Inflammatory Association between Periodontal Disease and Systemic Health

Abstract

Periodontitis is an oral disease that affects almost half of the adult population in United States. The complex relationship between oral and systemic health has been the focus of extensive research, aiming to unravel the mechanisms linking periodontal disease with various systemic conditions. This systematic review provides an overview of recent findings on the interrelationship between periodontitis and various systemic diseases. Specifically, it explores the associations between periodontal disease and several systemic disorders, including cardiovascular diseases, respiratory conditions, endocrine abnormalities, musculoskeletal disorders, and reproductive system issues. The review comprehensively examines the latest evidence on the bidirectional interactions between these diseases. By integrating data from several studies, this review provides insights into the underlying mechanisms including inflammatory pathways and microbial interactions, connecting the oral and systemic health. Understanding these relationships is essential for all healthcare providers, including periodontists and medical physicians alike, as it aids in the development of comprehensive treatment approaches that consider both periodontal and systemic health interactions and effects. For healthcare providers this understanding of complex interactions and connections is crucial for identifying disease etiology, treatment planning and determining prognosis for their patients. This includes multidisciplinary approach that address both periodontal and systemic health. In conclusion, this systematic review enhances the existing body of knowledge by providing a comprehensive and up-to-date synthesis of the most recent data available on the periodontal-systemic health relationship. By highlighting current findings, this review not only underscores critical areas for future research but also identifies opportunities for meaningful clinical application.

Introduction

Periodontal disease, a chronic inflammatory condition affecting the supporting structures of the teeth, has been increasingly recognized as a significant factor affecting systemic health. Characterized by gingival inflammation, attachment loss, and alveolar bone destruction, periodontal disease is primarily caused by pathogenic bacteria in dental plaque in susceptible individuals [1]. However, its impact extends beyond the oral cavity, as mounting evidence suggests a strong relationship between periodontal disease and various systemic conditions, including cardiovascular disease, diabetes mellitus, respiratory disorders, and adverse pregnancy outcomes [2, 3]. The underlying mechanisms linking periodontal disease to systemic health include chronic inflammation and immune system dysregulation [2, 3]. Understanding these interactions is crucial for developing integrated treatment approaches that address both oral and overall health, emphasizing the importance of periodontal care in systemic disease management.

Periodontal disease, which is usually bacterial in origin, is among the most common chronic inflammatory condition in the world [4]. In the US population, over 47% of adults presented periodontal disease (Fig. 1) [4]. Multiple studies indicate that the severity of periodontitis increases exponentially with increase in age [5]. Coincidentally this is also true for several systemic diseases [5]. Periodontitis presents a significant burden in the adult U.S. population [6]. The potential economic cost for prevention and treatment, especially among the aging population is significant [6].

Fig.1.

Clinical presentation of periodontal disease

Systemic diseases that have been interlinked with periodontal disease include cardiovascular diseases, cerebrovascular diseases, peripheral arterial disease, respiratory diseases, low birth weight, Type 2 diabetes mellitus, insulin resistance, rheumatoid arthritis, obesity, osteoporosis, and complications of pregnancy [2, 3, 7]. In some of these conditions, especially in type 2 diabetes mellitus evidence of a bi-directional relationship between periodontitis and systemic diseases has also been postulated [8].

Bacterial dissemination into the bloodstream plays a central role in the complex relationship between periodontal disease and systemic health [9]. Periodontal pathogens such as Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans can enter the circulatory system, triggering systemic inflammation and contributing to endothelial dysfunction, insulin resistance, and immune system disturbances [10]. This growing body of evidence underscores the importance of periodontal health as a crucial component of overall health [11]. Recognizing the interactions between periodontal disease and systemic conditions can help in developing integrated prevention and treatment strategies [11]. Healthcare professionals, including dentists, physicians, and researchers, are increasingly advocating for a collaborative approach in managing periodontal disease and its systemic implications [11]. By addressing periodontal disease as part of comprehensive healthcare, individuals can potentially reduce the burden of systemic diseases and improve their overall quality of life.

As our knowledge on the possible links between periodontal diseases and systemic health increases and becomes clearer, it is important that we consider sharing the information with our physician colleagues and working in teams to help improve the overall health of our patients. Treatment and management of our patients requires a systemic and systematic approach. Accordingly, an update on the inter-relationship between periodontal disease and systemic disease is timely.

