Open research questions in Oral microbiology and periodontitis research

What the literature leaves open

• Oral submucous fibrosis (OSF) is a precancerous condition closely associated with areca nut chewing, yet its pathogenesis remains incompletely elucidated.

  The multifaceted role of oral microbiota-host interactions in oral submucous fibrosis: from pathogenic mechanisms to microecological regulation therapies · 2026 · DOI

• to such as doctors and dentists, for a greater in the need To conclude, our research topic highlights the fact that oral health interventions that modify the microbiome show potential for improving oral health outcomes across a variety of pathologies and disease conditions. There is increasing evidence to support the empirical use of dietary modifications or improving patient outcomes. This supplement use demonstrates inter-professional coordination between nutritionists, and primary healthcare providers improve understanding of the connection between nutritional choices in order to promote better oral and general health for the population. Despite promising results, the existing evidence remains limited by significant methodological heterogeneity, including differences in study populations, dietary interventions, probiotic strains, routes of administration, duration of follow-up, and selection of clinical outcomes. Future research should focus on conducting well-designed, adequately powered randomized controlled trials with standardized protocols, clearly defined clinically relevant outcomes, and integrating modern multi-omic approaches to characterize the oral microbiome. Such an approach will allow for a more reliable assessment of the causal relationships between dietary interventions, oral microbiome modulation, and oral and general health outcomes, thereby providing a stronger the development of personalized preventive and therapeutic strategies. A shift from studies primarily focused on describing the oral microbiome interventional research will be toward rigorously designed essential for translating current knowledge into evidence-based dietary and microbiome-targeted strategies for the prevention and management of oral diseases. foundation for Finally, we would like to emphasize the need for research into the use of dietary modulations on systemic health outcomes via the modulation of the oral microbiome. Some studies are already showing the oral microbiome can modulate inflammatory cytokines, nutritional status and healthy aging, emphasizing interconnectedness of oral and systemic health (8, 9).

  Editorial: Nutrition and oral microbiology: integrative perspectives for improved oral health · 2026 · DOI

• referral, acknowledging the evidence that uncontrolled periodontitis is an active modifier of endocrine disease management outcomes.

  Periodontal disease and endocrine imbalance: a molecular pathways perspective · 2026 · DOI

• Periodontitis and endocrine dysfunction represent two of the most prevalent chronic conditions in global populations, and the evidence synthesized in this review demonstrates that their cooccurrence is neither coincidental nor merely epidemiological. At the molecular level, these two disease domains are coupled through an extensive and highly organized network of shared signaling pathways, hub genes, and regulatory mechanisms whose architecture has been made progressively more legible through the convergence of experimental, clinical, and systemslevel bioinformatics approaches. The central argument advanced the endocrine-periodontal that throughout this review is while chronic inflammation, relationship is genuinely bidirectional, mechanistically grounded, and clinically actionable: hormonal dysregulation shapes periodontal susceptibility through receptor-mediated effects on immune cells, connective tissue, and alveolar bone that lower to threshold at which microbial challenge escalates the destructive periodontal inflammation in turn disrupts endocrine homeostasis through the systemic dissemination of inflammatory mediators that impair insulin signaling, suppress adiponectin, activate the HPA axis, inhibit thyroid hormone conversion, and reduce functional vitamin D availability. These reverse effects are not trivial epiphenomena of shared risk factors; they are mechanistically reversible specific, quantitatively the through periodontal in glycemic control, adipokine profiles, and improvements systemic successful that periodontal disease management in patients with concurrent endocrine conditions [3, 4]. significant, and partially therapy, inflammatory markers as demonstrated by follow that concurrent patients with multiple As discussed in Section 8, the RANKL/OPG axis emerges from this analysis as the molecular hub that most coherently integrates the diverse endocrine and inflammatory inputs to alveolar bone homeostasis. The central clinical implication of this convergence is endocrine perturbations, such as postmenopausal women with type 2 diabetes, vitamin D deficiency, and obesity-associated adipokine dysregulation, face a compounded osteoclastogenic stimulus that exceeds what any single hormonal or inflammatory variable would predict in isolation, identifying this population as a priority group for integrated endocrine-periodontal management and for future validation of the RANKL/OPG ratio in GCF as a composite and inflammatory risk. biomarker combined hormonal of A similar case can be made for other emerging inflammatory pathways such as NLRP3 inflammasome-driven IL-1b and IL-18 functional and biomarker roles remain maturation whose incompletely understood. (PI3K/Akt, instrumental The molecular network perspective provided by the periodontitis diseasome analysis, detailed in Section 9, has in revealing the systemic scope of the been endocrine-periodontal relationship and in identifying the hub genes (TNF, IL6, STAT3, LEP, NOS3, VEGFA) and enriched pathways Th17 differentiation, HIF-1) through which this relationship operates at the molecular level. Future research should prioritize the functional validation of these network-predicted connections through test whether modulating specific hub gene products at the intersection of endocrine and periodontal signaling produces the predicted dual benefits in relevant disease models. targeted experimental AGE-RAGE, JAK-STAT, studies that Several specific directions for future investigation emerge from the mechanistic framework developed in this review as particularly scientifically productive and clinically impactful. The periodontal effects of GLP-1 receptor agonists, now prescribed at unprecedented scale for type 2 diabetes and obesity, represent antian urgent inflammatory and bone-protective mechanisms of GLP-1R activation large patient populations already receiving these agents who also carry randomized elevated periodontal disease research priority given risk.

