Eur J Oral Sci 2018; 126(Suppl.

1): 13–18 © 2018 Eur J Oral Sci

DOI: 10.1111/eos.12425 European Journal of
Printed in Singapore. All rights reserved
Oral Sciences

H
akon Valen1 , Anne A. Scheie2
Biofilms and their properties 1
Nordic Institute of Dental Materials, NIOM,
Oslo, Norway; 2Institute of Oral Biology,
Faculty of Dentistry, University of Oslo, Oslo,
Norway
Valen H, Scheie AA. Biofilms and their properties.
Eur J Oral Sci 2018; 126(Suppl. 1): 13–18. © 2018 Eur J Oral Sci
Bacteria within the oral cavity live primarily as complex, polymicrobial bio-
films. Dental biofilms are necessary etiological factors for dental caries and
periodontal diseases but have also been implicated in diseases outside the oral
cavity. Biofilm is the preferred lifestyle for bacteria, and biofilms are found on
almost any surface in nature. Bacteria growing within a biofilm exhibit an H
akon Valen, Nordic Institute of Dental
altered phenotype. Substantial changes in gene expression occur when bacteria Materials, Sognsvn 70, Oslo 0855, Norway
are in close proximity or physical contact with one another or with the host.
E-mail: hakon.valen@niom.no
This may facilitate nutritional co-operation, cell–cell signaling, and gene trans-
fer, including transfer of antibiotic-resistance genes, thus rendering biofilm bac-
teria with properties other than those found in free-floating, planktonic Key words: bacterial communication; biofilm
bacteria. We will discuss biofilm properties and possible consequences for formation; dental caries; oral biofilm
future prophylaxis. Accepted for publication April 2018

Until the late 20th century, bacteria were thought to exist
as solitary cells that were incapable of performing com-
plex tasks. Bacteria were then generally studied as free
floating in liquid media (planktonic), which is not the
preferred lifestyle of bacteria in nature. It is now appar-
ent that bacteria usually grow in biofilms, whether in nat-
ure or in our bodies. Bacterial biofilms comprise any
group of microorganisms in adherent consortia sur-
rounded by self-produced polymer matrixes composed of
polysaccharides, proteins, lipids, and extracellular DNA.
Biofilms may form on almost all kind of living or non-
living surfaces, and are universal phenomena in natural,
industrial, and medical ecosystems.
Biofilms may be both beneficial and detrimental. They
are responsible for functional and economic burdens in
health and in industry, and thus carry significant eco-
nomic costs. However, bacteria in biofilms are important
for both oral and general health (69). The properties of
microorganisms in a biofilm are different from those of
free-floating, planktonic bacteria. When a bacterium
switches to the biofilm mode of growth, it undergoes a
phenotypic shift in behavior in which a large number of
genes are differentially expressed (1, 2).
Dental plaque is a classical biofilm and the most well
studied. Dental biofilms are necessary etiological fac-
tors in oral diseases that pose public health challenges
globally (3). Thus, among dentists, dental plaque was
of central interest long before the term ‘biofilm’ became
a common concept. Dentists spend most of their time
repairing and preventing the consequences of biofilms.
From animalcules to bacterial communities
More than 300 yr ago, the Dutch tradesman and
scientist, ANTONIE VAN LEEUWENHOEK, described an
important characteristic of biofilms (4). He scraped pla-
que off his own teeth and studied the samples in his
self-made microscopes. He made the important first dis-
covery of microorganisms, which he viewed as small
animals, animalcules. He wrote about his findings from
samples taken from the oral cavity: ‘There are more
animals living in the scum on the teeth in a man‘s
mouth, than there are men in a whole kingdom’ (4).
VAN LEEUWENHOEK made another important observa-
tion. He rinsed his mouth with vinegar, took a sample
from his teeth and looked at it in his microscope. He
found that nothing happened; the organisms were still
there. He then carried out the crucial experiment, mix-
ing a sample from his teeth with vinegar, whereupon
the organisms died immediately. He made his conclu-
sion from this simple experiment, and wrote (4):
And from this I drew the conclusion that the vinegar,
when I filled my mouth with it, didn‘t penetrate
through all the matter that is firmly lodged between
the front teeth, or the grinders, and killed only those
animalcules that were in the outermost part of the
white matter.