Periodontitis—Systemic Disease Inter-Relationship

Smoking

Tobacco use remains one of the most significant public health concerns globally, contributing to a wide range of systemic diseases, including cardiovascular conditions, respiratory disorders, and malignancies [12]. Traditional cigarette smoking involves the combustion of tobacco, releasing thousands of harmful chemicals, many of which have cytotoxic, mutagenic, and inflammatory effects on human tissues [13]. In recent years, electronic cigarettes (e-cigarettes) have emerged as an alternative nicotine delivery system [14]. These battery-operated devices heat a liquid and flavoring agents to generate an aerosol that users inhale [14]. While e-cigarettes have been promoted as a harm-reduction tool, their increasing popularity, particularly among adolescents and young adults, has raised concerns regarding their long-term health effects [15]. Although some studies suggest e-cigarettes may assist with smoking cessation, growing evidence highlights potential risks, including cytotoxic effects on oral tissues and altered microbial compositions in the oral cavity [15, 16].

Link between Periodontal Disease and Smoking

Cigarette smoking is one of the most well-established risk factors for periodontitis, with smokers being 2.6 to 6 times more likely to experience periodontal destruction than nonsmokers [17, 18]. This risk follows a clear dose–response relationship, where greater tobacco exposure leads to more severe disease progression [19]. Smoking also compromises the effectiveness of both non-surgical and surgical periodontal therapies, whereas smoking cessation is linked to improved periodontal health [20]. The underlying mechanisms driving these adverse effects include reduced gingival perfusion, immune suppression, impaired tissue repair, and microbial dysbiosis, collectively contributing to delayed healing and accelerated disease progression [21].

Microcirculation, which is crucial for tissue nutrition and immune function, is notably impaired by smoking, affecting the soft tissues of the oral cavity [22]. Smoking exacerbates periodontitis through increased periopathogenic bacterial loads (P. gingivalis, T. forsythia, T. denticola, and A. actinomycetemcomitans), neutrophil dysfunction, heightened pro-inflammatory cytokines (e.g., TNF-α), and altered fibroblast activity [23–26]. Furthermore, smokers exhibit higher rates of disease recurrence [27].

While e-cigarettes are marketed as a safer alternative, they are not without risk. Both in vitro and in vivo studies have shown that e-cigarette aerosols negatively impact gingival epithelial cells and periodontal fibroblasts, and clinical research indicates alterations in the oral microbiome that may contribute to periodontal disease [28–30]. Given the evolving trends in tobacco and nicotine product use, further longitudinal studies are necessary to fully understand the long-term effects of newer nicotine delivery systems on periodontal health.

Diabetes

The American Diabetes Association defines diabetes mellitus as a group of metabolic disorders characterized by chronic hyperglycemia due to defects in insulin secretion, action, or both [31]. The condition leads to long-term complications affecting the eyes, kidneys, nerves, and cardiovascular system [32]. Diabetes is classified into Type 1 diabetes, caused by autoimmune β-cell destruction leading to absolute insulin deficiency, and Type 2 diabetes, which results from insulin resistance and relative insulin deficiency [31]. Other forms include gestational diabetes and diabetes due to genetic, pancreatic, or endocrine disorders. Diagnosis is based on fasting plasma glucose (FPG), the oral glucose tolerance test (OGTT), or HbA1c levels, with specific thresholds indicating diabetes or prediabetes [31, 32]. Management strategies emphasize glycemic control through lifestyle modifications, medications, and insulin therapy when necessary to prevent complications [32].

