Studio odontoiatrico dott Fecchi Cleto

01/02/2026

02/12/2025

Sarà difficile spiegarlo ai pazienti…

Revisioni critiche in biologia e medicina orale
Neuroinfiammazione: una conseguenza distale
della parodontite
Journal of Dental Research
2022, Vol. 101(12) 1441–1449
© International Association for Dental Research e American Association for Dental,
Oral, and Craniofacial Research 2022
Linee guida per il riutilizzo degli articoli:
sagepub.com/journals-permissions
https://doi.org/10.1177/00220345221102084
DOI: 10.1177/00220345221102084
journals.sagepub.com/home/jdr
X. Li1,2,3, M. Kiprowska1, T. Kansara4, P. Kansara1 e P. Li1
Abstract
La parodontite, una malattia infiammatoria cronica, induce infiammazione sistemica e contribuisce allo sviluppo di malattie neurodegenerative. L'eziologia precisa delle patologie neurodegenerative più comuni, come l'Alzheimer sporadico, il morbo di Parkinson e
la sclerosi multipla (rispettivamente AD, MP e SM), deve ancora essere svelata. La neuroinfiammazione cronica è una componente ben nota
di queste patologie e le prove suggeriscono che l'infiammazione sistemica sia un possibile stimolo per lo sviluppo della neuroinfiammazione.
L'infiammazione sistemica può avere conseguenze deleterie sul cervello se l'infiammazione è sufficientemente grave o se il cervello
mostra vulnerabilità dovute a predisposizione genetica, invecchiamento o malattie neurodegenerative. È stato proposto che la malattia parodontale
possa iniziare o contribuire alla patogenesi dell'AD attraverso molteplici vie, inclusi i principali patogeni parodontali. I batteri orali disbiotici
possono rilasciare prodotti batterici nel flusso sanguigno e infine attraversare la barriera emato-encefalica; questi batteri possono anche causare
alterazioni al microbiota intestinale che aumentano l'infiammazione e potenzialmente influenzano la funzione cerebrale attraverso l'asse intestino-cervello. Il nervo trigemino
è stato suggerito come un'altra via per collegare i prodotti batterici orali al cervello. Il morbo di Parkinson e la sclerosi multipla sono spesso preceduti da
sintomi gastrointestinali o da una composizione anomala del microbioma intestinale, e le alterazioni del sistema nervoso enterico accompagnano la
malattia. Evidenze cliniche hanno suggerito che i pazienti con parodontite sono a maggior rischio di sviluppare il morbo di Parkinson e la sclerosi multipla. Questo nesso tra
cervello, malattia parodontale e infiammazione sistemica preannuncia nuovi modi in cui le cellule microgliali, le principali cellule dell'immunità innata,
e gli astrociti, i regolatori cruciali delle risposte immunitarie innate e adattative nel cervello, contribuiscono alla patologia cerebrale. Attualmente,
la mancanza di comprensione della patogenesi della neurodegenerazione sta ostacolando lo sviluppo di trattamenti. Tuttavia, possiamo prevenire
questa patogenesi affrontando uno dei suoi possibili fattori contribuenti (la parodontite) all'infiammazione sistemica attraverso semplici misure preventive.

Journal of Dental Research (JDR) is a peer-reviewed scientific journal dedicated to the dissemination of new knowledge and information, encompassing all areas of clinical research in the dental, oral and craniofacial sciences. Average time from submission to first decision: 17 days View full journal...

01/12/2025

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1102084JDR###10.1177/00220345221102084Journal of Dental Research X(X)Neuroinflammation
research-article2022
Critical Reviews in Oral Biology & Medicine
Neuroinflammation: A Distal
Consequence of Periodontitis
Journal of Dental Research
2022, Vol. 101(12) 1441­ –1449
© International Association for Dental
Research and American Association for Dental,
Oral, and Craniofacial Research 2022
Article reuse guidelines:
sagepub.com/journals-permissions
https://doi.org/10.1177/00220345221102084
DOI: 10.1177/00220345221102084
journals.sagepub.com/home/jdr
X. Li1,2,3 , M. Kiprowska1, T. Kansara4, P. Kansara1 , and P. Li1
Abstract
Periodontitis, a chronic, inflammatory disease, induces systemic inflammation and contributes to the development of neurodegenerative
diseases. The precise etiology of the most common neurodegenerative disorders, such as sporadic Alzheimer’s, Parkinson’s diseases and
multiple sclerosis (AD, PD, and MS, respectively), remains to be revealed. Chronic neuroinflammation is a well-recognized component
of these disorders, and evidence suggests that systemic inflammation is a possible stimulus for neuroinflammation development.
