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20
Oral-systemicLinkandItsImpactonGeneralandOralHealth
Dáire Shanahan1 and Sarah Jane George
1
Bristol Dental School, University of Bristol, Bristol, UK
2
Bristol Medical School, University of Bristol, Bristol, UK
2
20.1 Introduction
In recent years, it has become increasingly clear that oral bacterial infections and inflammation
can have a negative effect on systemic health(1). This is no surprise given that teeth are the only
non- shedding surfaces in the human body, harbouring a diverse and often pathogenic array of
inflammation- producing bacteria (2). The rich blood supply of the supporting periodontium
around the teeth acts as the ideal portal of entry for bacteria, activated inflammatory cells and their
by- products into circulation(1). Subsequent translocation of these bacterial and inflammatory
components to distant sites within the body can have a detrimental effect on systemic health, as
will be discussed in this chapter.
Infective endocarditis (IE) is a rare but life- threatening microbial infection that affects the
endothelial surfaces of the cardiac values(3). Oral bacteraemia from daily activities such as toothbrushing and invasive dental procedures are risk factors for IE(4). The prophylactic use of antibiotics before dental procedures to prevent IE is an ongoing source of controversy and debate(5).
The pathophysiology of IE is less controversial, described in the next section.
The last 30 years have witnessed a proliferation of literature on the link between periodontitis
and systemic diseases, such as cardiovascular disease (CVD), diabetes mellitus and rheumatoid
arthritis(6, 7). Epidemiological studies support an association between periodontitis and systemic
diseases(8). Although evidence for causation is lacking, it is biologically plausible that several
systemic diseases are exacerbated by periodontitis(1). Given the high prevalence of this condition
in the adult population(9), clinicians need to be aware of its adverse effects on general health.
Researchers have now begun to examine the influence of non- periodontal inflammatory mucosal
disease on systemic health(10), and emerging evidence suggests that conditions such as oral lichen
planus (OLP) may accelerate CVD by promoting dyslipidaemia and hypertension in this patient
group(11, 12).
Inflammation appears to be of critical significance when finding a link between oral and systemic diseases. This chapter will review the evidence and explore the possible mechanisms to
explain these associations.
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Pathological Basis of Oral and Maxillofacial Diseases, First Edition. Edited by S. R. Prabhu, Syed Ali Khurram,
Omar Kujan and Merva Soluk Tekkesin.
© 2025 John Wiley & Sons Ltd. Published 2025 by John Wiley & Sons Ltd.
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20.2 Infective Endocarditis
20.2.1 BackgroundandClinicalPresentation
IE is characterised by the formation of an infected mass or vegetation involving the endocardial
surfaces of the heart, particularly the heart valves. Although IE is rare, the annual incidence is rising in high- income countries, with approximately 3– 10 cases per 100,000 people (3, 13, 14).
Moreover, IE is a life- threatening condition with a mortality rate of 22– 29% within the first year of
presentation in European populations, while those who do survive experience high morbidity rates
and reduced life quality(15, 16).
Most cases of IE are caused by transient bacteraemia, with 80% associated with streptococci, Staphylococcus aureus and enterococci bacteria. Up to 45% of cases are caused by
streptococci bacteria found in the oral cavity (17) and have entered the circulation from
dailyactivities such as toothbrushing and flossing rather than invasive dental treatments as
previously thought(4).
There is a broad spectrum of clinical presentation; symptoms of IE are usually subtle but can
include fever, night sweats, malaise, myalgia, shortness of breath and weight loss. Heart murmurs are detected on auscultation in 85% of patients(13), while 25% show evidence of embolic
phenomena, including stroke, splenic infarct, pulmonary infarct or cutaneous manifestations
such as Janeway lesions (haemorrhagic painless macules or plaques on palms and soles).
Suspicion of IE should be high in individuals with the predisposing risk factors summarised in
Table20.1(13, 18).
