alternatively, or additionally, these find- cording to metagenomics abundance data.152 Perturbations applied
ings could be explained by strain and virulence diversity within the to these species have been shown computationally to exert a large
population structure of P. gingivalis (ie, different strains are associ- impact on microbial community structure. Interestingly, one of two
ated with health vs disease). Regarding the former possibility, major such species identified by the Learning Interactions from MIcrobial
P. gingivalis virulence factors, including the gingipains which are re- Time Series algorithm, Bacteroides fragilis, is experimentally impli-
quired for complement subversion, are regulated by local environ- cated as a keystone pathogen (“alpha-bug”) in colon cancer.153-155
100
mental conditions that likely differ among different individuals. The other putative keystone species identified was Bacteroides ster-
Other environmental factors that can modulate the pathogenicity cosis,152 which has also been associated with an increased risk of
of P. gingivalis are antagonistic bacteria within the microbial commu- colon cancer.156 Overall, a great number of microbial keystone spe-
nity. For instance, Streptococcus cristatus inhibits the expression of cies have been recently identified, primarily through computational
fimbrial proteins and gingipains in P. gingivalis through the signaling approaches, in different ecosystems.101 Regardless of the specific
action of arginine deiminase.146,147 This inhibitory action requires a ecosystem, keystone species appear to act as drivers of microbiome
direct contact between S. cristatus arginine deiminase and specific structure and function irrespective of their relative abundance.101
147
receptors on the surface of P. gingivalis (Figure 3C). In line with this
antagonistic mechanism, the distribution of P. gingivalis and S. crista-
tus are negatively correlated in the human subgingival dental plaque 6 | H O M EOS TATI C CO M M E N SA L S :
biofilm.148
Furthermore, S. cristatus suppresses P. gingivalis-induced S TA B I LIZ ATI O N O F H E A LTH - CO M PATI B LE
alveolar bone loss in mice.148 CO M M U N ITI E S
Host genetic factors may also dictate the virulence potential of
P. gingivalis. Thus, it is possible there may be individuals who can In contrast to keystone pathogens, certain commensals that can sta-
resist the capacity of P. gingivalis to convert a eubiotic microbiota bilize a microbiota against perturbations, which increase its nososym-
into a dysbiotic one. Such individuals might have alterations in the biocity, are referred to as “keystone stabilizers”.157 As such bacteria
signaling pathways required for immune subversion by P. gingivalis are not always in low abundance, perhaps a more encompassing term
and induction of dysbiosis. Interestingly, rare immune deficiencies would be “homeostatic commensals”. 2 In this regard, B. thetaiotaomi-
leading to dysregulated and destructive periodontal inflammation cron induces the antimicrobial peptide angiogenin, which kills op-
are associated with a compositionally unique dysbiotic microbiome portunistic or pathogenic organisms, but not B. thetaiotaomicron or
that lacks P. gingivalis.149,150 Therefore, since the presence of P. gin- other indigenous bacteria.158 Moreover, B. thetaiotaomicron inhibits
givalis is not necessarily associated with disease, it is more accurate nuclear factor kappa-B-mediated inflammation in a manner depend-
to consider this organism as an important risk factor rather than as a ent upon the nuclear metabolic receptor peroxisome proliferator-
causal agent in periodontitis. activated receptor gamma.159 Although the organism does not block
nuclear factor kappa-B activation in the cytoplasm, it somehow trig-
gers the formation of a complex between peroxisome proliferator-
5.8 | Keystone pathogens in other settings activated receptor gamma and the p65 subunit of the nuclear factor
kappa-B, which is subsequently exported from the nucleus, thus pre-
A study investigating the intestinal innate immune response of gno- venting induction of nuclear factor kappa-B-regulated pro-inflam-
tobiotic zebrafish showed that combinations of distinct bacterial matory genes.159 However, as discussed earlier, B. thetaiotaomicron
|
can also upregulate virulence gene expression in enterohemorrhagic shown to inhibit the expression of several epithelial cell pro-inflam-
90
E. coli, highlighting the contextual nature of classifying bacteria in matory cytokines in response to the pathobiont F. nucleatum while