The Relationship between Periodontal Disease and Diabetes

A bi-directional relationship between Type 2 Diabetes Mellitus and periodontal disease has been established based on key research findings [33]. Patients with diabetes mellitus present with varied oral presentation (Table 1). Periodontal disease can lead to bacteremia which results in activation of immune cells that can have destructive effects systemically [34]. Uncontrolled DM can lead to significant changes on the tissues of the periodontium which leads to both soft and hard tissue loss around teeth [35]. Some of the proposed mechanisms to explain the bi-directional relationship include microvascular changes, changes in the composition of the gingival crevicular fluid, alteration in collagen metabolism, an alteration in the host response, changes in the sub-gingival microflora, genetic component and non-enzymatic glycation leading to an accumulation of advanced glycation end products [33, 35]. The role of increased apoptosis on wound healing and bone loss has also been reported to be significant [36, 37]. It has been reported that 1/3rd of the people with DM have severe periodontal disease with attachment loss measuring 5 mm or more [38]. Furthermore, several systematic reviews and meta-analyses have evaluated the impact of periodontal treatment on glycemic control in patients with diabetes [39–41]. Janket et al. reported that periodontal therapy resulted in an average HbA1c reduction of 0.38%, with a slightly greater decrease observed in type 2 diabetic patients [39]. Additionally, Simpson et al. concluded that there is evidence suggesting that scaling and root planing (SRP) improves glycemic control, with a mean HbA1c reduction of 0.29% at three to four months, although the long-term sustainability of this effect remains uncertain [40]. Teeuw, Gerdes, and Loos provided stronger support, demonstrating through a stricter meta-analysis that periodontal therapy led to a statistically significant average reduction of 0.40% in HbA1c compared to no treatment, emphasizing the clinical relevance of even modest improvements in glycemic control [41]. Despite variations in the strength of the evidence, all studies highlight a consistent trend that periodontal therapy may contribute to improved metabolic control in type 2 diabetic patients, although further large-scale, high-quality randomized controlled trials are necessary to confirm these findings and clarify the mechanisms involved.

Table 1.

Oral manifestation of diabetes mellitus

Oral Manifestations of Diabetes Mellitus [42]
1. Periodontal diseases including gingivitis, periodontitis, or periodontal abscesses
2. Salivary and taste dysfunction
3. Oral infections, fungal and bacterial
4. Poor wound healing
5. Non-candidal oral soft tissue lesions, including fissured tongue, irritation fibroma and traumatic ulcer
6. Oral mucosal disease including lichen planus and recurrent apthous stomatitis
7. Neuro-sensory oral disorders including oral dysesthesia or burning mouth syndrome
8. Dental caries and tooth loss

Implications for Management of Periodontitis in Diabetes Mellitus Patients

Hypoglycemic episodes can occur during dental procedures, particularly in patients with Type 1 diabetes mellitus (DM), necessitating careful management to prevent adverse outcomes. Patients with poorly controlled diabetes are at an increased risk of developing various oral diseases (Table 1), with periodontitis being among the most significant due to its association with systemic inflammation and impaired healing. Additionally, individuals with undiagnosed diabetes may present to dental practitioners for treatment, offering an opportunity for early detection. Dentists play a crucial role in recognizing oral manifestations of diabetes and referring patients for medical evaluation. Furthermore, successful periodontal treatment has been shown to contribute to improved glycemic control, highlighting the bidirectional relationship between diabetes and periodontal health.

Given the bidirectional relationship between periodontal disease and diabetes, recognizing periodontitis as a potential complication of diabetes is essential for comprehensive patient care (Table 2). Poor periodontal health can exacerbate systemic inflammation and insulin resistance, further complicating diabetes management. To address this, physicians should integrate oral health assessments into routine diabetes care, encourage patients to undergo regular dental evaluations, and collaborate with dental professionals to support optimal glycemic control. Strengthening interdisciplinary coordination between medical and dental providers can significantly improve both periodontal and systemic health, ultimately enhancing overall patient outcomes.

Table 2.

Key features in management of periodontitis in diabetes mellitus patients

Consensus report of the joint European Federation of Periodontology and the American Academy of Periodontology [43]
1. Diabetic patients should be educated on the bidirectional relationship between diabetes and periodontal disease, highlighting the mutual influence of these conditions on overall health
2. A comprehensive oral examination, including a detailed periodontal assessment, should be conducted to facilitate early detection and management of oral health complications
3. Oral health education should be provided to enhance patient awareness and promote preventive care strategies
4. Children and adolescents with diabetes should undergo annual oral screenings to monitor their oral health and prevent potential complications
5. Diabetic patients are at an increased risk for dry mouth, oral fungal infections, and impaired wound healing, necessitating proactive management and timely intervention

Obesity

Obesity has become a significant public health concern worldwide, with prevalence rates rising dramatically over the past few decades [44]. In the United States alone, the prevalence of obesity among adults increased from 15% in 1980 to over 30% by the early 2000 s, with similar trends observed globally​ [45]. Obesity is defined as excessive body fat accumulation that poses health risks, typically measured by body mass index (BMI), where a BMI of 30 or greater is classified as obese [46]​. It is associated with numerous comorbidities, including type 2 diabetes, cardiovascular disease, non-alcoholic fatty liver disease (NAFLD), and certain cancers, significantly increasing morbidity and mortality risks​ [47, 48].