  Periodontal disease and endocrine imbalance: a molecular pathways perspective · 2026 · DOI

• Although E-cadherin-mediated adhesion has been implicated in LC-epithelial cell interactions, its role in oral LC biology and periodontal immune homeostasis remains elusive.

  E-cadherin maintains oral Langerhans cell barrier surveillance to preserve microbiota-dependent immune homeostasis · 2026 · DOI

• Conclusions The extent of MB consistently correlated to C‐reactive protein, while a higher correlation with PISA could not be determined.

  Periodontal inflamed surface area (PISA) system and components: Potential for exploring the periodontal systemic interface · 2026 · DOI

• Future studies should consider including serum folate level assessments to better correlate supplementation doses with physiological effects and to ensure accurate folic acid–related interpretation of outcome. One limitation of the present study is the absence of pre- and post-intervention measurements of serum or tissue folic acid levels. Future studies are warranted to explore the relationship between CD34 expression and non- 65 March 2026 27(1):58-68 Meandros Medical and Dental Journal doi: 10.

  The Effects of Folic Acid Supplementation on Novel Biomarkers of the Endothelial Function in Rats with Experimental Periodontitis · 2026 · DOI

• The field of host modulation in periodontitis is dynamic and holds exciting prospects. Future research is likely to focus on refining existing therapies and discovering novel targets. A major direction is improving local delivery systems for host modulators to maximise periodontal benefits while minimising systemic exposure. For MMP inhibitors like doxycycline, formulations such as subgingival slow-release or injectable systems could be explored to supplement systemic dosing(63,64). There is also interest in whether combining host agents could have synergistic effects, for instance, SDD + NSAID together. One study found that a sub-antimicrobial dose of doxycycline combined with a low-dose flurbiprofen had additive effects on reducing GCF MMP levels compared to either alone(65).

  Host-modulatory therapy in periodontitis: Role of subantimicrobial-dose doxycycline and beyond · 2026 · DOI

• Although widely adopted in clinical and research settings, its validation has focused mainly on inter‐examiner agreement, diagnostic concordance and prognostic performance, with limited evidence on patient‐centred outcomes such as comprehension, recall and behavioural relevance.

  Does the 2018 periodontal classification improve patient understanding? A missing piece in periodontal care · 2026 · DOI

• [19-21] Our study strengths reside in focusing on a specific and under-researched population which is pregnant women in Jordan, addressing an important gap in the literature regarding oral health during pregnancy in lower-middle- income countries.

  THE PREVALENCE OF ORAL AND MAXILLOFACIAL DISEASE IN PREGNANT WOMEN AND ITS ASSOCIATION WITH ADVERSE PREGNANCY OUTCOMES · 2026 · DOI

• The elevated IL-10 levels observed in this study were insufficient to counterbalance the immune dysregulation and inflammatory damage mediated by IL-6 and IL-1β. Future stratified MR analyses are warranted to validate the stability of the causal. While our MR-Egger intercept test suggested no significant directional pleiotropy, the lack of MR-PRESSO is a limitation, and future studies with larger genetic datasets are warranted to apply this method for a more comprehensive validation of our findings.

