934 27 MAY 2022 • VOL 376 ISSUE 6596 science.org SCIENCEB y Timur Tuganbaev^1 , Koji Yoshida^1 ,
Kenya Honda1,T
he oral microbiota is shaped by mu-
tualistic coevolution with the host
and by the distinct physiology of the
mouth. In an evolutionary quid pro
quo, the host provides the commensal
bacteria with a stable ecological niche
and in return the oral microbiota supports
host health locally by forming symbiotic bio-
films that balance pH levels and suppress
pathogen growth, as well as potentially by
systemically reinforcing the body’s physi-
ological processes, such as cardiovascular
homeostasis. However, when a biofilm trans-
forms into a dysbiotic state, which is no
longer in homeostatic equilibrium with the
host, the oral microbiota may contribute to
the pathological processes of a wide range
of diseases, including inflammatory bowel
disease (IBD), arthritis, colorectal and pan-
creatic cancers, and Alzheimer’s disease,
by serving as a reservoir for opportunistic
pathogens. This in turn presents opportuni-
ties to identify predictive disease biomarkers
within the oral microbiota and the develop-
ment of intervention strategies to promote
oral and overall health.
The oral microbiota is the second most
diverse microbial community colonizing the
human body, after the intestinal microbiota.
In contrast to the relatively simple spatial or-
ganization of the intestinal microbiota, the
oral microbiota is formed by a collection of
compositionally distinct microbial commu-
nities reflecting an array of diverse micro-
environments. The host tightly controls the
composition of oral microbiota by imposing
selective pressures that require specialized
metabolic machinery (e.g., metabolism of
carbohydrates that are digested by salivary
a-amylase and of highly glycosylated salivary
proteins) and the ability to adhere to specific
substrates (e.g., buccal epithelium, epithe-
lium of tongue papillae, and teeth surfaces)
despite salivary flow, drinking, and chewing.
For instance, oral streptococci encode a fam-
ily of serine-rich repeat–containing glycopro-
teins and antigen I/II family of adhesins to
bind to the tooth pellicle, a thin layer formed
by salivary proteins. Streptococci have alsoevolved amylase-binding proteins to capture
human salivary amylase and use it to metab-
olize starch.
The host also controls the composition of
oral microbiota through salivary secretory
immunoglobulin A (SIgA) and antimicro-
bial peptides such as lysozyme and lactofer-
rin. Salivary SIgAs promote aggregation and
subsequent elimination of potentially patho-
genic bacteria, whereas SIgAs embedded in
tooth pellicles and mucin layers covering oral
epithelium provide binding sites for ben-
eficial bacteria, although it is unclear how
the salivary SIgAs discriminate beneficial
versus pathogenic microbes. The need to
control microbes with saliva is exemplified
in patients with xerostomia (dry mouth),
who often show an increased abundance of
fungi and acid-producing and acid-resis-
tant cariogenic bacteria (which cause tooth
decay). The multiple control pathways of
the host direct the assembly of spatially
specialized bacterial cooperatives called
oral biofilms. Within a biofilm, different
bacterial species are connected through
physical and metabolic associations that
confer a fitness advantage to the entire
microbial community. Biofilm structure
also promotes horizontal transfer of genes,
including antibiotic-resistance genes.
Although their origin is not well defined,
antibiotic-resistance genes can be detected
even in the oral microbiome of healthy
individuals not previously exposed to an-
tibiotics ( 1 ). Consequently, whereas the in-
testinal community is sensitive to dietary
change or antibiotic treatment, oral bio-
films are especially stable and resilient to
external perturbations.
The ability to self-assemble into complex
and site-specific biofilms on the soft and
hard tissues of the mouth plays a central
role in oral microbiota–host interactions
in health (see the figure). For example,
structural analysis of supragingival bac-
terial biofilms revealed complex layered
structures indicative of division of labor
among species ( 2 ). Corynebacterium fila-
ments form a structural underframe for
the entire biofilm and anchor it to the
salivary pellicle. At the surface of the bio-
film, cocci such as Streptococcus consume
sugars and oxygen and produce lactate, ac-
etate, and CO 2 , thereby supporting faculta-
tive anaerobic bacteria in the deeper layers
of the biofilm. Streptococcus also fulfills adefensive role by producing H 2 O 2 that may
protect the biofilm consortium and its host
from infections ( 2 ).
The dorsal tongue biofilms present on
the filiform papillae feature a distinct ar-
chitecture and composition, which contain
nitrate-reducing bacteria, such as Neisseria
and Rothia ( 3 ). Nitrate is actively trans-
ported from blood into saliva by the sialin
transporter and is further transformed to
nitrite by oral microbes, raising the salivary
nitrite concentration to 1000 times that of
plasma ( 4 ). The oral nitrate-reducing bac-
teria are mostly facultative anaerobes that
use nitrate as an alternative electron accep-
tor for respiration. It has been suggested
that absorbed nitrite is eventually con-
verted to NO, which in turn provides im-
portant benefits to the host including low-
ering blood pressure, improved endothelial
function, reversal of metabolic syndrome,
and reduction of oxidative stress, likely
through mechanisms involving activation
of the guanylate cyclase–cyclic guanosine
monophosphate pathway ( 4 ). Intriguingly,
the function of the filiform papillae remains
unclear because they lack taste buds. They
do, however, greatly increase the surface
area for biofilm formation and might thus
function as bioreactors that take advantage
of the large enzymatic repertoire of the mi-
crobiota. These observations suggest that
oral microbiota play integral roles in main-
taining host health systemically and locally.
Although the host and oral microbiota
probably exist in a mutually beneficial equi-
librium in homeostasis, external factors that
are not fully defined may trigger a vicious
cycle of self-perpetuating dysbiosis. Several
oral pathologies, including periodontitis, are
not contagious per se but result from oral
microbiota dysbiosis in which inflammation-
mediated tissue destruction leads to gen-
eration of metabolites that fuel pathogenic
proinflammatory microbes. In particular,
Porphyromonas gingivalis is considered a
“keystone pathogen” because it plays a criti-
cal role in maintaining the structure of an
inflammatory biofilm by subverting host im-
mune and inflammatory responses, and its
impact on the community is greater than
would be expected on the basis of its relative
abundance ( 5 ). Gingipains, virulence factors
that are secreted by P. gingivalis, are cysteine
proteases that promote proteolytic activa-
tion of complement and induce complementPERSPECTIVEThe effects of oral microbiota on health
Oral microbiota form complex biofilms that can affect local and systemic health
(^1) Department of Microbiology and Immunology, Keio
University School of Medicine, Tokyo, Japan.^2 RIKEN Center
for Integrative Medical Sciences (IMS), Kanagawa, Japan.
Email: [email protected]
SPECIAL SECTION THE SYSTEMIC MICROBIOME
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