The escalating prevalence of obesity is largely attributed to environmental and lifestyle modifications, including increased accessibility to energy-dense foods and a decline in physical activity levels [49]. Evidence suggests that even modest lifestyle interventions, such as reducing daily caloric intake by 100 kcal or engaging in moderate physical activity, may contribute to the prevention of further weight gain at the population level [49]. Furthermore, genetic predisposition, alterations in gut microbiota, and social networks have been identified as key determinants influencing susceptibility to obesity [50, 51]. Despite growing awareness and extensive public health initiatives, obesity remains a significant challenge, particularly in achieving sustained weight loss due to metabolic adaptations and behavioral influences.

Link between Periodontal Disease, Obesity, and Metabolic Disorders

The association between obesity and periodontal disease has been widely studied, with evidence suggesting a bidirectional relationship mediated by systemic inflammation [52]. Obesity is characterized by a chronic low-grade inflammatory state due to the dysregulation of adipose tissue, which secretes pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) [53]. These inflammatory mediators contribute to periodontal tissue destruction by promoting immune responses that exacerbate periodontal breakdown [54]​​.

Systematic reviews and meta-analyses indicate a consistent positive association between obesity and periodontal disease, with overweight and obese individuals having higher odds of developing periodontitis compared to those with normal weight​​ [55–57]. Longitudinal studies further suggest that obesity may serve as a risk factor for the progression of periodontal disease, though the precise causal relationship remains inconclusive [58–60]. Additionally, obesity has been associated with diminished treatment outcomes in periodontal therapy, potentially due to the adverse effects of systemic inflammation on tissue healing processes [61].

Recent research highlights the critical role of metabolic syndrome in increasing the risk of various health conditions [62, 63]. According to the American Heart Association, metabolic syndrome is a cluster of factors that collectively elevate the likelihood of developing coronary heart disease, diabetes, stroke, and other serious complications [64]. A diagnosis is made when an individual exhibits three or more of the following risk factors: elevated blood glucose levels, reduced HDL cholesterol, increased triglyceride levels, excessive waist circumference (often described as an “apple-shaped” body), and high blood pressure [64]. Metabolic syndrome-related insulin resistance, oxidative stress, and dyslipidemia create an environment that fosters periodontal inflammation and bone resorption​ [65]. Additionally, inflammation-driven adipokine imbalances in obese individuals, such as increased leptin and decreased adiponectin, further contribute to periodontal tissue degradation​ [66].

Overall, the evidence demonstrates a strong link between obesity and periodontal disease, highlighting the importance of integrated management strategies that incorporate lifestyle modifications, weight management, and specialized periodontal treatment to address both conditions effectively. Given the shared inflammatory pathways and metabolic dysregulation underlying both diseases, a multidisciplinary approach involving collaboration between medical and dental professionals is essential.

Cardiovascular Disease (CVD)

Cardiovascular diseases remain the leading cause of death among men, women, and individuals from most racial and ethnic backgrounds [67, 68]. Every 33 s, one person loses their life to cardiovascular disease [67, 68]. In 2022, heart disease claimed 702,880 lives, representing one in every five deaths [69]. Coronary heart disease (CHD) is the most common type of heart disease, according to the Centers for Disease Control and Prevention, CHD caused 371,506 deaths in 2022 [69]. Heart disease is the No. 1 killer of women and is more deadly than all forms of cancer combined [70].