  Causal association and molecular mechanisms of periodontal disease and muscle wasting and atrophy: Mendelian randomization and bioinformatics analysis · 2026 · DOI

• These findings suggest that EmunDo treatment was associated with a restructuring of the subgingival microbiota toward a less dysbiotic profile, warranting further investigation in larger controlled studies using higher-resolution approaches such as shotgun metagenomics.

  Subgingival Microbiota Shifts Following Diode Laser-Activated Indocyanine Green Treatment in Periodontitis: A Pilot 16S rDNA Study · 2026 · DOI

• The transition from identifying postbiotics as metabolic markers to utilizing them as therapeutic agents represents a significant shift in periodontal medicine. Postbiotics offer a more stable and predictable alternative to probiotics, as they do not require the colonization of live microorganisms in an often-unwelcoming dysbiotic niche. This clinical potential is particularly evident in the prospect of “reprogramming” the epigenetic landscape of the periodontium. To successfully translate these mechanistic insights into routine clinical practice, several key translational strategies and structural refinements must be considered: ● Targeted Local Delivery Systems: Modulating SCFA concentrations or introducing competing HDAC inhibitors could effectively dampen the overexpression of inflammatory cytokines at their source. Such metabolites can be integrated into local delivery systems, including mucoadhesive gels or chips, to provide a sustained anti-inflammatory effect directly within the periodontal pocket. ● Adjuvant Therapies for Dysbiosis: Postbiotics may serve as potent adjuvant therapies, enhancing the outcomes of scaling and root planing (SRP) by resolving the residual metabolic dysbiosis that frequently persists after mechanical treatment. ● Patient Stratification and Precision Medicine: These mechanistic insights provide a foundation for rational clinical trial design. Patients could be stratified based on gingival crevicular fluid levels of SCFAs or specific epigenetic signatures, such as increased histone H3 acetylation or reduced repressive methylation marks (e.g., H3K27me3). Biomarkers like these will help identify individuals most likely to benefit from targeted interventions, allowing future trials to adopt a precision medicine approach. Despite these promising applications, several critical research gaps remain. A primary limitation is the current reliance on cross-sectional clinical data or in vitro models; prospective longitudinal human studies are essential to determine whether SCFA-induced histone modifications are causative agents of clinical attachment loss or merely secondary byproducts. Additionally, the clinical application is complicated by a complex dose-response relationship, as SCFAs often exhibit a “double-edged sword” effect. For example, while low, homeostatic concentrations of butyrate are vital for maintaining the gingival epithelial barrier and regulating local immune tolerance, the millimolar concentrations generated by dysbiotic biofilms in deep periodontal pockets actively drive pathogenesis by inducing apoptosis in gingival cells and exacerbating osteoclastmediated bone resorption.

  SCFA-Mediated Histone Modification Mechanisms in Periodontal Disease · 2026 · DOI