VAN LEEUWENHOEK discovered the true nature of
biofilms without knowing anything about the exis-
tence of bacteria. Biofilm bacteria are phenotypically
distinct from planktonic bacteria of the same species,
and biofilm bacteria are less susceptible to antimicro-
bial agents than planktonic bacteria. This characteris-
tic was reported almost 200 yr before appreciation of
bacteria as factors causing some of the diseases that
may pass from one person to another, and almost
another 100 yr before the biofilm theory was
accepted. It is not until recent years that we came to
understand some of the complex interactions between
bacteria in a biofilm.
14 Valen & Scheie
Since the early observations reported in 1933 by
Arthur T. Heinrici, that bacteria living in water made
films on submerged glass slides (5), it has been
acknowledged that bacteria in nature establish them-
selves on surfaces in a matrix-enclosed biofilm (6). With
a publication in Scientific American in 1978, BILL
COSTERTON established a new microbiological paradigm,
‘The biofilm concept’. This work described the central
role of bacterially produced polysaccharides in the
adhesion to surfaces and to each other (7). Pioneering
work on dental plaque bacteria, performed by Ronald
Gibbons at the Forsyth Institute, had then already
shown the important role of bacterially synthesized
polysaccharides – glucans – in the adhesion of Streptoc-
cus mutans (8). COSTERTON was a microbiologist, but
also a mountain climber and an outdoor man. His
attention to bacterial biofilms originated not from the
laboratory, but from a tumble on a slippery rock in a
creek. He studied bacteria in the mountain creek and
noted that a slimy, slippery film consisting of numerous
sessile bacteria covered the rocks in the creek. The
number of bacteria in this film greatly exceeded the
number of floating, planktonic bacteria. In the water
fraction, there were 8–10 bacteria per ml, while in the
slippery film there were millions per mg (9). It is benefi-
cial for bacteria to adhere to a surface. This is also the
situation in the oral cavity: the bacteria need to stick to
a surface. If not, the saliva flow will wash them out.
The dental bacterial biofilm communities are unique,
with large variation in amount and bacterial composi-
tion among and within individuals (10–12). As late as
1990, the biofilm concept was still in its infancy. In the
decades to follow, it became obvious that biofilm infec-
tions are widespread. The dramatic increase in biofilm
publications since 2000 reflects the understanding of the
importance of biofilms.
How do dental biofilms form?
Dental biofilm formation starts immediately after clean-
ing of the tooth surface, with adsorption of an organic
film, the pellicle, which serves as ligands for receptors
on the bacteria (13) (Fig. 1). The pioneer bacteria are
the bacteria that have direct contact with the pellicle
surface. The later colonizing bacteria will adhere to the
bacteria already attached, a phenomenon called coad-
hesion, or to different components of the extracellular
matrix. The early colonizing microbiota is dominated
by streptococcal species (14, 15). It has been demon-
strated that if the dental biofilm is left undisturbed, it
undergoes microbial succession and maturation. During
this process, the composition of bacteria in the biofilm
changes from a gram-positive-cocci-dominated micro-
biota to a microbiota composed of cocci, filamentous
organisms, spirils, and spirochetes, and containing
higher numbers of gram-negative bacteria. The acquisi-
tion of bacteria and maturation of the biofilm micro-
biota induces the development of gingivitis (16). These
findings are confirmed by newer molecular techniques
(11, 17). Coaggregation (i.e. the adhesion of genetically
Fig. 1. Formation of dental biofilm. Pioneer bacteria coloniz-
ing the dental hard tissue are dominated by streptococcal spp.
The adhered bacteria start to produce an extracellular matrix
and become ‘irreversibly’ attached. The biofilm matures and
increases in bacterial diversity and complexity. Bacteria may
detach from the oral biofilm, enabling colonization of other
surfaces in the oral cavity. Bacterial communication may med-
iate several of the steps in biofilm formation.
distinct bacteria to each other) has been described to
play a pivotal role in dental biofilm formation and is a
widespread phenomenon among oral bacteria (18–20).
Coaggregation has been described to mediate coloniza-
tion of late colonizers. The late colonizers may not
directly coaggregate with the early colonizing species
but can coaggregate with strains of the gram-negative
bacterium, Fusobacterium nucleatum, which has been
reported to be able to coaggregate with both late and
early colonizers of the dental hard tissues (18, 21).