Diagnosis of IE is based on the Modified Duke Criteria, which consists of positive blood cultures for microorganisms associated with IE and using an echocardiogram to detect the presence
of valvular vegetations(13). This criteria has an overall sensitivity of 80% and can stratify patients
with suspected IE into three categories: ‘definite’, ‘possible’ or ‘rejected’ IE(19, 20). In cases of IE
where clinical suspicion remains high, additional microbiological investigations and imaging can
aid diagnosis such as whole- body computer tomography (CT), magnetic resonance imaging and
increasingly, the use of F- labelled fluoro- 2- deoxyglucose positron emission tomography (
PET)/CT(21).
IE can be classified by the clinical onset of symptoms (acute, subacute or chronic), the type of
heart valve affected (native value, prosthetic valve or device- related endocarditis) or the location of
the infection (left- sided or right- sided). Most cases of IE are left- sided and affect a native valve,
while infections of right- sided valves account for 5– 10% of cases and are usually associated with
intravenous drug use(13, 22).
18
F- FDG-
Table20.1 Predisposing risk factors forendocarditis.
● Previous IE
● Acquired valvular heart disease with stenosis or regurgitation
● Hypertrophic cardiomyopathy
● Structural congenital heart disease
● Valve replacement or implantation of a cardiac device
● Indwelling vascular catheter
● Intravenous drug use
● Poor oral hygiene/dental infections/invasive dental procedures
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20.2.2 PathophysiologyofIE
An infective endocarditis lesion predominantly consists of a platelet- fibrin blood clot infected with
bacteria and attached to the damaged endothelium of a heart valve.
The formation of an endocarditis lesions is dependent on three central factors:
1) Bacteraemia
2) Endothelial activation
3) Formation of a vegetation
20.2.2.1 Bacteraemia
Gram- positive bacteria account for 80% of all IE cases and predominantly comprise staphylococci
(mainly from the skin) or streptococci (mainly from the oral cavity) bacteria(23) (Figure20.1). A
bacteraemia can arise following healthcare interventions such as invasive dental procedures
(defined as manipulation of the dento- gingival junction, periapical region or perforation of the
oral mucosa excluding local anaesthetic injections in non- infected soft issues), recent vascular
catheterisation, haemodialysis and prosthetic heart valve placement(13, 24). Community- derived
bacteraemia can arise from daily activities such as chewing, oral hygiene practices, intravenous
drug use and rheumatic heart disease(25).
When bacteria enter the circulation there is instant and widespread activation and interplay
between the immune and clotting systems, an interaction called immunothrombosis (26). The
overall aim of immunothrombosis is to contain an infection; however, it has the opposite effect,
and clot formation provides a safe harbour for bacteria that are now protected from the immune
system and can grow without hindrance.
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20.2.2.2 EndothelialActivation
A healthy endocardium is lined with endothelial cells and is resistant to infection(27). When
cardiac abnormalities are present, such as prosthetic heart valves or congenital anomalies,
the resulting turbulent blood flow induces endothelial activation and damage (28). Bacteria
andtheir by- products further activate endothelial cells, making the cardiac valves vulnerable to
infection.
Activated endothelial cells can contribute to endocarditis in several ways(26). First, they release
tissue factor that triggers the extrinsic coagulation pathway, while at the same time, bacterial cell
wall components activate the intrinsic pathway creating a procoagulant environment (26).
Secondly, activated endothelial cells can produce and retain von Willebrand Factor (VWF) to
which platelets adhere, a necessary step in clot formation, as illustrated in Figure20.1(29). Platelets
adhere to other molecules on the endothelium and the layer beneath the endothelium, such as
fibrin, fibronectin and collagen(26). Bacteria such as S. aureus can also bind to VWF, fibrin and
platelets on the damaged endothelium, which facilitates the adhesion of bacteria to the developing
blood clot(26).
20.2.2.3 FormationofVegetation
As the endocarditis lesion matures, the bacteria present within it flourish. Activated endothelial
cells and immune cells, such as monocytes, attempt to contain the infection by producing more
tissue factors, triggering more coagulation and fibrin production(30, 31). Rather than having the
bacteria, this results in an ever- growing vegetation, shielding and protecting bacteria from the
immune system(26). As the vegetation matures it can result in clinical symptoms, destruction of
cardiac valves, heart failure and emboli.
