This review aims to critically analyze the epidemiological evidence and mechanistic insights linking periodontitis with the onset, progression, or severity of neuropsychiatric disorders. From an epidemiological perspective, eligible evidence was identified regarding disorders related to trauma, stress, anxiety, depressive, and bipolar disorders, whereas no studies meeting the predefined inclusion criteria were found for the remaining considered disorders. The strongest epidemiological evidence was observed for depressive disorders and anxiety- and stress-related conditions. However, the predominance of cross-sectional studies, together with substantial methodological heterogeneity, limits conclusions regarding temporality and causality. From a mechanistic perspective, the available evidence regarding the association between periodontitis and neuropsychiatric disorders predominantly supports as mechanisms (1) microbial pathways (microbial translocation and functional dysregulation of the oral microbiome), (2) inflammatory and immune pathways (systemic (meta)inflammation and trafficking of immune players systemic), and (3) shared underlying vulnerabilities (behavioral factors, medication-related effects, lifestyle and systemic health factors, and genetic mechanisms). Periodontitis may promote a persistent low-grade systemic inflammatory state through the release of bacterial products and inflammatory mediators into the circulation, thereby influencing immune, neuroendocrine, and vascular pathways relevant to neuropsychiatric vulnerability. Moreover, the hematogenous dissemination or swallowing of periodontal bacteria and their virulence factors may contribute to microbial remodeling at distant sites, including the gut, supporting the concept of an oral-gut-brain axis. Overall, the evidence analyzed supports periodontitis as a potential modifiable contributor within a broader biopsychosocial network linking oral and mental health, while highlighting the need for longitudinal studies and interventional trials to clarify causality and clinical relevance.
Periodontitis is a highly prevalent chronic inflammatory disease characterized by a dysbiotic biofilm-induced host immune dysregulation and sustained low-grade systemic inflammation. Psoriasis and other inflammatory skin disorders, including atopic dermatitis and alopecia, are immune-mediated conditions driven by complex interactions between genetic susceptibility, environmental triggers, microbial factors, and cytokine network activation. Mounting epidemiological and experimental evidence suggests a consistent association between periodontitis and psoriasis, with emerging links to other skin disorders. This narrative review critically appraised the current available evidence regarding the epidemiological association between periodontitis and inflammatory skin disorders, explored the shared pathogenic mechanisms underpinning a potential oral-skin axis, and evaluated the impact of periodontal therapy on dermatological outcomes. Epidemiological and meta-analytical data suggest a positive association between periodontitis and psoriasis across diverse populations, although direct causality remains unclear. Mechanistically, overlapping pathways include systemic dissemination of pro-inflammatory cytokines (e.g., IL-6, TNF-α, IL-17), Th17-driven immune responses, neutrophil priming and NETosis, microbial translocation, and shared lifestyle-related determinants within the multimorbidity framework. Preclinical and clinical randomized controlled trials suggest that non-surgical periodontal therapy may reduce psoriasis severity and extent over the short term (8-10 weeks), potentially acting as a relevant adjunct to dermatologic medications. While heterogeneity and residual confounding limit definitive conclusions, the convergence of epidemiological, mechanistic, and interventional evidence supports the plausibility of a bidirectional interaction between periodontal and skin inflammation and the potential existence of an oral-skin axis. Interdisciplinary clinical strategies integrating periodontal and dermatologic care should be implemented for the early diagnosis and management of both periodontal and skin diseases and conditions.
AIM:Drug-target Mendelian randomisation (MR) studies investigate whether genetically proxied modulation of druggable proteins affects the risk of periodontitis, thereby identifying potential pharmacological targets. METHODS:A systematic review was conducted following PRISMA 2020 guidelines. Three electronic databases (MEDLINE/Pubmed, Scopus, Web of Science) were searched. Eligible studies applied MR to evaluate causal relationships between druggable targets and periodontitis. Data on study design, population, exposure, and outcomes were extracted; risk of bias was assessed qualitatively. Supplementary searches of Google Scholar, reference lists, and medRxiv were also undertaken. RESULTS:Fifteen MR studies published between 2023 and 2026 were included. Underlying data on periodontal outcomes were derived from a limited number of studies. Identified targets spanned inflammatory cytokines (e.g., IL6R), complement components (C3 and C5), immune regulators (CXCL10 and CXCR4), calcium-binding proteins (S100A8/A9/A12), and proteins involved in angiogenesis, apoptosis, cell-cycle regulation, and extracellular-matrix remodelling, including VEGFA, CASP3, CCND1, and MMP25. Several studies integrated multi-omics, colocalization, and single-cell approaches. However, the therapeutic relevance of these targets remains to be established through independent replication and experimental or clinical validation. CONCLUSION:Drug-target MR provides a platform for investigating host molecular traits linked to periodontal disease and highlights multiple targets for possible drug repurposing in the future. Methodological and data constraints currently limit the validity of these findings and their potential clinical applications.