Systemic inflammation can lead to deleterious consequences on the brain if the inflammation is sufficiently severe or if the brain
shows vulnerabilities due to genetic predisposition, aging, or neurodegenerative diseases. It has been proposed that periodontal disease
can initiate or contribute to the AD pathogenesis through multiple pathways, including key periodontal pathogens. Dysbiotic oral
bacteria can release bacterial products into the bloodstream and eventually cross the brain-blood barrier; these bacteria can also cause
alterations to gut microbiota that enhance inflammation and potentially affect brain function via the gut–brain axis. The trigeminal
nerve has been suggested as another route for connecting oral bacterial products to the brain. PD and MS are often preceded by
gastrointestinal symptoms or aberrant gut microbiome composition, and alterations in the enteric nervous system accompany the
disease. Clinical evidence has suggested that patients with periodontitis are at a higher risk of developing PD and MS. This nexus among
the brain, periodontal disease, and systemic inflammation heralds new ways in which microglial cells, the main innate immune cells,
and astrocytes, the crucial regulators of innate and adaptive immune responses in the brain, contribute to brain pathology. Currently,
the lack of understanding of the pathogenesis of neurodegeneration is hindering treatment development. However, we may prevent
this pathogenesis by tackling one of its possible contributors (periodontitis) for systemic inflammation through simple preventive oral
hygiene measures.
Keywords: inflammation, dysbiosis, neurodegeneration, oral microbiome, periodontal disease, oral hygiene
Introduction
The incidence of periodontal disease increases with age, and in
the United States, 70.1% of adults aged 65 y and older are diag-
nosed with some form of periodontal disease, making it the
second most common oral ailment, after dental caries.
Periodontitis is a severe form of periodontal disease that results
in loss of tooth and damage of the jawbone structure if left
untreated. The detrimental consequences of periodontitis are
not limited to the oral cavity as an ever-growing number of
studies show that both periodontal bacteria and inflammatory
mediators induced by these bacteria can travel to distant organs
and contribute to the development of various pathologies,
including the brain. Periodontitis is triggered by certain Gram-
negative anaerobic bacteria in dental plaque and their metabo-
lites in addition to bacterial proteases (Kornman et al. 1997;
Delima et al. 2002; Stathopoulou et al. 2010; Taguchi et al. 2015).
The major periodontitis pathogens, including Aggregatibacter
actinomycetemcomitans, Porphyromonas gingivalis,
Tannerella forsythia, Treponema denticola, Prevotella inter-
media, and Fusobacterium nucleatum, stimulate proinflamma-
tory responses not only in oral cavity. The effects of these key
periodontitis pathogens on inflammation and immune
responses at systemic levels have been summarized in Table 1.
Animals infected with T. forsythia or P. gingivalis exhibited
significant elevations of specific IgG and IgM in the serum
(Velsko et al. 2014; Chukkapalli et al. 2015). Importantly, oral
epithelial cells exposed to repeated assaults by bacterial toxins,
such as lipopolysaccharide (LPS) and gingipain (cysteine pro-
tease secreted by P. gingivalis), secrete proinflammatory cyto-
kines, including tumor necrosis factor α (TNF-α), interleukins
1β (IL-1β) and 6 (IL-6), interferon γ (INF-γ), and prostaglan-
din E2 (PGE2), that trigger the cascade of molecular events
eventually leading to gingival cell death. The cytokines can
also be disseminated via the bloodstream, thus leading to
1Department of Molecular Pathobiology, New York University College
of Dentistry, New York, NY, USA
2Department of Urology, New York University Grossman School of
Medicine, New York, NY, USA
3Perlmutter Cancer Institute, New York University Langone Medical
Center, New York, NY, USA
4Cleveland Clinic- Union hospital, Dover, OH, USA
Corresponding Author:
X. Li, Department of Molecular Pathobiology, New York University
College of Dentistry, 345 E 24 Street, Room 901S, New York, NY
10010, USA.
Email: [email protected]
1442 Journal of Dental Research 101(12)
Table 1. Systemic Inflammation and Immune Responses Induced by Periodontitis Pathogens.
AD, Alzheimer’s disease; IL, interleukin; INF-γ, interferon γ; NK, natural killer; PCR, polymerase chain reaction; TNF-α, tumor necrosis factor α.
Periodontitis Pathogen Impacts beyond Oral Cavity Diseases/Models
Aggregatibacter
actinomycetemcomitans
Serum IFN-γ elevation associated with enhanced dental plaque load with
A. actinomycetemcomitans; presence associated with increased population of
CD3−/CD16+ (NK lymphocytes) in patients’ blood (Andrukhov et al. 2011)
Periodontitis patients
Porphyromonas gingivalis Serum TNF-α elevation associated with enhanced dental plaque load with
P. gingivalis (Andrukhov et al. 2011)
Periodontitis patients
P. gingivalis infection increased shedding of human umbilical vein endothelial cells;
upregulation in proinflammatory cytokines TNF-α, IL-6, and IL-8 (Bugueno et al.