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Endothelial cell Activated platelet
Damaged
endothelial cell
Platelet
Bacteria
von Willibrand factor
FibrinMonocyte
(a) Bacteraemia
Platelets
Endothelial cells
(b) Enodthelial activation
Turbulent flow
(c) Formation of vegetation
Monocyte
Tissue factor
Laminar flow
Bacteria
Activated platelets
von Willibrand factor
Damaged endothelial
cells
Clotting cascade
Fibrin
(d) Vegetation maturation and embolisation
Vegetation
Figure20.1 Pathophysiology of IE: (a) A healthy endocardium is lined with endothelial cells and is resistant
to infection, platelet adhesion and clotting. (b) Turbulent blood flow and/or infection induces endothelial
damage. von Willebrand Factor (VWF) on the endothelium can slow down platelets flowing in circulation and
encourage them to adhere to the valve. This initiates the formation of a blood clot. Similarly, bacteria such as
can also bind to VWF, encouraging clot infection. (c) Activated endothelial cells and
monocytes try to contain the infection by producing tissue factors. This process triggers more coagulation
and fibrin, which, rather than being helpful, forms a large, infected blood clot called vegetation. (d) The
vegetation increases in size and embolisation can occur. Original figure created with BioRender.com.
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20.2.3 Management of IE
The management of IE should optimally be led by a multidisciplinary endocarditis team comprising microbiologists, cardiologists and cardio- thoracic surgeons (13, 32). The causative organism
guides management and whether the valve infected is native or prosthetic. Typically, management
includes supportive care, broad- spectrum antibiotics and surgery to remove the infected tissue and
repair or replace the damaged cardiac valves(33).
Antibiotic prophylaxis for individuals undergoing invasive dental procedures and considered at
risk of developing IE is controversial and is examined by others(5, 7, 17). Global guidance varies,
and readers should refer to local protocols for more information.
20.3 PeriodontitisandSystemicDisease
20.3.1 PathophysiologyofPeriodontitis
Periodontitis is a chronic inflammatory condition characterised by interactions between a
dysbioticmicrobiome and a dysregulated immune response in susceptible individuals and results
in thedestruction of the periodontium(34). Periodontitis is the seventh most prevalent disease
inthe world(9, 35). Systematic reviews and meta- analysis of epidemiological studies estimate
that 42– 62% of adults globally have periodontitis, and 7– 24% have a severe form of the
disease(36– 40).
Periodontitis begins with the formation of a dental biofilm (Figure20.2). Bacteria adhere to a
film of salivary glycoproteins called the acquired pellicle on the surface of teeth(2). Once attached
to the biofilm, the bacteria can grow, organise and attract diverse species to its surface. As the biofilm thickens, the ability of oxygen and nutrients to diffuse is limited, and anaerobic conditions
develop(41). Subgingival bacteria tend to be anaerobic gram- negative rods such as Porphyromonas
gingivalis(2).
The development of periodontitis is characterised by a microbial shift from symbiotic bacteria
to pathogenic bacteria, resulting in dysbiosis(34). This transition is influenced by several factors, including the host’s inflammatory response and susceptibility, and risk factors such as
smoking and poor oral hygiene(42). Continued accumulation of supra and subgingival plaque
results in a persistent immune response, which consists of both the innate and adaptive immune
systems. Figure20.2 depicts the Page and Schroeder model of periodontitis which describes four
stages in the development of periodontitis: the initial stage is the infiltration of the periodontium by neutrophils; the early lesion stage involves a macrophage and T- cell response; and the
third and fourth stages are characterised by plasma cell and B cell involvement(43). The destruction of the periodontium occurs due to a combination of bacterial actions and the host response;
this process has been reviewed extensively by others(41, 42). In brief, the destruction of the
periodontium predominantly occurs through the activation of the complement system,
the recruitment of inflammatory cells and the release of various matrix metalloproteinase
(MMPs), collagenases and cytokines that destroy the soft and hard tissues of the periodontium.