The Link between Periodontal Disease and CVD

Atherosclerosis (ATH), according to The American Heart Association is a slowly developing process that occurs when the blood vessels that carry oxygen and nutrients from the heart to the rest of the body become narrow restricting blood flow to organs and tissues [71, 72]. It typically takes decades to worsen to the point of causing signs and symptoms [72]. Accumulating evidence suggests a potential link between common infectious processes and the development of ATH [73]. Endothelial injury induced by infectious agents may contribute to its pathogenesis, providing a possible explanation for the role of infections such as periodontal disease in ATH progression [73]. Periodontal infections may facilitate ATH and thromboembolic events by continuously introducing bacterial lipopolysaccharides and pro-inflammatory cytokines into the systemic circulation [74]. Additionally, studies have demonstrated that periodontitis is associated with elevated systemic levels of inflammatory mediators, including C-reactive protein (CRP), interleukin (IL)−6, and neutrophils [75]. Increased concentrations of these inflammatory biomarkers may promote the formation of atherosclerotic lesions, potentially heightening the risk of cardiovascular and cerebrovascular events [76]. Furthermore, oral bacteria identified within carotid atheromas have been implicated in platelet aggregation, suggesting a possible mechanistic link between periodontal pathogens and atherothrombotic complications [77].

Various studies have been conducted to investigate the potential association between periodontal disease and cardiovascular disease, including case–control studies, cohort studies, cross-sectional studies, and meta-analyses of observational research [78]. The findings suggest that bacterial infections play a significant role in modulating endothelial cell function, monocyte-macrophage activity, platelet aggregation, blood coagulation, and lipid metabolism [78]. These observations indicate that dental infections may have an independent association with the severity and progression of adult coronary atherosclerosis (ATH) [78].

Based on the different types of studies that have been done to date, there appears to be a potential link between periodontal disease and CVD. As integral members of the healthcare team, oral health professionals play a crucial role in identifying patients who may be at risk for CVD-related complications and require medical intervention.

Musculoskeletal System

Rheumatoid Arthritis

Rheumatoid arthritis (RA) is an autoimmune disease in which inflammation leads to swelling and pain in and around the joints [79, 80]. Persistent inflammation can lead to cartilage damage, damage to the elastic tissue that covers the ends of bones in a joint, as well as the bones themselves [80]. The joints can become stiff, unstable, painful and lose their mobility [81]. RA most commonly affects the joints of the hands, feet, wrists, elbows, knees and ankles (Table 3) [79, 81]. RA also can affect the cardiovascular or respiratory systems; it is accordingly called a systemic disease [82, 83]. RA occurs worldwide and affects approximately 1% of the world population in a female/male ratio of 3:1 and has a peak incidence of onset in women in the fourth and fifth decades of life [84].

Table 3.

Key Clinical Indicators for the Provisional Diagnosis of Rheumatoid Arthritis (RA)

Clinical Indicators Suggestive of a Provisional Diagnosis of Rheumatoid Arthritis (RA) [85]
• Persistent joint pain, tenderness, swelling, or stiffness lasting for a minimum of six weeks
• Morning stiffness persisting for at least 30 min
• Involvement of multiple joints
• Predominant involvement of small joints, particularly the wrists and specific joints in the hands and feet

Relationship between RA and Periodontal Disease

A recent commentary by de Smit et al. explores the"two-hit"model as a potential explanation for the shared pathogenesis of rheumatoid arthritis (RA) and periodontal disease [86]. This model suggests that both conditions share genetic and environmental risk factors, including smoking and infection with Porphyromonas gingivalis (Pg), a key pathogen implicated in citrullination [86, 87]. Citrullination, the conversion of arginine to citrulline, can provoke immune responses, contributing to autoimmune diseases such as RA [88]. The first hit involves the induction of anti-citrullinated protein antibodies (ACPAs), potentially triggered by periodontal inflammation, while the second hit leads to arthritis development and citrullinated antigen expression in the joints [86]. Alternatively, chronic periodontitis itself may act as the primary trigger, with an unidentified arthritogenic stimulus initiating RA in susceptible individuals [86, 87].

Additionally, newer studies have identified shared risk factors for RA and periodontitis, including age, gender, BMI, genetic predisposition, systemic diseases, socioeconomic status, stress, smoking, and alcohol consumption [89]. These overlapping factors highlight the common inflammatory and immune pathways linking RA and periodontal disease, reinforcing the need for integrated management and early intervention.

Data from epidemiological studies and case–control and cohort studies have reported a positive association with periodontal disease [90, 91]. Common clinical findings associated with periodontal inflammation such as bleeding on probing, and deep pockets have been reported to be more evident in patients with RA [92].