Bacteria may detach from the biofilm. This dispersal
from the biofilm can be a passive process or an active
process mediated by the bacteria themselves. Dispersion
from the biofilm enables the bacteria to colonize new
sites in the oral cavity (22).
The close contact between bacteria in the oral biofilm
enables both synergistic and antagonistic interactions
(23). Nutritional cooperation is an important feature of
oral biofilms, resulting in the generation of food chains
and nutritional webs. The bacteria may cooperate to
metabolize salivary molecules (24). The metabolic
capacity of a bacterium has recently been suggested to
dictate its spatiotemporal position in the oral biofilm
(25). Soon after adhering to a surface, bacteria will
start to produce an extracellular matrix composed of
polysaccharides, lipids, proteins, and extracellular
DNA. This matrix is essential for biofilm architecture,
integrity, and the characteristic properties of biofilms,
including increased tolerance to antimicrobial com-
pounds (26, 27). The importance of polysaccharides for
production of oral biofilms, and the association of oral
biofilms with dental caries, was recognized early (28).
Bacterial glucosyltransferases producing extracellular
polysaccharides, either soluble or insoluble, were associ-
ated with adhesion of S. mutans to tooth surfaces and
with cariogenicity (28) Glucosyltransferases have also
been identified in other oral bacteria. Moreover, in
addition to the production of extracellular polysaccha-
rides, glucosyltransferases have been assumed to glyco-
sylate proteins important for adhesion and biofilm
formation (29, 30).

Extracellular DNA may play an important role in
the extracellular matrix of oral biofilms, as shown both
in vitro and from ex vivo samples (31). The close prox-
imity of bacteria in a biofilm may enable increased fre-
quencies of horizontal gene transfer (32). For oral
streptococci, both intraspecies and interspecies recombi-
nation may occur (33–35).
Bacterial communication
Bacterial communication is described to mediate several
steps in biofilm formation and maturation (36). In one
type of communication, genes are regulated in response
to signal concentration, the so-called ‘quorum sensing’
communication. The concentration of signal molecules
depends on bacterial density (i.e. the quorum). By
quorum sensing, genes are turned on and off in unison.
This phenomenon was initially investigated in biolumi-
nescent bacteria. The term autoinduction and the
chemical substance that induces autoinduction and bio-
luminescence, the autoinducer, was first described in
Photobacterium fischeri (now called Vibrio fischeri)
in the 1970s and the signaling molecule was identified
in 1981 (37, 38). Bacterial communication was initially
thought to be linked to a few bacteria only. However,
it has been shown that bacterial communication is a
widespread phenomenon among bacteria. Bacteria
coordinate their activities by quorum sensing, thus
regulating diverse bacterial activities, such as adhe-
sion, biofilm formation, aggregation, virulence, motil-
ity, antibiotic resistance, and horizontal gene transfer
(39). The many different quorum-sensing-regulated
activities opens the possibility of interfering with bac-
terial communication through the development of
novel treatment strategies against bacterial infections
(40).
Three main classes of signaling molecules have been
described for communication between bacteria: autoin-
ducer peptides (AIPs); autoinducer-1 (AI-1); and
autoinducer-2 (AI-2). The classical view is that the sig-
nal molecules are produced, released, and accumulated
in the environment. At a critical signal concentration,
the signal molecules activate the cognate receptor or
response regulator that switches transcription of effec-
tor genes on or off. Quorum sensing is a type of regula-
tory process that ensures a sufficient number of
bacteria is present when the activity is synchronously
activated in the group (41). It would be futile for only
one bacterium to produce an enzyme or a virulence
protein. In polymicrobial biofilms, bacteria may be
exposed to several different signaling molecules pro-
duced by the bacteria residing in the biofilm. Thus,
receptor specificity for signal molecule detection differs:
some receptors are reported to be highly specific for
their ligand, whereas others are more promiscuous (42).