2020)
In vitro
Increased inflammation within the deep connective tissue (Delima et al. 2002)
Nonhuman primate with
periodontitis
Significantly elevated P. gingivalis–specific IgG and IgM antibodies; P. gingivalis genomic
data detected in hearts, aorta, spleens, and kidneys (Velsko et al. 2014)
ApoE-null mice orally infected
with P. gingivalis
Tannerella forsythia Treponema denticola Elevated levels of serum IgG and IgM antibodies; increased serum amyloid A and
significantly reduced serum nitric oxide; significantly increased serum lipoproteins
(Chukkapalli et al. 2015)
Mice orally infected with
T. forsythia
Presence associated with increased CD3+/CD8+ cells (cytotoxic T lymphocytes) in
patients’ blood (Andrukhov et al. 2011)
Periodontitis patients
Prevotella intermedia AD patients had at least 1 Treponema species detected in the brain cortex than
non-AD donors (χ2
=
11.99, P < 0.001) in PCR. Treponema was also detected in
trigeminal ganglia of 3 AD and 2 control donors (Riviere et al. 2002).
Frontal lobe cortex of human
donors with AD and controls
Prevotella significantly increased in β-amyloid–positive subjects (Kamer et al. 2021) Human subgingival periodontal
bacteria and cerebrospinal
fluid amyloid biomarker
Fusobacterium nucleatum Ventriculitis and brain abscess due to F. nucleatum infection in a man with no
significant predisposing factors (Kai et al. 2008)
Clinical case report
Caused the host to produce inflammatory factors and recruit inflammatory cells;
induced immune suppression of gut mucosa by suppressing the function of
immune cells (Wu et al. 2019)
Patients with colorectal cancers
Promoted intestinal inflammation, increased immune cell infiltration, and depleted
mucus layers (Engevik et al. 2021)
Mice harboring a human
microbiome
systemic inflammation and triggering inflammatory responses
in distant organs, including the brain. Many studies, whether
epidemiological, postmortem, or those performed in in vivo
models, have found an association between systemic inflam-
mation and neurodegeneration (Perry et al. 2007; Pott Godoy
et al. 2008; Londoño and Cadavid 2010).
Alzheimer’s and Parkinson’s diseases (AD and PD, respec-
tively) are the most prevalent neurodegenerative diseases, and
their incidence is increasing over time. Despite decades of
research and elucidated molecular pathological events and
symptoms, the etiology of many neurodegenerative disorders
remains unknown. At present, no effective disease-modifying
drugs for these disorders exist, and once the neurodegenerative
process begins, it will progress, leading to an increase in neu-
ronal death and loss of synapses that are clinically manifested
as cognitive or physical decline. Aducanumab, a new drug
recently approved by the Food and Drug Administration (FDA)
for AD targets β-amyloid (Aβ) aggregates, has provided
ambiguous clinical results (Mullard 2021). Therefore, it is of
utmost importance to identify more preventable risk factors to
prevent, slow down, or delay neurodegeneration.
It is widely agreed that chronic neuroinflammation may be
the initial molecular pathologies that lead to the neuronal demise
in neurodegenerative disorders. The questions that remain to be
answered are what starts and then perpetuates neuroinflamma-
tion and whether it can be prevented. In recent years, periodon-
titis has become the focus of research aimed at understanding the
root cause of chronic neuroinflammation due to its known role in
causing systemic inflammation and its proximity to the central
nervous system (CNS). Theoretically, these factors can contrib-
ute to the development of inflammation in the brain and then
possibly lead to neurodegeneration. In the current review, we
present the newest findings regarding the connection and under-
lying mechanisms between periodontitis and neurodegenerative
diseases linked through neuroinflammation in the hopes of
understanding the mechanisms of these interactions.
Periodontitis and Neuroinflammation
Neuroinflammation is a result of an innate immune response in
the brain with 2 forms: 1) acute form, characterized by a tran-
sient expression of the inflammatory mediators, and (2)
chronic, during which the resolution phase of inflammation is
significantly delayed. The latter process is a continuous, low-
grade inflammation accomplished by prolonged secretion of
proinflammatory cytokines by glial cells that over time con-
tribute to neuronal cell death. When the systemic inflammatory
stimulus is not resolved timely, it leads to a state in which con-
stantly activated microglia become overly sensitive to a new
immune trigger and respond in an exaggerated way (Perry and
Holmes 2014). Studies have demonstrated that Toll-like recep-
tor 4 (TLR4) activation by LPS in astrocytes and microglia
induced a proinflammatory signal in the brain (Gorina et al.
2011; Chen et al. 2012).
Neuroinflammation 1443
Table 2. Routes for Pathobiological Substance Entry into the Brain.
Routes Mechanisms References
Direct bacterial invasion Invasion of proinflammatory
cytokines
Indirect communication Bacteria and bacterial lipopolysaccharides can reach the CNS and activate matrix
metalloproteases, which disrupt the BBB, increasing its permeability and
allowing bacteria to pe*****te the brain parenchyma.
Pathogenic bacteria can enter the brain through the peripheral nerve route such
as the olfactory and trigeminal nerves.
The peripheral proinflammatory cytokines can activate the vagus nerve, which
then relays the information to the CNS.
The inflammatory mediators can enter the cerebral parenchyma and initiate the
inflammatory response through the region of the brain that lacks the BBB, like
the choroid plexus and circumventricular organs.