Although a definitive causal relationship between periodontal disease and rheumatoid arthritis (RA) has yet to be established, maintaining optimal periodontal health remains essential for all patients. This is particularly important for individuals with chronic conditions such as RA, given the potential for shared inflammatory pathways and mutual disease exacerbation. A proactive approach to periodontal care in these patients may contribute to improved overall health outcomes and potentially mitigate systemic inflammation associated with RA.

Respiratory System

Periodontal inflammation has been postulated to have a role in affecting the respiratory system [93]. In a systematic review, Azarpazhooh and Leake et. al concluded that there was evidence for an association between pneumonia and poor oral health [94]. In addition, they reported that evidence existed that improvements in oral hygiene because of an increased frequency of professional care reduced the occurrence and progression of respiratory diseases in the high-risk elderly population in nursing homes [94].

Respiratory infectious diseases such as bacterial pneumonia and chronic obstructive pulmonary disease are common especially in institutionalized and elderly inpatients [95]. Pneumonia is defined as an acute infection of the lung parenchyma by one or co-infecting pathogens [96]. Bacterial pneumonia can be classified as either community-acquired pneumonia (CAP) or hospital-acquired (nosocomial) pneumonia [97]. Aspiration of bacteria from the oropharynx and the oral cavity can lead to CAP [98]. In institutional settings, hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) account for approximately 22% of hospital-acquired infections in the United States. Among patients on mechanical ventilation, VAP develops in about 10% of cases, with an estimated mortality rate of 13% [99]. COPD includes chronic bronchitis and is associated with an irritation of the bronchial airway causes increased mucous production, persistent cough, and emphysema, with attendant damage to the lungs [100]. Common risk factors for COPD include smoking and exposure to pollutants in atmosphere [100, 101].

A Link between Periodontal Disease-Oral Bacteria and Respiratory Disease

The mechanisms by which oral bacteria may play a role in respiratory disease include A. direct inhalation of oral bacteria present in dental plaque which are shed into saliva, and small droplets and are then aspirated into the lungs. B. the presence of bacterial enzymes which may degrade the protective surface molecules on epithelial cells. The damaged epithelial cell surfaces maybe more susceptible to colonization by pathogenic bacteria. C. bacterial enzymes may also reduce the protection against colonization provided by mucosal secretions. D. cytokines produced as result of periodontal disease induced inflammatory surface changes on the epithelium may also contribute to colonization of the respiratory epithelium [101].

Further clinical, microbiological, and epidemiological research is needed to clarify the relationship between periodontal disease and respiratory conditions. However, it is well established that inadequate oral hygiene leads to an increased accumulation of bacterial plaque, accompanied by significant shifts in microbial composition. While this has implications for the general population, it is particularly critical for hospitalized patients and residents of long-term care facilities, who are at increased risk of infection due to compromised immune function. The presence of respiratory diseases such as pneumonia and chronic obstructive pulmonary disease (COPD) further exacerbates their vulnerability, complicating disease management and recovery. Given these associations, integrating periodontal care into routine medical management for these patients may contribute to improved oral hygiene, reduced healthcare costs, and enhanced overall quality of life.

Reproductive System

Research has shown that there is a relationship between preterm birth and/or low birth weight and periodontitis [102–104]. Preterm birth (PTB) is defined as any delivery that occurs after 23 gestational weeks and less than 37 weeks [105]. Long-term consequences of PTB include an increased risk of neurological impairments and behavior disorders and higher rates of chronic health disorders [106]. In the USA More than 400,000 babies are born prematurely each year [107]. Epidemiologic studies have identified many risk factors including smoking, history of preterm birth, low maternal BMI, short cervical length, elevated cervical-vaginal fetal fibronectin concentration, low socioeconomic status, nutritional deficiencies, multiple gestations, maternal infections, psychological stress, substance use, and pregnancy complications such as placental abruption or polyhydramnios [108].

The Link between Periodontal Disease and Pre-Term Birth

Offenbacher et al. first introduced the hypothesis that periodontal diseases could be a potential risk factor for preterm birth [109]. Based on epidemiological evidence three hypotheses have been developed (i) the role of bacteremia, (ii) dissemination of the mediators of inflammation, (iii) role of feto-maternal immune response against oral pathogens [109].