Fusobacterium is a genus of anaerobic Gram-negative bacteria that has been increasingly implicated in a range of diseases, including periodontitis and cancer. This review critically evaluates the reported role of Fusobacterium nucleatum in cancer, highlighting new findings that suggest a more nuanced cross-talk with the disease. We contextualise current evidence on the interactions with the wider tumour micro-environment, including the roles of polymicrobial communities, microbial metabolites and taxonomic heterogeneity. Collectively, the evidence suggests that Fusobacterium nucleatum should not be regarded as universally pathogenic or oncogenic. Rather, its behaviour is likely context-dependent and shaped by its surrounding microenvironment. Notably, opposing pro- and anti-tumoural mechanisms can coexist within the same cancer type. For example, in colorectal cancer, F. nucleatum is predominantly associated with poorer outcomes by promoting immune evasion (e.g., suppression of cytotoxic T cell responses) and oncogenic signalling (e.g., via the E-cadherin/β-catenin pathway), yet it also displays oncosuppressive activity through promotion of neutrophil-mediated anti-tumoural cytotoxicity and butyrate-driven cytotoxic T cell activation and potentiation of immunotherapy. In head and neck cancer, by contrast, F. nucleatum detection is associated with improved survival across independent cohorts, potentially reflecting a different balance of these same competing mechanisms. We suggest implications for its proposed use as a biomarker and as a target in cancer therapy. Lingering questions are also laid out to help investigators shape future research to better capture the complexity of the TME and elucidate the overall impact of Fusobacterium nucleatum in cancer.
AIM:To systematically evaluate whether periodontitis and edentulism are associated with the presence or development of inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), and to additionally assess evidence relating periodontitis to IBD activity and severity. METHODS:A systematic search of MEDLINE, Embase, Scopus, and Web of Science, supplemented by manual searches, was conducted through February 2026. Cohort and cross-sectional studies assessing periodontitis or edentulism in relation to IBD were included. Risk of bias was evaluated using the Newcastle-Ottawa Scale. Meta-analyzes were performed separately for longitudinal and cross-sectional studies using random-effects models, with subgroup and sensitivity analyzes conducted where appropriate. RESULTS:Twenty-two studies met the eligibility criteria, including 6 cohort studies and 16 cross-sectional studies, comprising 12 627 564 participants. In cohort studies, periodontitis was associated with a trend toward increased incident IBD overall (RR 1.25; 95% CI 0.98-1.58), although statistical significance was not reached, while no significant association was observed for CD (RR 1.05; 95% CI 0.86-1.29). In contrast, a significant association emerged between periodontitis and incident UC (RR 1.18; 95% CI 1.07-1.31). No longitudinal estimates were available for severe periodontitis or edentulism. In cross-sectional studies, periodontitis was significantly associated with prevalent IBD (OR 2.11; 95% CI 1.53-2.93), CD (OR 2.02; 95% CI 1.59-2.55), and UC (OR 2.48; 95% CI 1.71-3.59). Severe periodontitis was also associated with UC in a limited number of studies, whereas evidence regarding edentulism was scarce and inconsistent. Evidence linking periodontitis to IBD activity or severity was more limited and heterogeneous, although several studies suggested associations with markers of disease burden. CONCLUSION:Longitudinal evidence suggests that periodontitis has a modest association with incident UC, whereas associations with IBD overall and CD appeared weaker and less consistent. At the same time, cross-sectional studies consistently support the coexistence of periodontitis and IBD, possibly reflecting shared susceptibility, bidirectional interactions, or common oral-gut inflammatory pathways. Whether periodontitis contributes to IBD burden or disease expression over time warrants further longitudinal and mechanistic investigation.