Gram-negative bacteria use various acyl homoserine
lactone (AI-1) molecules for intraspecies communica-
tion, whereas gram-positive bacteria use AIPs as signal-
ing molecules. However, the AI-2 signaling molecule
produced by both gram-positive and gram-negative
Biofilm properties 15
bacteria has been described to allow communication
across gram-classification and species borders (41). The
luxS gene transcribes S-ribosylhomocysteine lyase,
which is responsible for production of AI-2. The luxS
gene is widespread in bacteria but the known receptor
proteins for AI-2 do not have the same distribution
(43). In addition to production of AI-2, S-ribosylhomo-
cysteine lyase plays an important role in bacterial meta-
bolism in the activated methyl cycle (44). Therefore, the
presence of the luxS gene in a bacterial genome may not
necessarily indicate that the bacteria use AI-2 as a
quorum-sensing molecule. The absence of a known
receptor for AI-2 could signify that either the bacteria
do not respond to AI-2 or that other unidentified recep-
tors may exist. Recently, a fructose-specific phospho-
enolpyruvate-phosphotransferase, FruA, was reported
to function as a receptor/transporter for AI-2 in Strep-
tococcus pneumoniae, enabling the use of galactose as a
carbon source, leading to increased capsular production
and virulence (45).
Autoinducer-2 and luxS in oral streptococci
Autoinducer-2 AI-2 signaling has been shown to regulate
many different activities in a diverse panel of bacteria,
including oral streptococci (46). Inactivating the luxS
gene renders bacteria unable to produce AI-2. In the
absence of a functional luxS, Streptococcus anginosus
produced 50% less biofilm than did the wild-type
S. anginosus with an intact luxS (47). MCNAB and
coworkers showed that biofilm formation between
Streptococcus gordonii and Porphyromonas gingivalis
requires intact luxS. The two species may form biofilm
together but P. gingivalis depends on the prior adhe-
sion of S. gordonii. Streptococcus gordonii is an early
colonizer and part of the resident microbiota, whereas
P. gingivalis is a putative periodontal pathogen. Both
species of bacteria produce AI-2. When luxS is inacti-
vated in either S. gordonii or P. gingivalis, biofilm is
still formed, indicating that both species may respond
to heterologous AI-2. When luxS is inactivated in both
S. gordonii and P. gingivalis, the ability of these two
species of bacteria to form biofilm together is lost (48).
RICKARD and coworkers showed, in another study, the
importance of AI-2 communication for combined bio-
film formation of Streptococcus oralis and Actinomyces
naeslundii (49). In a more recent study, WANG and
coworkers showed that AI-2 communication was
important for dual biofilm of S. mutans and S. gor-
donii. Furthermore, inactivation of the luxS gene (and
consequent failure to produce AI-2) leads to increased
sensitivity to chlorhexidine (50).
Autoinducer-2 signaling in bacterial biofilms has also
been reported to affect antibiotic sensitivity. The
biofilm formed by a Streptococcus intermedius luxS-
negative strain exposed to subinhibitory concentrations
of ampicillin or tetracycline was reduced compared to
that produced by an S. intermedius luxS-positive strain.
However, after adding synthetic AI-2, the biofilm-form-
ing ability was restored (51). This finding supports the
16 Valen & Scheie
importance of communication in bacterial sensitivity
and antibiotic tolerance as well as in biofilm formation.
Autoinducer peptides in oral streptococci
The competence stimulating peptide (CSP) pheromone
was initially discovered in S. pneumoniae, in which it
induced competence for genetic transformation (i.e.
uptake and incorporation of DNA into the host gen-
ome) (52). The CSP is excreted by a transporter and
binds to a membrane-located receptor, ComD. This
activates a response regulator, ComE, which induces
transcription of the alternative sigma factor, ComX,
which regulates genes necessary for transformation.