The Role of Bacteremia

This hypothesis is based on the dissemination of periodontal pathogens and other oral pathogens through the systemic circulation [110]. Periodontal bacteria reach the amniotic fluid with subsequent chorio-amniotic infections [111]. Periodontal disease, particularly pregnancy-associated gingivitis, is a common condition during pregnancy, with prevalence rates ranging from 30 to 100% [112]. Neutrophils, upon activation, release several cytokines and enzymes that degrade extracellular matrix components, facilitating cervical remodeling and membrane rupture [113]. Additionally, neutrophil-derived cytokines, such as IL-8, further amplify the inflammatory response, promoting the progression of labor [113].

Dissemination of the Mediators of Inflammation

Offenbacher et al. speculated that cytokines produced by local inflammation in patients with periodontitis have systemic effects [114]. It has been shown that periodontal disease leads to an increase in the secretion of cytokines, like PGE-2, TNF-α, IL-6 or IL-1β [75]. Amniotic fluid from women who had preterm births was analyzed and showed elevated levels of inflammatory cytokines [104].

Feto-Maternal Immune Response

Immune responses to various oral pathogens are strongly linked to inflammatory reactions [115]. Notably, elevated levels of immunoglobulin M (IgM) have been associated with an increased risk of preterm birth [116]. Additionally, maternal infections with periodontal pathogens can elevate systemic levels of pro-inflammatory cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), which are implicated in the onset of preterm labor [116, 117].

While evidence regarding the efficacy of periodontal treatment in preventing preterm birth remains inconclusive, it is essential to recognize that periodontal disease is one of multiple risk factors contributing to pregnancy complications. Research indicates that periodontal therapy is a safe and well-tolerated intervention during pregnancy, with no adverse effects on maternal or fetal health [118, 119]. Given the potential systemic implications of periodontal inflammation, early diagnosis and timely management of periodontal disease are strongly recommended in pregnant patients to support overall maternal health and potentially reduce the risk of adverse pregnancy outcomes.

Alzheimer's Disease

Alzheimer’s disease (AD) is a progressive, irreversible neurodegenerative disorder and the most common cause of dementia among older adults [120]. As of 2023, an estimated 6.7 million Americans aged 65 years and older are living with Alzheimer’s dementia, a number expected to nearly double to 13.8 million by 2060 in the absence of medical breakthroughs [121]. The disease is characterized by the gradual destruction of neurons, particularly those responsible for memory, language, and cognitive processing, with pathological changes—including beta-amyloid plaque accumulation and tau protein tangles—beginning decades before the onset of clinical symptoms [120, 121]. Alzheimer’s disease significantly contributes to morbidity and mortality, ranked as the seventh leading cause of death overall and the fifth among Americans aged 65 and older [121]. Despite the availability of symptomatic treatments and recent advances in disease-modifying therapies targeting amyloid pathology, there remains no cure [121]​. The societal burden of Alzheimer's is profound, with total healthcare and caregiving costs reaching $345 billion in 2023, alongside substantial emotional and physical impacts on over 11 million unpaid caregivers​ [121].

The Link between Periodontal Disease and Alzheimer

Growing research supports a strong biological and clinical connection between periodontitis and Alzheimer's disease (AD) [122–125]. Periodontitis is increasingly recognized as a potential modifiable risk factor for neurodegenerative disorders [122].