AIM:This study aimed to assess the antimicrobial performance and biocompatibility of our drug delivery platform, based on layer-by-layer (LbL) coating incorporating tetracycline (TC) complexed with anionic β-cyclodextrin (TCβCD) and a pH-responsive poly(methacrylic acid) (PMAA) film, applied to titanium (Ti) surfaces representing abutment components. METHODS:A rat subcutaneous implant-related infection model was established using a polymicrobial biofilm derived from peri-implantitis patient saliva. Contaminated Ti controls and coated discs were implanted and analyzed after 1 and 7 days through clinical, microbiological, confocal, and histological assessments. In parallel, in vitro experiments using fibroblast cultures were conducted to evaluate the expression of genes associated with collagen synthesis and extracellular matrix remodeling. RESULTS:Coated implants exhibited minimal inflammatory response, whereas control specimens presented with purulent exudate. Microbiological analysis demonstrated sustained antimicrobial activity, with > 3 log10 reduction in viable bacteria at both time points. Confocal microscopy confirmed strong microbicidal effects, particularly in the PMAA group. Coatings also modulated host responses, decreasing pro-inflammatory cytokines and increasing anti-inflammatory mediators and matrix remodeling markers. Histology revealed enhanced collagen deposition and accelerated connective tissue maturation, especially with LbL/TCβCD/PMAA, consistent with upregulated collagen-related gene expression observed in vitro. CONCLUSION:The multifunctional coating provides sustained antimicrobial activity alongside immunomodulatory and pro-regenerative effects, supporting its potential to treat implant-related infections while enhancing peri-implant soft tissue remodeling.
AIM:To explore circadian involvement in periodontitis and provide insight into mechanisms. METHODS:Clinical samples from patients with periodontitis and a ligature-induced periodontitis mouse model were used in the present research. The rhythmic pattern of cortisol, the core circadian rhythm proteins BMAL1 and CLOCK, the expression of senescence markers (p16, p21, and p53), and the percentage and length of primary cilia were detected in hPDLSCs (human periodontal ligament stem cells) exposed to cortisol as an in vitro model of cortisol-associated circadian disruption. BMAL1 expression was manipulated by siRNA transfection to knock down BMAL1 expression, and SR8278 treatment was used to modulate BMAL1-related circadian regulation. Moreover, the effects of SR8278 on the progression of periodontitis were evaluated by micro-CT, mouse behavior tests, the number of primary cilia, and senescence assays. RESULTS:Patients with periodontitis and ligature-induced periodontitis mice exhibited elevated cortisol levels, reduced BMAL1 expression, increased senescence-associated markers, and decreased primary cilia abundance. Elevated cortisol was associated with circadian disruption, accompanied by reduced BMAL1 expression and impaired ciliary homeostasis. BMAL1 regulated ARL13B expression, a key regulator of ciliogenesis. BMAL1 knockdown impaired Hedgehog signaling and induced hPDLSC senescence. SR8278 partially recovered BMAL1-related circadian alterations and primary cilia abundance while attenuating cellular senescence in both periodontitis model mice and cortisol-treated hPDLSCs. CONCLUSIONS:Collectively, these findings support the involvement of the cortisol-BMAL1-ARL13B pathway in periodontitis-associated primary cilium dysfunction and hPDLSC senescence. Modulation of BMAL1 partially restored primary cilium homeostasis and attenuated periodontal tissue damage, supporting its potential as a therapeutic target for periodontitis.
AIM:To investigate whether pharmacological modulation of Nrf2 signaling influences oxidative stress, inflammatory responses, and periodontal tissue destruction in experimental ligature-induced periodontitis. METHODS:Ligature-induced experimental periodontitis was established in rats treated with dimethyl fumarate (DMF), an Nrf2 activator, and/or ML385, a selective Nrf2 inhibitor. Alveolar bone loss, oxidative stress markers, inflammatory mediators, and histopathological changes were evaluated. RESULTS:Nrf2 activation attenuated alveolar bone loss, reduced oxidative stress, and decreased inflammatory mediators, accompanied by improved periodontal tissue organization. In contrast, Nrf2 inhibition exacerbated inflammation and increased periodontal tissue destruction. CONCLUSION:Nrf2 signaling plays a regulatory role in periodontal inflammation and tissue breakdown. Pharmacological activation of Nrf2 exerts protective effects, whereas its inhibition aggravates disease severity.