functional categories of disease potential. Faecalibacterium praus- upregulating anti-inflammatory mediators.171 Thus, it is possible that
nitzii, whose counts are massively diminished in inflammatory bowel certain oral streptococci can act as homeostatic commensals and
disease but which normally comprises about 5% of total bacteria in help maintain host-community equilibrium, although direct in vivo
feces, was shown to oppose dysbiosis and suppress colitis in mice confirmation is currently lacking.
by secreting a metabolite with anti-inflammatory action.160,161 In a
gnotobiotic zebrafish model, low-abundance Shewanella (a probiotic
species that is used in aquaculture) secretes an anti-inflammatory 7 | I N FL A M M O PH I LI C PATH O B I O NT S :
factor that overrides the pro-inflammatory effect (intestinal neutro- CO M M E N S A L-T U R N E D PATH O G E N S
phil influx) of high-abundance species of the community.151 Because
numerically minor constituents of microbial communities can either Pathobionts are generally benign commensal organisms within an
enhance or reduce nososymbiocity, it can be argued that functional indigenous microbial community, but their numbers can increase
cataloging of community members is a more relevant prognostic fac- considerably and these organisms can become pathogenic when
tor than abundance determinations. host-microbe homeostasis is disrupted under certain conditions,
In a manner similar to that previously explained for B thetaiotao- such as inflammation, antibiotic treatment, tissue damage, dietary
micron, certain strains of F. nucleatum use a specific lipoprotein to in- shifts, and especially immune deficiencies2,40,157,172-174 (Figure 1).
duce oral epithelial cell production of human beta defensins to which These conditions can favor the outgrowth of pathobionts and thus
they are resistant, but the same molecules kill P. gingivalis at low mi- further destabilize the microbiota, thereby contributing to or exac-
cromolar concentrations.162 Whether these in vitro observations are erbating immune-mediated or inflammatory disorders. Pathobionts
relevant in vivo (ie, to suppress P. gingivalis-induced dysbiosis) is cur- are therefore resident organisms that are conditionally pathogenic as
rently uncertain. Assuming that this is the case, then those strains opposed to exogenously acquired infectious agents. A typical patho-
of F. nucleatum may act as homeostatic commensals locally in the biont is Clostridium difficile, which can be found at low levels in the
periodontal tissue, whereas their dissemination to extra-oral sites healthy human gut. However, after treatment with broad-spectrum
may be associated with pathology, given their resistance to human antibiotics that disrupt the indigenous microbiota, the abundance of
beta defensins. In this regard, F. nucleatum has been associated with C. difficile is massively increased and correlates with severe intestinal
colorectal carcinogenesis and adverse pregnancy outcomes.163-165 inflammation.40 Consistently, in a mouse model of C. difficile infec-
Although homeostatic commensals can induce antimicrobial pro- tion, antibiotic treatment promotes the ability of this organism to
teins that preferentially target periodontitis-associated bacteria,162 colonize the gut at high levels and induce inflammation.40
the reverse is also true. Indeed, P. gingivalis activates notch-1 signal- In the periodontium, inflammation not only mediates tissue de-
ing in oral epithelial cells leading to production of phospholipase A 2- struction but also appears to be a major mechanism for the emer-
IIA, an antimicrobial protein that differentially affects oral bacterial gence of pathobionts (Figure 4). As a consequence of inflammatory
species in a manner consistent with the promotion of dysbiosis.166 tissue destruction and bleeding in periodontitis, degraded collagen
Moreover, in oral epithelial cells, P. gingivalis induces CXC motif li- and heme-containing compounds (haptoglobin, hemopexin, and he-
gand-14, a chemokine with bactericidal activity against oral strep- moglobin) can be released into the gingival crevicular fluid and thus
tococci but not against P. gingivalis, which is relatively resistant by be utilized by subgingival proteolytic and asaccharolytic bacteria to
degrading it.167,168 obtain essential amino acids and iron.30,75,76,106 Thus, a subset of
In in vitro multispecies biofilms, hydrogen peroxide production species termed “inflammo-philic” (loving or attracted to inflamma-