Several lines of evidence suggest that Porphyromonas gingivalis plays a critical role in the pathway of Alzheimer’s disease (AD). The bacterium, a keystone pathogen in periodontitis, has been identified in the brains of individuals diagnosed with AD, where both P. gingivalis DNA and its toxic proteases, gingipains, were detected at significantly higher levels compared to non-demented controls [125]. Gingipain load strongly correlated with tau and ubiquitin pathology, key features of Alzheimer's neurodegeneration [125]. Experimental models demonstrated that oral infection with P. gingivalis led to brain colonization, increased amyloid-β₁₋₄₂ production, and cognitive decline in mice [125]. Moreover, gingipains were found to be neurotoxic, promoting tau protein fragmentation and neuronal loss [125]. Therapeutic inhibition of gingipains in infected mice significantly reduced bacterial load, suppressed amyloid-β production, decreased neuroinflammation, and rescued hippocampal neurons, reinforcing the concept that targeting P. gingivalis could modify disease progression [125]. In addition to direct microbial invasion, several inflammatory mechanisms have been proposed to explain the relationship between periodontitis and Alzheimer's disease. Periodontitis initiates systemic inflammatory responses through the release of bacterial toxins such as lipopolysaccharide (LPS) and gingipains [122]. These toxins stimulate the production of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6), which can disseminate via the bloodstream [122]. Such systemic inflammation disrupts the integrity of the blood–brain barrier (BBB), facilitates microglial activation, and initiates chronic neuroinflammation, all of which contribute to the pathogenesis of AD [122, 124]. Supporting this biological link, clinical studies have substantiated these mechanistic insights by demonstrating correlations between periodontal disease and neurodegenerative brain changes [123]. Greater severity of periodontitis has been significantly associated with reduced entorhinal cortex volume and decreased cortical thickness on brain magnetic resonance imaging (MRI), two critical biomarkers of early Alzheimer's disease [123]. Additionally, longitudinal data indicated that in 20 out of 24 studies, periodontal disease was positively correlated with cognitive impairment and neurodegeneration [124].

Emerging Relationship between Systemic Health and Peri-Implantits

Recent research indicates a growing connection between peri-implantitis and systemic diseases, paralleling the well-established link between periodontitis and systemic inflammation [126]. Several studies highlight that peri-implantitis is associated with elevated systemic inflammatory markers, including C-reactive protein (CRP) and interleukin-6 (IL-6), indicating a potential systemic inflammatory burden [127]. Research also suggests that metabolic disorders, such as diabetes and obesity, may predispose individuals to peri-implantitis due to shared inflammatory pathways [128]. Additionally, peri-implantitis has been linked to cardiovascular risk factors, including increased triglycerides, and white blood cell counts, suggesting a broader impact on systemic health [129, 130]​. Moreover, bacterial dissemination from peri-implant lesions has been proposed as a mechanism contributing to systemic diseases, similar to periodontitis-related bacterial influx [131]. These findings underscore the importance of considering systemic health factors in the prevention and management of peri-implantitis and suggest a bidirectional relationship between peri-implant inflammation and systemic disease progression.

Conclusion

Periodontal disease is one of the most widespread chronic conditions affecting humans, with growing evidence supporting its intricate relationship with various systemic diseases. Recognizing the interdependence between oral and systemic health is crucial, as periodontal disease has been linked to cardiovascular disease, obesity, respiratory disorders, diabetes, smoking-related complications, rheumatoid arthritis, and adverse pregnancy outcomes, including preterm delivery. Additionally, emerging research suggests a potential connection between peri-implantitis and systemic conditions, further underscoring the need for a holistic approach to patient care.

To achieve effective coordination between dental and medical professionals, several strategies can be implemented. First, providing dental practitioners with access to patients’ relevant medical histories and systemic health information would facilitate more informed and comprehensive periodontal care. Additionally, the development of extended referral protocols in medical practices could encourage physicians to routinely refer patients at risk—such as those with diabetes or cardiovascular disease—for dental evaluation and periodontal management. Integrating structured education on the periodontal-systemic health relationship into both medical and dental curricula is essential for fostering a deeper understanding among future healthcare providers. Incorporating basic periodontal screening within primary care settings and establishing formal referral pathways would further strengthen interdisciplinary collaboration. Importantly, enhancing patient education regarding the bidirectional relationship between oral and systemic health should be a priority, empowering individuals to take an active role in preventive care. Furthermore, showcasing successful models of collaboration can offer practical guidance for the implementation of these strategies in clinical practice. Collectively, these efforts hold the potential to improve early detection, prevention, and the integration of oral health into systemic disease management, ultimately advancing public health outcomes.

Author Contribution

FH was responsible for summarizing each article. HA provided structure and organization support in identifying different systemic relationships. AT and MS critically reviewed and edited the manuscript. VJ and MPG as the senior author oversaw the entire project and guided the thematic structure of the review, ensuring accuracy and literature search.

Funding

This work is supported through Indiana University Research Seed Grant and School of Dentistry pilot grants to MPG and MS respectively.

Data Availability

No datasets were generated or analysed during the current study.

Declaration

Competing interests

The authors declare no competing interests.