Activated peripheral monocytes can be actively recruited by the chemokine
system into the brain parenchyma, where they secrete proinflammatory
cytokines, such as TNF-α, which activate microglia, leading to
neuroinflammation.
Leptomeningeal cells, present in the innermost layer of the meninges, transduce
the peripheral inflammatory signals from macrophages to microglia in the brain
via Toll-like receptor 2.
Systemic route (Wright et al. 2007;
Frister et al. 2014)
Cranial route (Riviere et al. 2002;
Olsen and Singhrao 2015)
Neural pathways (Capuron and
Miller 2011)
Humoral pathways (D’Mello and
Swain 2017)
Cellular pathways (D’Mello and
Swain 2017)
Leptomeningeal cells (Wu et al.
2005; Liu et al. 2013)
BBB, blood–brain barrier; CNS, central nervous system; TNF-α, tumor necrosis factor α.
Patients with periodontitis could have neuroinflammation
due to sustained systemic inflammation. C-reactive protein
(CRP), a marker of systemic inflammation, has also been
shown to be significantly higher in the serum of periodontal
disease patients (Goyal et al. 2014; Chang et al. 2020).
Likewise, a study identified a correlation between higher pro-
portions of certain periodontal bacteria in the dental plaques of
patients with periodontitis and increased levels of specific pro-
inflammatory cytokines and changes in the types of lympho-
cytes in their serum. Increases of A. actinomycetemcomitans
were associated with significantly increased serum levels of
IFN-γ while a high P. gingivalis load was associated with an
increase in serum levels of TNF-α (Andrukhov et al. 2011).
This finding suggests that predominance of certain periodontal
bacteria is associated with different subsets of immune cells in
the peripheral blood of the periodontitis patients since different
immune cells produce different types of cytokines. The fact
that periodontitis induces systemic inflammation and leads to
increased levels of proinflammatory cytokines in the serum
together with microglial priming make periodontitis a likely
source of chronic neuroinflammation.
The CNS is protected by the blood–brain barrier (BBB), but
extended exposure to noxious species can disrupt and increase
the BBB permeability, allowing them to reach the brain through
a systemic route or a cranial route (Table 2). In addition, the
peripheral proinflammatory cytokines may activate the vagus
nerve (Capuron and Miller 2011), which then relays the infor-
mation to the CNS. Leptomeningeal cells, present in the inner-
most layer of the meninges, may transduce the peripheral
inflammatory signals from macrophages to microglia (Liu
et al. 2013; Wu et al. 2019). Various types of infectious agents,
including the keystone periodontal pathogens, P. gingivalis and
T. denticola, have been found in postmortem brain tissue
obtained from AD patients, which provide a link between bac-
teremia and neurodegeneration (Riviere et al. 2002; Poole et al.
2013; Dominy et al. 2019).
The link between periodontitis and neuroinflammation
observed in human subjects is supported by animal studies.
Systemic inflammation induced by peripheral injection of bac-
terial LPS leads to expression of proinflammatory cytokines,
such as TNF-α and IL-1β in the rodent brain. Animal studies
also show that age exacerbates the level of neuroinflammation
and behavioral deficits in mice after peripheral administration
of LPS in a manner similar to elderly patients who have cogni-
tive deficits in addition to frequent systemic infections
(Godbout et al. 2005). In a murine model of periodontitis in
which a ligature was placed around the second maxillary
molar, increased expression of proinflammatory cytokines was
detected in the gingival tissue and in the brain, indicating that
the periodontitis-induced inflammation can trigger the immune
response in the brain and cause neuroinflammation (Furutama
et al. 2020). Importantly, it has been demonstrated that even
without infection of periodontitis pathogens, ligature-induced
experimental periodontitis can affect the microglia and the
brain’s cytokine profile in wild-type mice and cause a signifi-
cant decrease in plaque-associated microglia in 5×FAD mice, a
well-established mouse model of AD with rapid Aβ accumula-
tion (Kantarci et al. 2020).
Another possible mechanism linking periodontitis and sys-
temic inflammation is by disturbing the gut microbiome. Oral
microorganisms and bacteria can be found in f***l samples of
participants. The gut microbiome is critical in regulating mul-
tiple neurochemical pathways through a highly complicated
host-microbiome system, termed the gut–brain axis, and any
disruption that occurs could upset this homeostasis. The BBB
and blood cerebrospinal fluid (CSF) barriers are important in
regulating neuroinflammation. The gut can affect the BBB by
using gastrointestinal (GI)–derived hormonal secretion, meta-
bolic cofactors, and production of small molecules or through
cytokine or oxidative stress and other inflammatory mecha-
nisms that can affect BBB permeability (Main and Minter
2017; Lanza et al. 2018). Braak and Del Tredici (2008) had
presented a staging system for PD based on the specific pattern
of α-synuclein spread and postulated that sporadic PD begins
in 2 places—the neurons of the nasal cavity and the neurons of
the gut—and the pathology spreads by the olfactory tract and
1444 Journal of Dental Research 101(12)
vagal nerve, respectively, to and within the CNS. The concept
of “leaky gut–leaky brain” suggests that with age and under
certain pathological conditions, bacterial molecular metabo-
lites from the gut epithelial barrier can translocate or diffuse
systematically or disseminate to a distal site by passing through
the BBB or CSF barriers. Consequently, they may contribute to
disease or modulate health immunologically or biochemically
by both direct and indirect means (Main and Minter 2017;
Lanza et al. 2018). Chronic periodontitis caused by microbial
dysbiosis can lead to neuroinflammation and cognitive impair-
ment through partial activation of the TLR4/myeloid differen-
tiation primary response 88/nuclear factor–κβ signaling
pathway (Xue et al. 2020), suggesting the oral–gut–brain axis.