• Macrophage reprogramming represents a paradigm shift in the adjunctive management of periodontal and periapi- cal diseases. However, key challenges remain. The devel- opment of orthotopic AP models for therapeutic intracanal delivery, along with the adoption of standardized evaluation criteria, is essential to strengthening the translational valid- ity of experimental findings. Optimizing the delivery systems is another priority. Although microparticles, extracellular vesicles (EVs), and local injections have shown efficacy, future platforms must ensure safety, specificity, and sustained controlled release within periodontal and periapical tissues. A deeper understanding of the molecular and cel- lular mechanisms underlying macrophage plasticity is also needed. Advanced technologies, such as single-cell sequencing and spatial transcriptomics, can provide pre- cise mapping of macrophage interactions with stromal and immune cells, as well as the metabolic pathways governing their polarization. Finally, scalability and clinical integration will determine real-world applicability. Cell-free therapies (e.g., MSC- derived exosomes or miRNA carriers) and cell-based inter- ventions require rigorous assessment of safety, feasibility, and cost-effectiveness. Their most significant potential lies in combination with conventional periodontal and endodon- tic procedures, where synergistic effects may achieve both inflammation resolution and functional regeneration. 1 3Clinical Oral Investigations (2026) 30:234 Conclusion This review highlights experimental preclinical approaches for treating periodontal and apical periodontitis (AP) by reprogramming macrophage polarization, underscoring their potential to transform regenerative endodontics and periodontology. A broad spectrum of strategies -including cytokines (CCL2, IL-37), inhibition of extracellular matrix proteins (FBLN3, Gremlin-1), functionalized biomateri- als, MSC-derived exosomes, regulatory miRNAs, pharma- cological agents (glipizide, apabetalone, DMOG, Stattic, azithromycin), and adoptive M2 macrophage transfer- have been shown to promote M2 polarization while suppress- ing M1-driven inflammation. These interventions converge on reducing bone loss, dampening destructive immune responses, and enhancing osteogenic and dental tissue regeneration. Collectively, both prophylactic and therapeutic mac- rophage-targeted therapies hold substantial promise as adjunctive strategies to conventional biofilm control for periodontitis and AP. Whether administered locally or sys- temically, these approaches require future studies to estab- lish standardized macrophage readouts, optimize delivery and dosing, and validate outcomes in orthotopic models to ensure successful clinical translation.

  Immunotherapies based on macrophage reprogramming in periodontitis and apical periodontitis · 2026 · DOI

• Future research should focus on clarifying the molecular mechanisms linking oral microbial ecosystems with vascular mineralization and identifying translational strategies for early detection and intervention. Integration of multi-omics technologies, including genomics, epigenomics, metabolomics, and transcriptomics, will be essential for identifying regulatory pathways involved in vascular calcification (74, 75). Noncoding RNAs such as microRNAs, long noncoding RNAs, and circular RNAs are emerging as important regulators of calcification pathways and represent promising therapeutic targets (76, 77). Advances in imaging technologies are improving detection of early calcification events. Molecular imaging probes capable of initial binding hydroxyapatite can enable visualization of emission mineral deposition of using tomography 79), while positron allows ^18F-NaF detection (78, and approaches, including calcified OMVs microcalcifications associated with high-risk plaques (80–82).

  Mineral encapsulation of microorganisms in calcified oral biofilms: implications for immune dysregulation and vascular calcification · 2026 · DOI

• It is recommended that future research should focus on evaluating CEO activity in polymicrobial and in vivo models to better reflect clinical conditions, as well as on improving its aqueous solubility and cost-effective formulation for practical application in oral hygiene products.

  In vitro inhibition of Streptococcus mutans by cardamom essential oil · 2026 · DOI