by commensal species (eg, Streptococcus sanguinis, Streptococcus ora- tion)75 can selectively expand at the expense of those others which
lis, S. gordonii, S. cristatus, S. parasanguinis, and Streptococcus mitis) cannot exploit the new environmental conditions, in essence pro-
decreases the growth of periodontitis-associated bacteria (P. gingi- moting a dysbiotic imbalance in the microbial community.75,106 In
valis, A. actinomycetemcomitans, and Prevotella intermedia). However, this context, the addition of serum, hemoglobin, or hemin to an in
this growth inhibition is counteracted by enzymes that use hydrogen vitro-generated oral multispecies community selectively induces the
peroxide as substrate, such as myeloperoxidase and catalase, both of outgrowth of pathobionts that upregulate the expression of genes
which are elevated in the gingival crevicular fluid during periodon- encoding proteases, hemolysins, and molecules mediating the acqui-
titis (myeloperoxidase can be released by neutrophils and catalase sition of hemin.175 The altered community also displays increased
169,170
from erythrocytes through the action of bacterial hemolysins). pro-inflammatory potential.175
Peroxidases, therefore, can potentially contribute to dysbiosis Consistent with the concept that potential pathobionts should
(Figure 4). not only withstand the harsh inflammatory environment of the
As alluded to earlier, another probable oral homeostatic com- periodontal pockets but also take advantage of it, a gamma-proteo-
mensal is S. cristatus, which uses its arginine deiminase to antagonize bacteria species in the mouse oral cavity (designated NI1060) was
the virulence of P. gingivalis and suppress its ability to induce peri- shown to selectively accumulate at damaged periodontal tissue, os-
odontitis in mice.146-148 Moreover, in epithelial cells, S. cristatus was tensibly to procure nutrients from inflammatory tissue breakdown
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components.176 Moreover, NI1060 proactively aggravates destruc- increased expression of proteolysis-related genes and genes for iron
tive periodontal inflammation by activating the cytosolic receptor acquisition and lipopolysaccharide synthesis.182 Moreover, the bac-
Nod1. By contrast, other commensals, such as NI440 and NI968, terial numbers of periodontitis-associated subgingival biofilms in-
dominate healthy sites and do not thrive under destructive inflam- crease with increasing clinical inflammatory markers.109 Conversely,
mation, and therefore do not behave as pathobionts.176 but consistently, intervention studies in preclinical models have
Potassium ion was recently proposed as an additional inflam- shown that different anti-inflammatory treatments not only inhibit
mation-related environmental signal that can remodel the oral mi- experimental periodontitis in mice, rats, or rabbits, but also reduce
crobiome from a eubiotic community to a dysbiotic one.177 It was the periodontal bacterial load and reverse dysbiosis.62,96,183-186
previously shown that the concentrations of potassium in gingival Besides fostering the growth of inflammophilic bacteria, inflam-
crevicular fluid samples correlate positively with mean pocket depths mation may have direct effects on shaping the microbial virulence
in periodontitis patients.178 The study showed that an increase in the phenotype. In this regard, certain bacteria can sense pro-inflamma-
concentration of potassium ion in an ex vivo model altered the com- tory cytokines and, in response, upregulate the expression of vir-
position and virulence of the microbial community. These alterations ulence genes. For example, interleukin 1-beta and tumor necrosis
modified the microbiota interactions with epithelial cells resulting factor can promote, respectively, the growth and virulence poten-
in increased production of pro-inflammatory cytokines and reduced tial of certain pathogens (eg, Shigella flexneri and virulent strains
production of human beta defensin-3.177 of E. coli) that use specific receptors to bind these cytokines.187,188
Another factor contributing to the emergence of dysbiotic com- Similarly, Ps. aeruginosa uses the outer-membrane porin F to bind
munities of pathobionts is the redox potential. During the develop- interferon-gamma, thereby upregulating the expression of quo-
ment of subgingival biofilms, the metabolic activity of facultative rum-sensing–dependent virulence determinants (pyocyanin and
anaerobes causes depletion of oxygen and generation of carbon a lectin known as PA-I), which disrupt epithelial cell function.189