Paradoxically, the inflammatory environment generates a nutritionally favourable milieu for the
continuing growth of pathogenic bacteria called inflammophillic pathobionts, creating a positive feedback loop (44). These bacteria can also damage the periodontium; they do this by
impairing leucocyte function, degrading immunoglobulins, producing collagenases and lipopolysaccharides (LPS), activating complement and upregulating RANKL expression in osteoblasts(45) (Figure20.2).
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s
344
Macrophage Bacteria
Plasma cell
Neutrophil
Positive feedback loop
Dental biofilm
consisting of
bacteria
Subgingival dysbiotic biofilm
Inflammation
Macrophage
Neutrophils
Bone loss
Plasma cells
Periodontitis
Dysbiosis
Figure20.2 Periodontitis is characterised by the formation of a dysbiotic dental biofilm on the root
Inflammation
surface of teeth followed by an influx of various inflammatory cells such as neutrophils, macrophages and
plasma cells into the periodontium. These inflammatory cells and their by- products destroy the soft and
hard tissues of the periodontium. The inflammatory environment promotes the growth of pathogenic
bacteria called inflammophillic pathobionts, creating a positive feedback loop. Original figure
created with BioRender.com.
Clinically, periodontitis may present with bleeding and swollen gingiva, halitosis, gingival reces-
sion, mobile teeth and early tooth loss.
Periodontitis is associated with up to 57 systemic diseases, particularly chronic inflammatory
comorbidities(6). It is important to note that no evidence suggests that periodontitis causes any of
these systemic diseases. Instead, the presence of periodontitis is commonly observed with these
conditions.
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20.3.2 MechanismbyWhichPeriodontitisCanContributetoSystemicDisease
Evidence suggests that periodontitis can exacerbate inflammatory systemic diseases by either
initiating or intensifying an inflammatory response.
20.3.2.1 DisseminatingOralInfection
This direct mechanism involves the spread of periodontal pathogens and their by- products into
the circulation, where they provoke a systemic inflammatory response, and/or the ability of
these pathogens to travel to, invade and cause inflammation at sites distant to the oral cavity
(Figure20.3).
The escape of periodontal pathogens into the circulation is plausible given that these bacteria
colonise near the ulcerated epithelium of periodontal pockets. This ulcerated epithelium has a
2
combined surface area of 8– 20 cm
and provides a portal for bacteria and their inflammatory prod-
ucts into the circulation(46). Transient bacteraemia of oral pathogens occurs in individuals with
345
Activated T cells
5
Lymphocyte
trafficking
1
Cytokines
2
Bacteraemia/
Aspiration/Oro-
digestive translocation
Hyperresponsive
neutrophils and
monocytes
IL-1
TNF-α
Haematogenous
1
3
Altered
haematopoiesis
IL-6
LPS
Acute phase
reactants
Invasion at
distant site
4
Auto-
antibodies
Figure20.3 Mechanisms by which periodontitis can cause systemic disease: (1) Periodontal bacteria and
their by- products can enter circulation and initiate an inflammatory response by triggering the production
of acute phase reactants such as C- reactive protein (CRP) and infecting distant sites. Oro- pharyngeal and
oro- digestive routes can also disseminate periodontal pathogens. (2) Inflammatory cytokines produced at
the site of periodontitis disseminate into the circulation and trigger an acute- phase response in the host.
(3) Bacteraemia and systemic inflammation can alter haematopoiesis in the bone marrow resulting in a
pool of pro- inflammatory hyperresponsive innate immune cells. (4) Molecular mimicry occurs when
antibodies produced in response to periodontal pathogens cross- react with host antigens. (5) Lymphocyte
trafficking ensues when T- cells are activated at the site of periodontitis and can then migrate via the
lymphatics to distant sites where they react against similar antigens. Original figure created with
BioRender.com.
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periodontitis following daily activities such as chewing, toothbrushing and flossing(47, 48), and to
a greater extent following professional dental interventions such as periodontal probing, tooth
scaling and dental extractions(49). While most of these transient bacteraemia will be appropriately dealt with by the host’s immune system, the chronicity of periodontitis and the frequency of
bacteraemias result in an inflammatory domino effect. This includes the activation of leucocytes
such as monocytes and neutrophils, the release of inflammatory mediators such as cytokines
(Interleukin [IL]- 1, IL- 6, Tumour necrosis factor- alpha [TNFα]), acute phase reactants, and oxygen
free radicals, the stimulation of platelets resulting in a pro- coagulant environment and the opportunity for the bacteria to directly invade distant tissues(50).