• The oral microbiome as diagnostic and prognostic biomarkers Saliva and dental plaque samples are promising candidates for disease screening and monitoring because of their noninvasive and easily accessible nature. Clinical evidence indicates that the oral microbiome can serve as an effective noninvasive biomarker capable of distinguishing patients with liver disease from healthy controls and facilitating longitudinal monitoring of disease progression. For instance, a metagenomic sequencing analysis of saliva samples identified characteristic alterations in the salivary microbiota of patients with cirrhosis and constructed a diagnostic model whose accuracy was comparable to that of models based on the fecal microbiome (51). Research on NAFLD further reveals that the relative abundance of specific bacterial taxa in the salivary microbiota correlates with the degree of hepatic steatosis and stage of fibrosis, suggesting its potential utility for stratifying NAFLD severity. In the context of HCC, the detection of F. nucleatum within tumor tissue has been established as an independent predictor of poor prognosis, indicating that patients harboring this bacterium typically experience shorter overall and recurrence-free survival (52). While current detection methods rely on tissue biopsies, a critical future direction involves identifying circulating microbial or immune markers in blood or saliva associated with intratumoral F. nucleatum, thereby enabling non-invasive prognostic assessment. 4.2 Oral health intervention: a novel adjunctive management strategy for liver disease A core question in translational research is whether improving oral health, particularly through periodontitis treatment, can positively influence liver disease progression. Preliminary clinical intervention studies have provided encouraging evidence. The preventive role of oral care in serious complications of cirrhosis is gaining recognition. Studies have indicated that a patient’s oral hygiene status is independently associated with the risk of hepatic encephalopathy. Furthermore, intervention trials have demonstrated that implementing intensive oral care, including professional periodontal cleaning and daily chlorhexidine mouthwash use, in patients with decompensated cirrhosis can significantly reduce systemic inflammatory markers and show a trend toward decreased hospitalization rates. This directly supports the beneficial effects of periodontal treatment on liver-related metabolism and inflammation (53, 54). A randomized controlled trial specifically showed that non-surgical periodontal therapy in patients with cirrhosis not only improved their oral health but also beneficially modulated the oral– gut–liver axis by improving gut microbiota profiles, reducing systemic inflammation, and enhancing cognitive function related to hepatic encephalopathy. This provides strong interventional evidence for incorporating periodontal therapy into comprehensive cirrhosis management (53). Although larger prospective randomized controlled trials (RCTs) are warranted for confirmation, these findings underscore the importance of integrating oral care into multidisciplinary management of cirrhosis. From a pragmatic standpoint, oral interventions, such as basic periodontal therapy, are mature, safe, and relatively low-cost clinical procedures. Their integration as a routine adjunctive strategy for patients with liver disease is highly feasible and offers favorable cost-effectiveness. Such interventions are not intended to replace established liver therapies but serve as a complementary approach capable of improving systemic inflammatory status, potentially slowing disease progression, and securing a role in the early prevention and holistic management of liver disease. 4.3 Towards precision medicine Future therapeutic strategies targeting the oral microbiota may evolve beyond conventional periodontal treatment toward more precise and targeted modulations. The development of specific interventions against key oral pathogens encompasses several strategies.

  The oral–gut–liver axis: linking periodontal microbiota to the pathogenesis of liver diseases · 2026 · DOI

• Substantial evidence indicates that oral microbiota dysbiosis is closely associated with major urinary system diseases (CKD, urolithiasis, benign prostate diseases, urologic cancers, pediatric HSPN) via the oral-urinary axis, and bacterial invasion, chronic inflammatory response, and oxidative stress are the three core pathogenic mechanisms disease-specific with manifestations.

  Oral microbiota and urinary system diseases: from mechanistic insights to clinical implications—a comprehensive review · 2026 · DOI

• Patient-specific postbiotic-phage combinations guided by AI-based diagnostic platforms analyzing individual dysbiotic signatures, virulence gene profiles, and phage susceptibilities have not been tested in randomized controlled trials to establish superiority over traditional preventive dentistry approaches.

  Postbiotics and phage synergy in precision oral microbiome engineering: systems biology strategies targeting Streptococcus mutans in dental caries · 2026 · DOI

• Standardized protocols for efficacy testing, safety assessment, and regulatory framework definition for engineered postbiotics combined with bacteriophage-based interventions in oral microbiome engineering do not currently exist, preventing clinical translation of precision microbiome strategies.

  Postbiotics and phage synergy in precision oral microbiome engineering: systems biology strategies targeting Streptococcus mutans in dental caries · 2026 · DOI

• Digital twin computational models integrating multi-omics datasets (metagenomics, metatranscriptomics, metabolomics, virome profiling) with host immune parameters to forecast caries risk and predict postbiotic-phage combination outcomes have not been clinically validated or benchmarked against conventional caries risk assessment tools.

  Postbiotics and phage synergy in precision oral microbiome engineering: systems biology strategies targeting Streptococcus mutans in dental caries · 2026 · DOI

• Postbiotic-derived quorum-sensing inhibitors targeting S. mutans competence development and virulence gene expression pathways lack mechanistic characterization in vivo and long-term ecological impact assessment in terms of biofilm resilience and microbial community composition stability.

  Postbiotics and phage synergy in precision oral microbiome engineering: systems biology strategies targeting Streptococcus mutans in dental caries · 2026 · DOI

• CRISPR-modified paraprobiotic systems engineered to deliver antimicrobial peptides or gene-targeting components face unresolved challenges in delivery efficiency to oral biofilms, quantification of off-target effects on commensal bacteria, and definition of regulatory approval pathways specific to oral applications.