A recent study found that oral administration of P. gingivalis
induced cognitive impairment and gut dysbiosis in mice (Chi
et al. 2021). Importantly, this study showed that the oral gavage
of P. gingivalis decreased the solute clearance function of the
glymphatic system. The glymphatic dysfunction could lead to
accumulations of metabolic wastes, including Aβ, and contrib-
ute to AD.
Periodontitis and Neurodegenerative
Diseases
Alzheimer’s Disease
On a molecular level, AD is characterized by deposition of
β-amyloid plaques and neurofibrillary tangles (NFTs). These
inclusions are associated with progressive synaptic and neuro-
nal loss, especially in learning and memory storage areas, such
as the hippocampus and entorhinal cortex. Continuous neuro-
nal demise leads to brain atrophy and cognitive impairment
that results from this continuous process. Clinically, AD symp-
toms include memory deficits, negative impact on judgment
and decision-making, lack of orientation to physical surround-
ings, and decline in language processing, among others. Cross-
sectional analysis of a population-based study found that an
increase in peripheral inflammatory markers, such as CRP,
IL-1β and IL-6, and TNF-α, in AD patients is associated with
an increase in the incidence of dementia in elderly patients
(Gorelick 2010; Metti and Cauley 2012). In addition, activated
complement cascade factors were found bound to Aβ plaques
in the brains of AD patients, again indicating the involvement
of the immune responses (Yasojima et al. 1999). These studies
implicate systemic inflammation as a key element that may
cause or exacerbate AD-related cognitive decline.
It is plausible that systemic inflammation induced by peri-
odontitis could affect the neuronal environment in the brain
and contribute to neuroinflammation. The proinflammatory
mediators produced by inflamed gingiva may disseminate
from the periodontal pockets and reach the brain via the blood-
stream or directly via the trigeminal nerve, and dysbiotic oral
bacteria can cause an imbalance in CNS homeostasis indi-
rectly. Supporting evidence has been provided by postmortem
histopathological examinations that detected P. gingivalis and
T. denticola in addition to bacterial proteases in the brains and
trigeminal nerves of AD patients, suggesting that these virulent
species could have contributed to the development of AD
pathology (Riviere et al. 2002; Poole et al. 2013; Dominy et al.
2019). Dominy et al. (2019) provided compelling evidence
with the detection of P. gingivalis and its proteases in postmor-
tem brain tissues and trigeminal nerves from AD patients and
correlated its presence with tau pathology.
Further links between periodontitis and AD have been iden-
tified using AD transgenic mouse models, such as human amy-
loid protein precursor transgenic (hAPP-tg) and 5×FAD. Oral
application of P. gingivalis mimicking the effects of periodon-
titis revealed significant impairment in cognitive function and
an increase in Aβ deposition (Ishida et al. 2017; Kantarci et al.
2020). In addition, the levels of proinflammatory cytokines,
such as TNF-α and IL-1β, were higher in the brains of P. gin-
givalis–treated transgenic mice compared to untreated mice
(Ishida et al. 2017; Kantarci et al. 2020). This result suggests
that periodontitis may directly exacerbate the pathology, neu-
roinflammation, and cognitive functions in AD patients.
Analogous results have been obtained with wild-type mice in
which gingipain was orally applied over the course of 22 wk to
mimic the chronic effects of periodontitis (Ilievski et al. 2018).
At the end of the study, gingipain was detected in the mice
brain tissue, including glia and neurons, in addition to extracel-
lularly, confirming translocation of oral bacteria into the brain.
The same study also showed a correlation between gingipain-
induced chronic periodontitis and neurodegeneration as visual-
ized by Fluoro-Jade staining in treated versus untreated mice.
Astro- and microgliosis and extracellular deposition of Aβ42
and NFTs were also detected in the treated group but not in the
control group, strongly indicating a causative effect between
periodontitis and AD-like pathology in wild-type mice (Ilievski
et al. 2018). Other studies recorded learning deficits and
impaired memory storage in both mouse and rat models of
periodontitis in addition to greater memory deficits in older
animals compared to younger controls (Ding et al. 2018; Hu
et al. 2020). Overall, as summarized in Table 3, periodontitis
induces systemic inflammation and correlates with cognitive
decline in human subjects and in animal models. A direct
causal connection between periodontitis and AD is under-
scored by the detection of periodontal bacteria in the brains of
AD patients and the presence of AD pathology in murine mod-
els of periodontitis.
