Science - USA (2022-05-27)

GRAPHIC: KELLIE HOLOSKI/

SCIENCE

SCIENCE science.org 27 MAY 2022 • VOL 376 ISSUE 6596 935

receptor–mediated inflammatory cytokine

production by neutrophils. Concurrently, P.

gingivalis inhibits neutrophil bacterial kill-

ing activity by disarming the host-protective

Toll-like receptor pathways. P. gingivalis

thus creates the inflammatory conditions

that it needs to thrive, yet avoids the anti-

bacterial response, thereby perpetuating

dysbiosis and periodontitis ( 5 ). Gingipains

also induce vascular permeability, which

thus grants P. gingivalis, and other bacteria,

systemic reach. Notably, gingipain genes of

P. gingivalis are detectable in calcified tooth

tartar samples from ancient humans ( 6 ),

suggesting that these virulence factors have

aided P. gingivalis to persist in the oral mi-

crobiota for 100,000 years.

In a pathological context, oral cavity–

associated microbes have been detected in

distant organs in humans, including the

intestine, lungs, heart, and brain. Indeed,

numerous studies have suggested a relation-

ship between oral hygiene and respiratory

diseases, including asthma, chronic obstruc-

tive pulmonary disease, and pneumonia

( 7 ). Although these findings demonstrate

associations rather than causality, oral mi-

crobiota are likely microaspirated and af-

fect the lung microbiome. Oral bacteria are

also swallowed with saliva (1 ml of saliva can

contain up to 10^7 to 10^8 microbes) but are

exposed to gastric acid, bile acids, anaerobic

environments, and numerous other colo-

nization resistance mechanisms conferred

by the gut microbiota. Therefore, intestinal

colonization by oral microbiota is limited in

healthy individuals. However, an increased

proportion of oral microbes among the in-

testinal microbiota can be observed in sev-

eral diseases. For example, oral microbes are

significantly more abundant in the fecal mi-

crobiota of patients with IBD, primary scle-

rosing cholangitis (bile duct inflammation),

multiple sclerosis, and gastroesophageal re-

flux disease compared with healthy controls

( 8 ). Although the enrichment of oral bacte-

ria in the intestine could be a consequence

of a depleted gut commensal population,

several reports demonstrate the causal con-

tribution of oral microbes to disease patho-

genesis. For example, Klebsiella strains car-

rying antibiotic-resistance genes isolated

from saliva samples from patients with IBD

can persist in the intestine of antibiotics-

treated mice and drive intestinal inflamma-

tion ( 8 ). Consistently, intestinal enrichment

of Klebsiella species has been associated with

IBD in multiple human studies ( 9 ).

Opportunistic infections by oral microbes

may also contribute to the development of

cancer in the alimentary tract. For exam-

ple, oral microbes such as Fusobacterium,

Parvimonas, and Peptostreptococcus have

been associated with colorectal cancer (CRC)

development. In mice, F. nucleatum colonizes

CRC tissues through FadA adhesin–mediated

binding to host E-cadherin and accelerates

proliferation of tumor cells through activa-

tion of the Wnt– b-catenin signaling pathway

( 10 ). Moreover, Fusobacterium species can

migrate with metastasizing CRC cells, and

intracellular Fusobacterium-positive CRC

cells established metastatic lesions more ef-

fectively than Fusobacterium-negative cells

in mice ( 11 ). Therefore, the oral cavity could

act as a reservoir for opportunistic pathogens

that can colonize the intestine and might

causally affect chronic inflammation, as well

as cancer development and metastasis.

The mouth is a highly vascularized organ.

As a result, oral microbes and microbial mol-

ecules might directly enter the bloodstream

and contribute to the pathogenesis of sys-

temic diseases. The development of rheuma-

toid arthritis is promoted through a loss of

immune tolerance to citrullinated proteins.

Concordantly, amounts of anti-citrullinated

protein antibodies (ACPAs) are predictive

for current and future disease onset. ACPA-

positive individuals exhibit a higher relative

abundance of P. gingivalis in their oral mi-

crobiota. Although it is unclear whether P.

gingivalis plays a causal role, it may contrib-

ute to disease pathogenesis through the gen-

eration of citrullinated proteins. Gingipains

proteolytically cleave bacterial and host

proteins at arginine residues, and the short

peptides with carboxyl-terminal arginine are

immediately citrullinated by bacterial pepti-

dylarginine deiminase (PAD) that is secreted

with gingipains. It has been suggested that

citrullinated proteins elicit the generation of

antibodies that cross-react with bacterial and

host citrullinated molecules through molecu-

lar mimicry ( 12 ). Aggregatibacter actinomy-

cetemcomitans, associated with periodontitis,

also has the capacity to produce citrullinated

autoantigens through a mechanism distinct

from that of P. gingivalis, thereby also induc-

ing ACPAs through molecular mimicry ( 13 ).

Epidemiological studies have identi-

fied an association between periodontitis,

cognitive function, and dementia. Recent

work using brain specimens and cerebro-

spinal fluid from individuals diagnosed

with Alzheimer’s disease suggested that

P. gingivalis could colonize the brain and

induce neurodegeneration ( 14 ). P. gingi-

valis gingipains are found in association

with neurons, tau tangles, and amyloid-b

(Ab1-42) depositions in Alzheimer’s disease

specimens. Although further investiga-

tions will be required, P. gingivalis might

translocate to the brain by hematogenous

routes, leading to activation of the comple-

ment cascade, increasing amyloid- b pro-

duction, augmenting proinflammatory

cytokine expression, and causing neuroin-

flammation and neurodegeneration ( 14 ).

These studies suggest that oral microbiota

dysbiosis may have systemic ramifications

that promote development of autoimmune

and neurodegenerative diseases.

The oral microbiota is of particular in-

terest in the search for taxonomic and

molecular biomarkers of oral and systemic

diseases owing to the ease of sampling and

its compositional stability. Although the

Supragingival biofilm

Oral microbiota inuence disease

fungiform

Papillae:

filiform

Dorsal tongue biofilm

Fa p 2 Fa d A

E-cadherin

Fa d A , F. nucleatum adhesin;

Gal-GalNAc, N-acetylgalactosamine

Fusobacterium

Porphyromonas

gingivalis

Ta r g e t

protein

Peptidylarginine

deiminase,

gingipains

O

HN

H 2 N

Citrullinated

proteins

Production of

anti-citrullinated

protein antibodies

Wnt pathway

Corynebacterium

Streptococcus

Neisseria

Fusobacterium

Leptotrichia

Porphyromonas

Haemophilus

Rothia

Veillonella

Actinomyces

Streptococcus

Neisseria

Colorectal cancer Rheumatoid arthritis

Tumor cell proliferation

Gal-GalNAc

Cross-react to

citrullinated

α-enolase

O

HN

H 2 N

Oral microbiota in health and disease

Oral microbiota form distinct biofilms in different regions of the mouth that protect host tissues [based on ( 2 , 3 )].

When homeostasis between host and microbiota is lost, oral microbiota can affect distant tissues and

influence, for example, colorectal cancer cell proliferation and autoimmunity that leads to rheumatoid arthritis.