  Postbiotics and phage synergy in precision oral microbiome engineering: systems biology strategies targeting Streptococcus mutans in dental caries · 2026 · DOI

• Engineered postbiotics designed to inhibit glucosyltransferase-mediated extracellular polysaccharide synthesis and metabolic acidogenesis have been explored preclinically, but validation in complex multi-species biofilm models and clinical caries lesion environments remains absent.

  Postbiotics and phage synergy in precision oral microbiome engineering: systems biology strategies targeting Streptococcus mutans in dental caries · 2026 · DOI

• The co-evolutionary dynamics between oral bacteriophages and S. mutans hosts remain poorly characterized, particularly regarding how phages influence bacterial virulence gene expression, horizontal gene transfer mechanisms, and the long-term stability of cariogenic biofilms under repeated phage exposure.

  Postbiotics and phage synergy in precision oral microbiome engineering: systems biology strategies targeting Streptococcus mutans in dental caries · 2026 · DOI

Most-cited papers in Oral microbiology and periodontitis research

• Peri‐implant diseases: Consensus Report of the Sixth European Workshop on Periodontology · Journal Of Clinical Periodontology · 2008 · 1,103 citations
• Oral microbiome: Unveiling the fundamentals · Journal of Oral and Maxillofacial Pathology · 2019 · 825 citations
• The oral microbiome: Role of key organisms and complex networks in oral health and disease · Periodontology 2000 · 2021 · 658 citations
• Epidemiology and Etiology of Denture Stomatitis · Journal of Prosthodontics · 2011 · 572 citations
• Scientific evidence on the links between periodontal diseases and diabetes: Consensus report and guidelines of the joint workshop on periodontal diseases and diabetes by the International Diabetes Federation and the European Federation of Periodontology · Journal Of Clinical Periodontology · 2017 · 564 citations
• Influence of residual pockets on progression of periodontitis and tooth loss: Results after 11 years of maintenance · Journal Of Clinical Periodontology · 2008 · 541 citations
• Oral microbiota in human systematic diseases · International Journal of Oral Science · 2022 · 524 citations
• Global, regional, and national burden of severe periodontitis, 1990–2019: An analysis of the Global Burden of Disease Study 2019 · Journal Of Clinical Periodontology · 2021 · 490 citations
• Basic biology and role of interleukin‐17 in immunity and inflammation · Periodontology 2000 · 2015 · 414 citations
• Prevalence of periodontitis in dentate people between 2011 and 2020: A systematic review and meta‐analysis of epidemiological studies · Journal Of Clinical Periodontology · 2023 · 407 citations

Most recent work

• Selenium-albumin corona rinse ameliorates diabetic periodontitis by inhibiting inflammation, anti-bacterial and improving osteogenesis via activating TrxR1/ROS/β-catenin anti-oxidation cascade · Biomaterials · 2026
• Periodontitis-associated salivary microbiota exacerbates systemic osteoclastogenesis via gut modulation and tryptophan metabolism suppression in ovariectomized mice · International Journal of Oral Science · 2026
• DNA and RNA-based amplicon sequencing of paired supragingival and dentin lesion plaque in children with severe early childhood caries · International Journal of Oral Science · 2026
• Postbiotics and phage synergy in precision oral microbiome engineering: systems biology strategies targeting Streptococcus mutans in dental caries · Frontiers in Molecular Biosciences · 2026
• Periodontitis pathogen Porphyromonas gingivalis promotes chronic obstructive pulmonary disease via affecting neutrophils chemotaxis and function · International Journal of Oral Science · 2026
• The Impact of Periodontitis on Oral Health Outcomes in Older Adults: A Systematic Review · Gerodontology · 2026
• Porphyromonas gingivalis-derived extracellular vesicles aggravate bone destruction in rheumatoid arthritis by promoting Syk-dependent osteoclastogenesis · International Journal of Oral Science · 2026
• Unraveling the diagnostic and prognostic signatures of oral microbiota in head and neck cancer · BMC Biology · 2026
• Association of periodontitis with reduced kidney function and albuminuria in early chronic kidney disease: a population-based study · International Journal of Oral Science · 2026
• Machine learning-driven discovery of therapeutic nucleoside hydrogels for periodontitis · International Journal of Oral Science · 2026

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