Meta-analysis has become an indispensable tool in medical and dental research, providing an estimate of treatment efficacy or harm by combining data from all relevant studies identified by a systematic review. Meta-analysis produces evidence at the highest level of the study design hierarchy. Meta-analysis is a broad term for a set of statistical tools used to analyse data across a range of research questions. Different research questions have different criteria for selecting relevant studies and extracting and organising data in different forms and require different statistical approaches to synthesising the data. This article focuses on meta-analysis for comparing interventions. We use plain but precise language to explain the statistical concepts and assumptions underlying these methods. This article is divided into three parts. We begin with statistical models for and key assumptions of standard pairwise meta-analysis, comparing two treatment groups. We then extend our discussion to network meta-analysis, comparing multiple treatment groups. Finally, we discuss a few issues that arise in selecting studies and preparing data for a meta-analysis. Throughout, we use examples from periodontal regeneration; all analyses were conducted using the free statistical software R. We strongly encourage close collaboration between periodontal researchers and experienced statisticians when planning and conducting meta-analyses.
In this narrative review we present our perspective on the past, present and future of periodontal and peri-implantitis diagnostic biomarkers. This topic parallels aetio-pathogenic research in that our understanding of the pathogenic, biological and biochemical mechanisms of these diseases is deeply entwined in the search for potential biomarkers of utility to diagnose them. Germane to this point is the marked success of bone-related molecules in saliva compared to cytokines and metalloproteinases in differentiating soft and hard tissue destruction. Despite these advances, translation into routine practice remains limited. Methodological heterogeneity, lack of standardised sampling protocols, biological variability, and insufficient longitudinal validation continue to impede progress. The roadmap ahead requires harmonised protocols, robust multicentre studies, clinically validated thresholds, and technologies that are rapid, affordable, and easily integrated into daily workflows. Biomarkers combined with other factors and interpreted by AI tools may be utilised in future to disclose current disease, predict future disease and aid in monitoring treated conditions: they may provide prognostic tools and have potential in epidemiological screening, particularly if readily available and easily accessible sample matrices such as saliva are used. Ultimately, the future of periodontal and peri-implant diagnostics lies in biologically informed, multi-modal assessment frameworks that complement traditional examination rather than replace it. As molecular technologies mature and AI-assisted personalised models evolve, biomarker-based diagnostics have the potential to transform early detection, risk prediction, and treatment monitoring-bringing us closer to precision periodontology and implantology. The salivary sample matrix is feasible for home use with utility for population screening, whereas the gingival and peri-implant crevicular fluid and the simple periodontal probe will continue to be invaluable in the analysis of localised disease.
Alveolar ridge preservation (ARP) remains challenging in extraction sockets, particularly in the presence of buccal bone dehiscence, where post-extraction remodeling predominantly affects the coronal ridge. The Biologically-oriented Alveolar Ridge Preservation (BARP) concept and its modified application for compromised sockets (mBARP) were developed as innovative biologically driven protocols based on selective compartmentalized grafting. Instead of completely filling the socket, these approaches preserve spontaneous healing in the apical compartment while reinforcing the coronal portion, where dimensional changes are greatest. The protocols combine a collagen sponge in the apical part of the socket with xenograft particles and a collagen sponge sealing the coronal compartment. In compromised sockets, an additional collagen sponge is positioned between the residual buccal or lingual wall and the mucoperiosteal flap to enhance graft containment and soft tissue support. Thirty extraction sites were treated using this approach. After 4-6 months, ridge dimensions were effectively preserved, with a slight vertical loss (+0.3 mm), limited horizontal reduction (0.7-1.0 mm), controlled buccal soft tissue contraction (2.0-2.2 mm), and substantial new bone formation (38%-40%), while residual graft particles remained mainly confined to the coronal compartment. Within the limitations of this study, the BARP concept and its modified application demonstrated favorable clinical, radiographic, and histological outcomes, supporting selective coronal grafting as an innovative strategy to preserve ridge dimensions while maintaining physiological healing in the deeper portion of the extraction socket.