dioxide and hydrogen. This activity gradually lowers the redox Whether periodontal pathobionts use similar inflammation-depen-
potential in the crevice, generating an environment that prohibits dent mechanisms to enhance their virulence is uncertain. In this
the growth of aerobic bacteria but which promotes the growth of context, combined metagenome/metatranscriptome longitudinal
anaerobic species, including strict anaerobes associated with peri- analysis of the subgingival dental plaque microbiome in progressing
odontal dysbiosis.76,179 In stark contrast to this, oxygen limitation and nonprogressing sites has shown that progressing sites (those
in the colon (colonic epithelial hypoxia; <1% O2) promotes host-mi- showing an increase in pocket depth and clinical attachment level)
crobe homeostasis (eg, through the generation of short-chain fatty contain communities that express genes associated with periodontal
acids produced by the anaerobic fermentation of fiber), whereas disease pathogenesis (related to oxidative stress response, ferrous
increased oxygenation drives the selective expansion of facultative iron transport, amino acid transport, and lipopolysaccharide syn-
180
anaerobic proteobacteria associated with dysbiosis. However, the thesis).190 On the other hand, the relatively stable environment of
unifying theme in both periodontal and colon dysbiosis is inflamma- nonprogressing sites displays almost the same metagenomic compo-
tion. Indeed, inflammatory byproducts generated in the gut, such sition and gene expression profile at baseline and 2 months later.190
as tetrathionate and nitrate, can be used as electron acceptors by These data imply that the inflammatory environment of the pocket
proteobacteria, which bloom at the expense of anaerobic fermenting regulates the gene expression pattern of dysbiotic communities to
microbes.180,181 Overall, the altered conditions in the oral environ- perpetuate periodontal disease activity. Alternatively, it could be
ment discussed above support a microbial community with higher argued that if the community is sufficiently pathogenic to upregu-
proportions of anaerobic and inflammophilic bacteria that thrive at late virulence genes, this propensity can eventually promote inflam-
the expense of those species that cannot endure inflammation, or matory tissue destruction. Consistent with this, Dabdoub et al191
which fail to capitalize on the developing inflammatory environment. showed that the core microbiomes of clinically healthy sites in in-
Consistent with the concepts discussed above, the ecological dividuals with periodontitis are functionally more aligned (in terms
succession from periodontal health to disease has demonstrated of virulence gene expression) with diseased sites than healthy sites
the emergence of newly dominant community members rather than from periodontitis-free individuals, implying a potential for disease
novel species.109 Thus, genera or species that dominate microbial initiation or the presence of environmental conditions conducive for
communities in periodontitis are also present, albeit at severely dysbiosis. Interestingly, investigation of changes in gene expression
reduced relative abundance in health, as predicted by the ecologi- associated with the initial stages of dysbiosis showed that, among
cal plaque hypothesis. This holds that “periodontal pathogens” can those bacteria traditionally associated with the red complex, only
be found in the normal microbiota but at levels too low to initiate P. gingivalis was actively expressing virulence factors at baseline; by
disease; however, changes in ecological conditions may favor the contrast, T. denticola and Tannerella forsythia upregulated expression
outgrowth of such organisms (now known as pathobionts) beyond a of virulence genes later when tissue breakdown was clinically de-
179
threshold level that is sufficient to induce periodontitis. In keep- tected.190 These findings are consistent with a keystone pathogen
ing with the notion that inflammation is exploited by pathobionts to role for P. gingivalis (thus contributing to dysbiosis initiation) and with
serve their nutritional needs, in situ community-wide transcriptomic a role as pathobionts for T. denticola and Ta. forsythia, which may ag-
analysis of subgingival biofilms from periodontitis patients revealed gravate periodontitis when tissue homeostasis breaks down.
|
8 | S U M M A RY A N D CO N C LU D I N G whereas dysbiosis promotes destructive inflammation, inflammation