For periodontal bacteria to survive in the circulation and cause infection at distant sites, they
have developed techniques to evade and subvert the host’s immune system(51) as illustrated in
Figure20.5. For example, periodontal bacteria such as P. gingivalis that have been phagocytosed by
leucocytes such as dendritic cells and macrophages can survive unharmed within these cells, and
therefore protected from further immune attacks while in circulation. Having survived within
these cells, the bacteria can escape, and re- infect multiple other cells and tissues (Figure20.5). This
means that a minor infection of P. gingivalis can propagate a prolonged and sustained inflamma-
tory response, which may promote the progression of inflammatory conditions(53, 54). Other
bacteria can evade the host immune response by adhering to erythrocytes, allowing them to travel
unharmed to distant sites in the body(52, 55).
Translocation of periodontal bacteria from the oral cavity to distant sites is not limited to the
circulation; there is evidence of bacteria being swallowed and colonising the gut and aspiration
into the lungs(56, 57) (Figure20.3).
The inflammatory destruction of the periodontium produces local inflammatory mediators
and cytokines such as IL- 1, IL- 6 and TNF- α that can spill into the circulation and propagate sys-
temic inflammation(58, 59) (Figure20.3). These inflammatory mediators can trigger an acutephase response in the host(1). This is corroborated by the detection of elevated levels of acute
phase reactants such as IL- 6, C- reactive protein (CRP), fibrinogen, haptoglobin and serum amyloid in individuals with periodontitis and association with systemic pathologies such as
atherosclerosis.
20.3.2.2 TrainedImmunityandHaematopoieticStemandProgenitorCells
Another important mechanism is periodontitis affects the trained immunity and haematopoietic
stem and progenitor cells (HSPCs) found in bone marrow (Figure20.4). Innate immune cells can
develop a memory of earlier microbial and inflammatory challenges(60). Future exposure to the
same or unrelated stimuli produces a robust, rapid but non- specific immune response(60, 61). The
innate memory originates in HSPCs found within the bone marrow, whereby inflammatory mediators such as IL- 1β can alter long- term metabolic activity epigenetic and transcriptomic reprogramming of HSPCs (62). These altered HSPCs are now ‘trained’ to preferentially differentiate into
hyper- responsive myeloid cell populations, eventually comprising hyperactive neutrophils, monocytes and macrophages(63), as illustrated in Figure20.4. The circulating, hyper- responsive, trained
innate immune cells may be beneficial in repeated infection episodes. However, the response
canbe detrimental when inappropriate induction occurs against endogenous stimulus such as
lipoprotein (cholesterol) in the case of heart disease, resulting in a prolonged, augmented, and
aberrant inflammatory response, which may exacerbate inflammatory conditions(64). Individuals
with periodontitis have more significant numbers of circulating hyper- responsive neutrophils and
monocytes compared to controls(65, 66), and this characteristic can persist even after periodontal
treatment(67). This response may be explained by periodontitis, which induces HSPC and innate
immune memory.
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Periondontitis
Hyperresponsive cells in
circulation
347
Bacteraemia and Systemic
inflammation
Metabolic/epigenetic
rewiring of HSPC
Trained HSPC
Hyperresponsive neutrophils/
Secondary
challenge
(e.g. lipids)
macrophages
Atherosclerosis
Figure20.4 Trained immunity in bone marrow stem and progenitor cells: periodontitis results in
bacteraemia and systemic inflammation, which alters the metabolic activity of and causes epigenetic
programming of the haematopoietic stem and progenitor cells (HSPC) found in bone marrow. These altered
HSPCs are now ‘trained’ to preferentially differentiate into hyper- responsive myeloid cell populations
following subsequent infection. However, an inappropriate secondary challenge against endogenous
stimulus (such as lipoprotein) can lead these hyper- responsive cells to respond in a heightened and
sustained inflammatory manner. These cells can be recruited to the periodontium and coronary arteries,
exacerbating periodontitis and atherosclerosis. Original figure adapted from Hajishengallis and
Chavakis(44) and created with BioRender.com.