Parkinson’s Disease
PD is a progressive neurodegenerative disorder characterized
by deterioration of dopaminergic neurons in the substantia
nigra pars compacta that is associated with the presence of
Lewy body inclusions composed mainly of α-synuclein. PD
mostly affects motor neurons and results in adverse symptoms,
such as tremor, rigidity, bradykinesia, or involuntary move-
ment, among others, which are related to movement. PD
patients can also suffer from cognitive impairment (Dickson
2012). Neuroinflammation has been long implicated in PD eti-
ology in addition to a number of environmental and genetic
Neuroinflammation 1445
Table 3. Association between Periodontitis and Neurodegenerative Diseases.
Types of Study Finding
8,640 patients with dementia without prior periodontal disease and
8,640 individuals without dementia history
48 elderly cognitively normal subjects 5,396 cases of newly diagnosed PID, 10,792 cases without PID Human cerebral cortex lysates of 3 AD and 6 control brains; CSF from
10 patients diagnosed with probable AD with mild to moderate
cognitive impairment
4,765 newly diagnosed cases of PD, 19,060 without PD 74 PD patients and 74 controls 316 patients diagnosed with MS and 1,580 randomly selected controls 153,165 PD participants with prescription for anti-PD medication Young and middle-aged mice (control or infected) with live
Porphyromonas gingivalis ATCC 33277 by oral gavage
FVB/N mice and mutant LRRK2 mice (transgenic R1441G PD model)
with and without oral gavage of P. gingivalis
Wild-type C57/BL6 mice with ligature Young male Sprague-Dawley rats periodontitis models Periodontitis mice induced by oral application of Pg/gingipain and control Oral inoculation of P. gingivalis in APP-Tg AD mice Ligature-induced periodontal disease on 5×FAD mice and
wild-type mice
Oral administration of P. gingivalis 3×/wk for 1 mo in mice MS mouse model received control, subcutaneous, or oral gavage
of P. gingivalis
CP induced with ligature and control Dementia and AD were associated with a higher risk of periodontal disease
dependent of age and independent of systemic confounding factors (Ma
et al. 2022).
Higher subgingival periodontal dysbiosis was significantly associated with
reduced CSF amyloid β at both genera and species levels (Kamer et al.
2021).
Patients with PID had a higher risk of developing PD (adjusted hazard
ratio
=
1.431; 95% CI, 1.141–1.794; P
=
0.002) (Chen et al. 2017).
Gingipains load were significantly higher in AD patients than control brains
(P < 0.0001) and significantly correlated with tau pathology (P < 0.0001)
and ubiquitin load (P < 0.0001) (Dominy et al. 2019).
Dental scaling decreases the development of PD (Chen et al. 2018).
PD patients had weakened oral health status and reduced oral hygiene care
(van Stiphout et al. 2018).
MS patients were 1.86 times (95% CI, 1.39–2.48) more likely to have
previously diagnosed chronic periodontitis than controls after adjusting
for variables (Sheu and Lin 2013).
Competent dental care and toothbrush frequency significantly reduced risk
of development of new-onset PD (Woo et al. 2020).
P. gingivalis can impair spatial learning and memory, with significant
increased inflammatory cytokines in brain tissues of middle-aged mice
but not in young mice (P < 0.01) (Ding et al. 2018).
P. gingivalis increased gut inflammation and permeability in PD mice.
α-Synuclein was higher in the myenteric plexus of colon in P. gingivalis–
treated PD mice (Feng et al. 2020).
Periodontal inflammation-induced IL-6 led to neuroinflammation and
disrupted the BBB (Furutama et al. 2020).
Periodontitis induced by P. gingivalis–LPS led to neuroinflammation and
impaired learning and memory in rats (Hu et al. 2020).
P. gingivalis/gingipain led to brain inflammation, neurodegeneration, and
amyloid β production in wild-type mice (Ilievski et al. 2018).
Periodontitis induced by bacterial infection exacerbated features of AD in
transgenic mice (Ishida et al. 2017; Hao et al. 2022).
Ligature-induced periodontitis increased neuroinflammation in wild-type
mice and disrupted the neuroinflammatory response in 5×FAD mice
(Kantarci et al. 2020).
P. gingivalis impaired cognition associated with gut dysbiosis,
neuroinflammation, and glymphatic dysfunction (Chi et al. 2021).
Infection with P. gingivalis had significantly greater maximal clinical scores of
autoimmune encephalomyelitis compared to control (P***k et al. 2018).
CP mice exhibited significant neuronal loss in cortex, reduction of
synaptophysin in hippocampus and cortex, increase of proinflammatory
cytokine levels, disruption of the BBB, gut microbiota dysbiosis, and
systemic inflammation (Xue et al. 2020).