Bacterial sigma factors associate with the RNA poly-
merase and enable promoter-recognition specificity for
transcription of genes. In S. mutans, a similar quo-
rum-sensing system was discovered (53). However, the
ComDE of S. mutans is more closely related to the
BlpRH of S. pneumoniae, which regulates bacteriocin
production than ComDE (54). Recently, a peptide
named comX/sigX inducing peptide (XIP), encoded by
the comS gene, was discovered in S. mutans. This pep-
tide was shown to control competence by binding to
an intracellular Rgg (regulator gene of glycosyltrans-
ferase) transcriptional regulator, ComR, which regu-
lates competence in this species by activating
transcription of ComX (55). It is assumed that the
ComCDE system controls induction of competence in
the mitis and anginosus groups of streptococci,
whereas the ComRS system controls induction of com-
petence in the mutans, salivarius, bovis, and the pyo-
genic groups of streptococci (56). Although ComCDE
and ComRS are intimately linked to transformation and
the alternative sigma factor controls a core regulon
related to transformation, other genes are upregulated,
apparently without being directly involved in the trans-
formation process (57). Competence-stimulating peptide
has been shown to affect biofilm formation of the oral
streptococci S. gordonii, S. mutans, and S. intermedius
(58–60). In addition, LI and coworkers have shown that
adaptation to an acidic environment increases with CSP
signaling (61). Competence-stimulating peptide has also
been shown to induce fratricide, killing, and lysis of non-
competent cells in the environment. The biological role
of fratricide may be to provide DNA for genetic
exchange (62).
The close contact between bacteria in biofilms may
enable interstrain and interspecies communication.
However, allelic variations of the genes encoding the
CSP pheromone and the receptor, ComD, have been
described for streptococci (63, 64). Thus, only strains
belonging to the same pherotype are able to communi-
cate. However, the ComRS system has recently been
suggested to mediate interspecies communication
among streptococci as the ComR receptors in strepto-
coccal species differ in their promiscuity for signal
recognition (65). Cross-talk between streptococcal spe-
cies has also been reported for other peptide phero-
mones (66).
Biofilm control
The dental biofilm may be composed of several hun-
dred different bacterial species and strains (67). This
enlarges the total genetic pool of enzymes that can
inactivate antibacterial compounds. In a biofilm, bacte-
ria are protected by the extracellular matrix. This
matrix may bind antibacterial compounds, impeding
their penetration, thus preventing such compounds
from reaching their target. Bacteria may also excrete
and concentrate enzymes that inactivate the antibacte-
rial compounds. The growth of bacteria is altered in a
biofilm, and they may enter a dormant state that
reduces their susceptibility to antibacterial compounds
(27). In addition, the close contact and proximity
between bacteria in a biofilm may allow genetic
exchange and transfer of, for instance, antibacterial-
resistance genes to occur readily.
There is currently considerable activity aimed to
understand the complex properties and interplay among
bacteria in oral biofilms and to identify novel com-
pounds, technologies and methods to eradicate or pre-
vent the formation of oral biofilms (68). Several
compounds and technologies with antibacterial effect
have been introduced. Antimicrobial compounds may
be added to products, such as dentifrices and oral
rinses, or be incorporated into dental-restorative mate-
rials for control of oral biofilm. Material and tooth sur-
faces may be engineered to reduced bacterial adhesion.
Products for antibacterial photodynamic therapy to kill
bacteria in biofilms are commercially available. Their
main antibacterial effect is mediated through the pro-
duction of reactive oxygen species generated after
absorption of visible light by a photosensitizer. Probi-
otic bacteria may be administered to maintain biofilm
ecology in a state compatible with health or to restore
biofilm ecology to this state. Interference with bacterial
communication may inhibit expression of virulence
genes or biofilm formation. This latter form of therapy
differs from the traditional antimicrobial mechanism
of action by not aiming to kill bacteria but rather to
render bacteria less virulent.
Future prospects
Oral biofilm-associated diseases, such as caries and
periodontitis, represent global public health challenges
(3). The diseases develop as a result of dysbiosis of the
oral microbiome (69). There is a long tradition in medi-
cine for treating bacterial infections by the use of
antibiotics. Unfortunately, biofilm bacteria are signifi-
cantly less sensitive to antibacterial agents than are
their planktonic counterparts (70). This property of
biofilm challenges us in our daily work as dentists, and
might explain why many oral prophylactic agents pre-
dicted to be efficacious in vitro, only show marginal
effect in vivo.
In view of the prevalence and cost related to preven-
tion and treatment of biofilm-induced dental diseases,
there is a need for research to elucidate, in further

detail, the complex properties and interplay among bac-
teria in oral biofilms. We should aim to identify agents,
technologies, and methods that comply with health and
are without adverse effects. At present, educating
patients in mechanical biofilm disruption, in combina-
tion with supporting change in lifestyle factors asso-
ciated with oral biofilm associated diseases remains the
cornerstone for controlling oral biofilm levels compati-
ble with oral health for the individual.
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