20.3.2.3 Molecular Mimicry
Periodontitis may also contribute to systemic disease progression via molecular mimicry, a
mechanism whereby infectious agents can induce autoimmunity(68). This occurs when antibodies caused by periodontal bacteria cross- react with non- bacterial host antigens, resulting in a
subsequent inflammatory response that may accelerate diseases such as rheumatoid arthritis,
atherosclerosis and pregnancy complications(50) (Figure20.5).
20.3.2.4 LymphocyteTrafficking
T- cells can become activated at the site of periodontitis in response to oral pathogens(69). Once
activated, the T- cells may then migrate from the oral cavity via lymph nodes that drain the head
and neck, and travel to distant sites(70) as revealed in Figure20.3. These activated T- cells will react
against similar antigens, causing an inflammatory response, especially at extra- oral sites where
periodontal pathogens are known to colonise, such as the gut in individuals with inflammatory
bowel disease(70).
20.4 PeriodontitisandItsRelationshipwithSystemicDiseases
This section focuses on the conditions with clear epidemiological associations and clinical
and experimental evidence to support a link between periodontitis and systemic diseases.
Emphasis is placed on CVD, type 2 diabetes mellitus (T2DM), rheumatoid arthritis and
Alzheimer’s disease(44).
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VSMC
348
1
Bacteraemia
Transmigration
Internal elastic
lamina
2
Leukocyte
Escape
3
Erythrocyte
Re-infection
7
Platelet
activation
5 Invasion
VSMC proliferation
4
Foam cell
6
8
Cytokines
9
endothelial cells
Activated
10
Plaque rupture
MMPs
Figure20.5 Cellular and molecular mechanisms by which periodontitis may accelerate atherosclerosis:
(1)Translocation of periodontal bacteria into circulation occurs after daily activities such as toothbrushing and
following interventional dental treatment. (2) Internalised bacteria travel within leukocytes where they are
protected from the host immune system. This can facilitate transport to distant sites where bacteria escape,
cause infection and inflammation and re- infect other cells. (3) Bacteria can evade circulating phagocytes by
adhering to erythrocytes and remain viable once released from the erythrocyte. (4) Bacteria can migrate
towards the vascular smooth muscle cells (VSMCs) and promote calcification. (5, 6) Invasion of bacteria into
the artery wall is followed by infection of macrophages that accelerates foam cell formation. (7) Platelet
activation and aggregation is accelerated by resulting in accelerated blood clotting
and thrombosis formation. (8)Infectious agents induce autoimmunity. (9) Bacteria can invade endothelial cells,
increasing endothelial permeability, oedema and vascular inflammation. (10) Plaque rupture is accelerated by
the production of matrix metalloproteinase (MMPs) which degrade the extracellular matrix. Monocytes
exposed to P. gingivalis secrete MMPs. Original figure adapted from Hajishengallis(52) and created
with BioRender.com.
20.4.1 AssociationBetweenPeriodontitisandAtheroscleroticCardiovascular
Disease(CVD)
Atherosclerosis is the underlying pathological process that leads to coronary heart disease. It is a
chronic progressive inflammatory condition characterised by the accumulation of lipid deposits
called plaques within the walls of medium and large- sized arteries(71). Rupture of atherosclerotic
plaques of the coronary arteries can result in luminal thrombosis, thereby narrowing the artery
lumen and disrupting the blood supply to the heart, leading to coronary heart disease and, in some
instances, myocardial infarction (MI)(72, 73).
Epidemiological evidence supports a significant association between periodontitis and atherosclerotic CVD, independent of known confounders (74– 76). A recent systematic review and
meta- analysis of 32longitudinal cohort studies found that individuals with periodontitis had a
14% increased risk of atherosclerotic CVD compared to controls (Risk Ratio [RR]=1.14, 95% CI:
1.08– 1.21) (77). There is a lack of randomised control trials on the effect of periodontal treatment on cardiovascular events such as MI, stroke and death. Yet, observational data suggests
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