Dental implants rely on a stable and functional interface between the implant surface, surrounding tissues, and the oral microbial environment. While titanium remains the clinical gold standard due to its mechanical properties and capacity for osseointegration, peri-implant inflammation and biofilm-associated infection continue to compromise long-term outcomes. Consequently, there is growing interest in multifunctional implant surfaces capable of simultaneously regulating microbial colonisation, immune responses and peri-implant tissue integration. Advances in surface engineering and biomaterials science have revealed that implant surface chemistry and micro- and nanoscale topography strongly influence protein adsorption, immune activation, cellular behaviour, and bacterial attachment at the host-implant interface. Inspired by naturally antimicrobial and self-cleaning biological surfaces, biomimetic approaches have led to the development of mechano-bactericidal nanostructured titanium interfaces capable of physically inactivating bacteria while maintaining cytocompatibility and enhancing osteogenesis. This review examines the mechanobiological principles governing host-implant interactions and examines current strategies for engineering multifunctional antimicrobial, immunomodulatory, and regenerative implant surfaces. The translational challenges limiting clinical implementation, including mechanical durability, biological masking of engineered surfaces and long-term functional stability, are also discussed, together with emerging interest in alternative implant materials such as zirconia. Collectively, biomimetic multifunctional implant surfaces represent a promising strategy for improving long-term implant integration and peri-implant tissue health, although further translational and clinical validation remains necessary before widespread clinical adoption.
The study of causal relationships is central to scientific inquiry. Understanding what disease is, why it arises, and how it can be treated are a set of fundamentally causal questions. In this article, an overview of causal inference is provided for the applied researcher, with an emphasis placed on intuition and the use of examples from periodontology to support understanding. Causal reasoning goes beyond the description of associations, with a focus instead placed on questions of the form: what would happen to an outcome if a particular exposure were changed? Directed acyclic graphs are introduced as tools through which assumptions can be made explicit and structures that may threaten valid causal inference can be identified, including confounding, mediation, and collider pathways. Randomized controlled trials are highlighted as the gold standard of causal evidence, primarily because they ensure that, on average, comparisons are made between like-with-like groups. However, observational data must often be relied upon due to ethical, practical, and logistical constraints. A three-step framework to answering causal questions is presented, based on (i) asking a causal question, (ii) identifying the causal effect, and (iii) carrying out the analysis. Within this context, two principal strategies for causal identification are outlined: design-based identification and adjustment-based identification. It is illustrated that each approach relies on different sets of assumptions to connect observed data to causal effects. The analysis stage carries out a pre-defined associational comparison that is taken to have a causal interpretation under the proposed assumptions. Across all approaches, a central theme is that causal inference is inherently driven by assumptions. The credibility of a causal claim is determined not primarily by the statistical method, but by whether the underlying assumptions are considered plausible within the context of the scientific question.
Over 40 years of clinical research, Periodontal Plastic Surgery has evolved from a niche topic into an issue of great collective interest in Periodontology.
Iconodiagnostic analysis suggests features consistent with pathologic tooth migration, potentially associated with periodontitis. These findings highlight how visual art can support interdisciplinary reflections on history of oral health and the interface between Medicine and Art.
This technical report describes the clinical rationale for TCAF and introduces a papilla-based decision tree to assist clinicians in selecting the most appropriate strategy (open vs. tunnel) for each individual papilla.