AD, Alzheimer’s disease; BBB, blood–brain barrier; CI, confidence interval; CP, chronic periodontitis; CSF, cerebrospinal fluid; IL-6, interleukin-6; LPS,
lipopolysaccharide; MS, multiple sclerosis; PD, Parkinson’s disease; PID, periodontal inflammatory disease.
factors. Neuroinflammation in PD has mostly been demon-
strated by activated microglia, which are the main immune
cells in the brain and produce cytokines; increased levels of
cytokines have been detected in postmortem brains of PD
patients. These cytokines include IL-1β, IL-6, IL-8, IL-10,
IL-12, IL-15, and TNF-α. Activated microglia may lead to
neurotoxicity by causing an increase in the levels of toxic reac-
tive oxygen species (ROS) that interfere with the function of
several proteins and affect cellular homeostasis.
PD patients with increased tremor or cognitive impairment
experience difficulty maintaining oral hygiene and are thus at
increased risk of oral dysbiosis and oral disease (van Stiphout
et al. 2018). The influence of PD on periodontitis is well
accepted, while studies that link periodontitis to PD have
started to surface only recently. More direct evidence from a
retrospective matched-cohort study by Chen et al. (2017)
established that patients with periodontitis are at a higher risk
of developing PD. A subsequent population-based cohort study
from the same group noted that dental scaling over 5 consecu-
tive years has a protective effect against development and pro-
gression of PD in patients with and without periodontal disease
(Chen et al. 2018). Another group found a positive correlation
between an increase in tooth loss and the development of new-
onset PD in a longitudinal study (Woo et al. 2020). Studies
reported by these groups showed for the first time that oral
dysbiosis and poor oral health might predispose patients to
1446 Journal of Dental Research 101(12)
mechanisms behind this process and answer the
question of whether there is any causality between
periodontitis and PD, but as of now, more studies
are needed to provide conclusive evidence.
Figure. Periodontitis stimulates neuroinflammation, leading to neurodegenerative
diseases. Oral pathogens contribute to manifestation of neurodegeneration through
the following: (1) proinflammatory cytokines, which reach the brain parenchyma via
the bloodstream; (2) oral–gut–brain axis; and (3) bacteria that travel to the brain
via the trigeminal nerve.
developing PD. A further association between periodontal dis-
ease and PD has been provided by Adams et al. (2019), who
detected that gingipain R1 (RgpA), a protease produced by
P. gingivalis, was present in the clots from blood samples of
PD patients to a significantly higher extent than in the clots
obtained from healthy patients. The study proved the clotting
ability of RgpA and LPS by showing that incubating recombi-
nant gingipain with fibrinogen leads to hypercoagulation, con-
firming that the clots detected in PD patients are most likely
induced by bacterial pathogens. The group also confirmed the
presence of systemic inflammation by demonstrating an
increase in the levels of inflammatory cytokines in PD patients
(Adams et al. 2019).
One of the latest studies investigating the involvement of
dysbiotic periodontal bacteria in PD used a known PD mouse
model, the leucine-rich repeat kinase 2 (LRRK2) R1441G. The
R1441G mutation in the LRRK2 gene results in late-onset PD.
To mimic chronic periodontitis, P. gingivalis was administered
to LRRK2 R1441G mice orally over the course of 1 mo. The
treatment increased α-synuclein in the myenteric plexus of the
colon, decreased the number of dopaminergic neurons in the
substantia nigra, and increased the number of activated microg-
lia (Feng et al. 2020). This study also revealed another possible
mechanism by which periodontitis can lead to neuroinflamma-
tion. According to these data, periodontal bacteria can nega-
tively affect the epithelial lining in the gut, causing the cells to
secrete proinflammatory cytokines that can then enter the
bloodstream and reach the brain, where they contribute to neu-
roinflammation. Recent studies just have begun to uncover the
Multiple Sclerosis
Multiple sclerosis (MS) is a progressive neurodegen-
erative disorder in which deterioration of myelin
sheaths is followed by axonal injury in the CNS that
then results in number of sensory, motor, and cogni-
tive impairments. Although the trigger for MS relapse
is unknown, it is considered an autoimmune inflam-
matory disease in which a combination of environ-
mental and genetic factors can cause CNS antigens,
such as myelin basic protein (MBP), to be targeted by
the immune system, which then leads to demyelin-
ation, axonal loss, gliosis, and inflammation.
A study by Moreno et al. (2011) used Lewis rats
to develop an experimental autoimmune encephalo-
myelitis (EAE) model in which the rats were
injected intraperitoneally with LPS to investigate
whether systemic inflammatory stimulus can lead
to an enhanced axonal damage. The study recorded
microglial activation, increased expression of
inducible nitric oxide synthase (iNOS), and IL-1β
in addition to an increase in axonal injury by which
an association between peripheral inflammation and increased
levels of circulating cytokines with deterioration of axons in
the rodent model of MS was shown (Moreno et al. 2011). P***k
et al. (2018) studied a mouse model of MS by exposure to
myelin oligodentrocyte glycoprotein (MOG), in which either
subcutaneous or oral infection with P. gingivalis aggravated
MS pathology with an increase in proliferation of lymphocytes
and clinical symptoms, such as weakness of the limbs and tail,
palsy, and other signs of disease. Both experiments suggest
that pathological MS symptoms might be related to peripheral
inflammation due to the presence of periodontal bacteria.