REMARKS creates a nutritionally favorable environment for further expansion
of inflammophilic pathobionts, thereby creating a positive-feedback
Periodontitis is not caused by individual bacteria perceived as causa- loop that can ultimately cause overt periodontitis in susceptible in-
tive agents, but rather by a multispecies community under the individuals (Figure 2). In this regard, the polymicrobial synergy and
fluence of organisms with specific functions and environmental dysbiosis model provides mechanistic underpinnings for the eco-
conditions that can tip the balance from homeostasis to dysbiosis logical plaque hypothesis.179 The notion that certain commensals
and destructive inflammation. In an inflammatory environment, the can conditionally exacerbate destructive inflammation is consistent
dysbiotic community continues to develop and further stimulates with the emerging association with periodontitis of previously un-
inflammatory responses (Figure 2). In susceptible hosts, the inflam- derappreciated bacteria, including the Gram-positive Filifactor alocis
matory response is poorly controlled and is ineffective at constrain- and Peptoanaerobacter stomatis and other species from the genera
ing the dysbiotic microbiota. Even worse, frustrated and misdirected Prevotella, Megasphaera, Selenomonas, and Desulfobulbus.109,110,193
responses contribute to tissue damage and thus perpetuate the in- Although most of these species are as of yet uncultivated, evidence
75
flammophilic community of pathobionts. derived from more tractable organisms has revealed virulence cre-
From the discussion in the earlier sections, it becomes evident dentials consistent with a pathobiotic status. For example, Fi. alocis
that polymicrobial communities exhibit a sophisticated level of struc- was shown to resist immune and inflammatory host responses and
tural and functional integration among their constituent species that thrive in a host-destructive inflammatory environment to which it
confers upon them quasi-organismal status. The functional interde- contributes.194-197 Pilot evidence also supports a pathobiotic status
pendence among constituent members of a polymicrobial commu- for Desulfobulbus oralis.198
192
nity is consistent with the “black queen hypothesis”. According In a state of disrupted homeostasis, the expansion of pathobi-
to this concept, those functions that are energetically costly can onts marks a potential tipping point in the development of noso-
be discarded as dispensable by “cheaters”, as long as they are not symbiocity as host-microbe homeostasis is unlikely to be restored
lost completely from the community, in other words that they are without intervention to control a robust, tissue-destructive inflam-
retained by a subset of community members (“helpers”), thus ben- matory response. Approaches to inhibit inflammation and promote
efiting the entire community. This provides a theoretical founda- its resolution, restore immune function in cases of immunodeficient
tion for the emergence of keystone pathogens (and perhaps other patients, and control environmental variables that promote dysbi-
specialized roles) that provide an indispensable public benefit to the osis (eg, antibiotics and diet) in patients regardless of immune sta-
community. Whereas exogenous pathogens responsible for classic tus, should contribute to immune homeostasis in periodontitis and
infectious diseases employ strategies to overcome colonization re- other mucosal inflammatory disorders.76,199-203 Moreover, strategies
sistance, endogenous bacteria with pathogenic potential, such as to interfere with the synergistic mechanisms that drive nososym-
keystone pathogens, exploit the inherent metabolic and/or coloniza- biocity (eg, targeting key interspecies interactions or host signaling
tion properties of their microbial neighbors (accessory pathogens) to pathways exploited by the microbes to subvert the host response)
increase the nososymbiocity of the community. should also be useful for the treatment of periodontitis and other
The functional categories associated with the polymicrobial syn- polymicrobial diseases.79,97,106,147,204-208
ergy and dysbiosis model (accessory pathogens, keystone patho-
gens, and pathobionts) are not invariable intrinsic properties of AC K N OW L E D G M E N T S
specific bacterial species or strains but rather refer to contextual The work of the authors is supported by NIH grants DE01111,
properties of constituent members in a nososymbiotic community. DE012505, DE017921, DE023193, GM125504 (RJL), and DE024153,
As discussed above, the same bacteria may act as homeostatic DE024716, DE026152 and DE028561 and DE029436 (GH).
commensals in one context and as accessory pathogens in another.
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Received: 26 February 2020 | Revised: 5 March 2020 | Accepted: 28 March 2020

Polymicrobial communities in periodontal disease: Their quasi-

George Hajishengallis1 | Richard J. Lamont2

2 | CO M M U N IT Y I N FR A S TRU C T U R E I N of many immune effector molecules. On tooth surfaces, a layer, or

P. gingivalis and C. albicans may have increased nososymbiocity. 3 | I N D I G E N O U S M I C RO B I OTA A N D

F I G U R E 4 Significance of inflammation in host-microbe interactions. Ideally, inflammation is an integrated component of a homeostatic

performance with cell type-specific actions and spatiotemporal 4 | ACC E S S O RY PATH O G E N S : U N W IT TI N G

8 | S U M M A RY A N D CO N C LU D I N G whereas dysbiosis promotes destructive inflammation, inflammation

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