Viruses are increasingly recognized as potential modulators of oral biofilm ecology and periodontal inflammation, expanding the traditional bacterial paradigm of periodontitis. Members of the Herpesviridae family, including Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), and herpes simplex virus (HSV), are frequently detected in periodontal tissues and may influence disease activity through latency, reactivation, immune modulation, epithelial barrier disruption, and interactions with bacteria. These processes may contribute to local dysbiosis and sustained periodontal inflammation. The potential systemic relevance of oral viruses is biologically plausible but remains incompletely established. Viral persistence or reactivation in oral niches may contribute to systemic immune activation through hematogenous spread, saliva-mediated dissemination, aspiration, or amplification of inflammatory mediators as IL-1β, IL-6, and TNF-α. Accordingly, viruses may act as disease modifiers within the broader relationship between periodontitis and systemic conditions including cardiovascular, metabolic, respiratory, neurogenerative, pregnancy-related, and cancer-associated outcomes. However, the strength of evidence differs across these conditions. Current data support a model in which oral viruses, bacteriophages, bacteria, and fungi form an interconnected biofilm ecosystem that may influence periodontitis progression and systemic inflammatory burden. Nevertheless, most available evidence is observational, associative, or derived from mechanistic experimental models, and definitive proof that viruses are independent etiopathogenic drivers of periodontitis is lacking. Future longitudinal and interventional studies are needed to determine whether viral detection reflects bystander association, disease amplification, or a true pathogenic role, and whether antiviral or phage-based strategies offer clinical benefit beyond established periodontal therapy.
AIM:Antihypertensive medications are widely prescribed for hypertension, yet evidence regarding their oral health safety remains limited. We aimed to investigate whether genetically proxied pharmacological actions of antihypertensive drug classes influence the risk of periodontitis and dental caries using a two-sample drug-target Mendelian randomization framework. METHODS:Genetic instruments were obtained for 12 antihypertensive drug classes using variants within or near target genes associated with systolic blood pressure (SBP) in two genome-wide association study (GWAS) meta-analyses: one combining data from the International Consortium of Blood Pressure and UK Biobank, and another additionally including the Million Veteran Program (MVP) and Vanderbilt University's biorepository. Summary statistics for chronic periodontitis were obtained from the MVP GWAS, and for dental caries from the Gene-Lifestyle Interactions in Dental Endpoints consortium using the decayed, missing, and filled surfaces index. Causal effects were estimated using the inverse-variance weighted method with Benjamini-Hochberg correction for multiple testing. Colocalization analyses assessed whether drug targets and outcomes shared causal variants. RESULTS:Genetically proxied diazoxide acting through the KCNJ11 locus was associated with chronic periodontitis after multiple-testing correction (odds ratio [OR] per 1 mmHg lower SBP: 1.06, 95% confidence interval [CI]: 1.02-1.09), with consistent estimates after excluding variants associated with type 2 diabetes. No other associations were observed. Colocalization analyses provided no evidence of shared causal variants. CONCLUSION:We found little evidence that genetically proxied on-target pharmacological actions of antihypertensive drug classes were associated with periodontitis or dental caries. The diazoxide-periodontitis association should be interpreted with caution, given possible residual pleiotropy at the KCNJ11 locus and the absence of colocalization.
Poor oral hygiene and periodontitis influence lung diseases such as pneumonia, chronic obstructive pulmonary disease (COPD), COVID-19, and asthma. The normal lung is not sterile, with a distinct microbial ecosystem that is spatially varied along the respiratory tract. The biogeography of the lung microbiome is balanced between microbial microaspiration from the oral-pharynx and clearance. The mouth is an important reservoir for respiratory pathogens including Streptococcus pneumoniae, Haemophilus influenzae, Pseudomonas aeruginosa, and Staphylococcus aureus, as well as oral microbes (Porphyromonas, Prevotella, Fusobacterium, etc.). Poor oral hygiene and periodontitis increase the bacterial load that can be aspirated, and the host produces pro-inflammatory components that enhance microbial virulence and compromize epithelial integrity. Both poor oral hygiene and periodontitis have been associated with pneumonia, particularly in hospitals and nursing home settings. Periodontitis may also facilitate viral pneumonia (including COVID-19) by altering receptor expression and immune function. Periodontitis correlates with COPD severity and exacerbation frequency through pathways involving matrix metalloproteinases and cytokines. Periodontitis also is associated with asthma and acute exacerbations. Inflammation shapes the lung microbiome by impacting microbial nutrient availability through vascular leakage, inducing changes to epithelial cells which facilitate bacterial adherence, and inducing the production of cytokines, leading to mucus overproduction, inhibition of phagocytosis, and enhancement of microbial pathogen virulence. Multiple biological pathways have been examined in vitro that suggest how "the oral-lung axis" influences pneumonia, COPD, and asthma. Periodontal treatment and effective oral hygiene should be well integrated into medical care to prevent and manage respiratory diseases.