A case control study conducted in a Taiwanese population
found an association between chronic periodontitis and MS in
women but not in men (Sheu and Lin 2013). A similar study
conducted in the Norwegian population found no significant
correlation between periodontitis and MS (Gustavsen et al.
2015). More population-based studies are required to answer
whether an association between periodontitis and MS exists in
general or whether the association is ethnicity and gender
dependent.
Conclusions and Perspective
The incidence of these neurodegenerative diseases is on the
rise, and no treatment that would prevent or reverse the pathol-
ogy once it has already taken place has been found. Identifying
preventable risk factors is the best and, most likely, the only
strategy. Nevertheless, chronic neuroinflammation is an impor-
tant factor contributing to the development and progression of
Neuroinflammation 1447
neurodegenerative diseases that are not hereditary. It has also
been elucidated that neuroinflammation is associated with
peripheral inflammation as repeated systemic infections and
inflammatory insults cause exacerbation of the existing pathol-
ogy in addition to causing an increase in the incidence of
developing the neuropathology and cognitive deficits in human
subjects and animal models. We summarized the clinical and in
vivo studies supporting the correlation between periodontitis
and the 3 neurodegenerative diseases (Table 3). Current animal
studies suggested that periodontitis may be a causal factor for
the neurodegeneration. Of note, most of the studies were con-
ducted in animal models using P. gingivalis, which is not part
of murine normal flora. However, P. gingivalis ATCC 33277, a
genetically identical strain originally isolated from an adult
periodontitis patient strain, is the most commonly used strain
in the mouse model and can induce alveolar bone loss in mice
similar to humans. Moreover, P. gingivalis–induced periodon-
titis models are especially informative in examining down-
stream events related to the host immune reaction (Graves
et al. 2008). More clinical studies using human oral and brain
samples are warranted, and at the same time, a mouse peri-
odontitis model with a humanized oral bacterial community
will be of significant value.
Our current understanding of how systemic inflammation
causes chronic neuroinflammation together with the newest
data presented in this review allows us to elucidate 3 possible
mechanisms by which oral pathogens can contribute to the
development and progression of neurodegeneration (Fig.): 1)
proinflammatory cytokines secreted by epithelial cells in the
diseased periodontal pockets induced by the toxic products of
dysbiotic oral bacteria, such as P. gingivalis, can reach the
brain parenchyma via the bloodstream. Once in the brain, the
cytokines activate the resident immune cells (microglia and
astrocytes) in the brain by inducing them to obtain proinflam-
matory phenotypes and secrete their own proinflammatory
mediators, such as TNF-α. These mediators activate the signal
transduction pathways that lead to neuronal apoptosis. If this
process proceeds for a long period of time, the extent of neuro-
nal cell death manifests as neurodegeneration. 2) Pathogenic
periodontal bacteria can induce dysbiosis in the gut, leading to
its inflammation. Inflamed epithelial cells in the gut secrete
proinflammatory mediators that travel through the bloodstream
and induce neuroinflammation in the brain, as discussed above.
3) Bacteria can travel to the brain via the trigeminal nerve, and
once in the brain parenchyma, the oral pathogens and their
toxic products can directly induce neurotoxic effects. For
example, the LPS or gingipain produced by the oral pathogens
can interact with the microglia and astrocytes to initiate the
cascade of events leading to neuronal cell death.
These findings provide a strong background and warrant
future studies of the links between chronic periodontitis and
chronic neurodegenerative diseases, especially considering the
high incidence and severe detrimental effects these conditions
have on the general population. Revealing the mechanisms and
types of pathogenic periodontal bacteria and bacterial products
that activate astrocytes and microglial cells may provide new
therapeutic targets for the prevention and treatment of neuro-
degenerative diseases. For now, the knowledge we gathered for
this article should enable us to make vulnerable patients aware
that adequate oral care can go beyond preventing disorders of
the oral cavity and inspire more research on this topic.
Prevention and treatment of periodontitis and its related
inflammation could be a potential therapeutic strategy, at least
in combination with other remedies, to reduce neuroinflamma-
tion and prevent and treat neurodegenerative diseases.
Author Contributions
X. Li, contributed to conception, drafted manuscript, critically
revised the manuscript; M. Kiprowska, T. Kansara, P. Kansara, P.
Li, contributed to data acquisition, drafted the manuscript. All
authors gave final approval and agree to be accountable for all
aspects of the work.
Acknowledgments
We thank Dr. Deepak Saxena for his effort and time on proofread-
ing this manuscript. The figure was created with BioRender.com.
Declaration of Conflicting Interests
The authors declared the following potential conflicts of interest
with respect to the research, authorship, and/or publication of this
article: X. Li is the cofounder of Periomics Care LLC.
Funding
The authors disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: This
work was partially supported by National Institutes of Health
grants R01DE02707401A1S1 and R01AG068857.
ORCID iDs
X. Li https://orcid.org/0000-0002-7414-5734
P. Kansara https://orcid.org/0000-0002-9268-2402
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