The International Association for Dental, Oral, and Craniofacial Research (IADR) and the American Association for Dental, Oral, and Craniofacial Research (AADOCR) have announced the publication of a special issue of Journal of Dental Research that highlights the experimental studies, advances in data architecture, and population-based investigations that seek to provide a more comprehensive understanding of the relationship between oral health and systemic health.
The relationship between oral and systemic disease has evolved from early speculation to systematic investigation. A century after William Hunter’s focal infection theory placed the mouth at the center of myriad illnesses, the field now interrogates that premise with contemporary tools—causal frameworks, large registries, rigorous trials, and integrated clinical data, as well as experimental studies that allow approaches to isolate variables and to perform cause-and-effect experiments to investigate the mechanisms underlying oral and systemic disease connections.
The goal of this Special Issue is not to deliver a final verdict on whether “oral health affects systemic health,” but to refine the question to one that is clinically actionable: for which people, through which pathways, and at what points in the life course does oral health alter systemic risk, and how should health systems respond? By combining methodological rigor, mechanistic insight, population-scale data, and interprofessional practice, as well as experimental studies to test in a straightforward and precise way hypotheses generated by human-derived data, the studies in this issue bring that question within reach. The charge now is rapid, responsible, and equitable translation to interventions that promote both oral and systemic health and enable more effective prevention or management of chronic diseases, and healthy aging across diverse communities.
The injectable bioceramics-containing composite hydrogel could enable pulp-dentin complex repair by facilitating innervation and odontogenic differentiation.
Traditional treatment strategies involved in pulp-dentin complex repair do not promote innervation or odontogenesis. A newly developed injectable composite hydrogel now shows promising results on this front, promoting neural differentiation and odontogenesis, and paving the way for a new treatment strategy.
Credit: UN Women Asia & the Pacific from openverse Image Source Link: https://openverse.org/image/df79ffba-d6fc-466a-9631-e57f722f6896?q=dentist+chamber&p=19
The dental pulp is a soft tissue of the teeth involved in sensory information transmission, immunoprotection, and dentin formation. Odontoblast cells in the pulp differentiate and lead to the formation of dentin that helps in maintaining the structure and function of the teeth. The pulp-dentin complex is also densely innervated by a variety of nerve fibers that are crucial for tooth sensation and pain perception.
The dental pulp is sensitive and susceptible to microbial infection that can damage not only the pulp but also the dentin-oral complex structure. Moreover, the process of odontogenesis (tooth development) and nerve differentiation in the pulp-dentin complex are affected by the defects caused by microbial infection. Unfortunately, traditional treatment strategies, including root canal therapy and vital pulp therapy, which target the pulp instead of the complex do not promote neural regeneration, and thus cannot completely repair this damage.
Modern treatment plans, involving biomaterials such as hydrogels, aim to overcome these limitations. Biomaterials find applications in drug delivery, remineralization, and tissue regeneration. Silicate-based bioceramics are often used in oral therapies owing to their biocompatibility and biodegradable properties. Involvement of lithium (Li) ions, known for neuroprotective properties, and calcium (Ca) ions, which is primarily involved in dentin formation, can further improve the effectiveness of the biomaterials.
A team of researchers from China, led by Professor Chengtie Wu from Shanghai Institute of Ceramics, Chinese Academy of Sciences, set out to explore the efficiency of Li-Ca-Si (LCS) bioceramics in promoting innervated pulp-dentin complex regeneration. “Most biomaterials that are currently used are focused on antibacterial properties, immune regulation, and mineral deposition. As nerves play a very important role in the dentin-pulp complex, the re-innervation property of the biomaterial used in the treatment is equally important,” explains Prof. Chengtie Wu, speaking about the motivation underlying the study, which was published in International Journal of Oral science on October 01, 2025.
The researchers developed a composite hydrogel composed of LCS bioceramics particles and gelatin methacryloyl (GelMA) matrix for the treatment of pulp-dentin complex defects. Both in vivo and in vitro experiments were conducted to check the innervation properties of the hydrogel.
Property analysis of the LCS bioceramics hydrogel showed good injectability, shape fidelity, and photo-crosslinking ability, along with enhanced mechanical strength and mineralization ability. This resulted in convenient dental filling along with a rapid curing as observed by the team. “The composite hydrogel maintained stable structure once filled in even under the erosion of flush water and maintained its stability when immersed in a simulated oral fluid,” highlights Prof. Zhiguang Huan, the Co-corresponding author of the study.
Schwann cells (SCs), which form a prominent glial network in the dentin-pulp complex, play a crucial role in nerve and dental tissue repair and regeneration. The hydrogel promoted SC regeneration and migration. Moreover, the hydrogel showed cytocompalitibility for both SC cells and dental pulp stem cells (DPSCs), along with promoting the proliferation, migration, and odontogenic differentiation of DPSCs.
“DPSC differentiation is usually regulated by the nerve cells in the dentin-pulp complex. We also wanted to see if the odontogenic differentiation of DPSCs was modulated by neural cells under the treatment of bioceramics-containing composite hydrogels,” explains Ms. Xingyu Tao, the first author of this study. The team’s findings suggested that the composite hydrogel helped create a suitable neuro-modulatory microenvironment for odontogenesis, facilitating an integrated dentin-pulp repair via the coupling of neuro-odontogenesis.
Studies in rat model also showed promising results. There was an increase in bone volume and bone mineral density following a hydrogel-based treatment. Innervation and pulp-dentin regeneration was achieved in the in vivo model and pulp tissue morphology also indicated the repairing property of the hydrogel.
Further research on these composite hydrogels could aid our understanding of the biological mechanism of innervation and regeneration process influenced by the treatment. “While the immunomodulatory and antibacterial properties of the hydrogel remain to be fully understood, our study offers a promising approach for functional pulp-dentin integrated repair,” concludes Prof. Chengtie Wu.
There is increasing evidence that gum disease is associated with increased risk of cardiovascular events, including heart attack, stroke, atrial fibrillation, heart failure and cardiometabolic health conditions. Effective prevention and treatment of gum disease, also called periodontal disease, could potentially decrease the burden of cardiovascular disease, according to a new scientific statement published today in the American Heart Association’s flagship journalCirculation.
The new American Heart Association scientific statement, “Periodontal Disease and Atherosclerotic Cardiovascular Disease,” features new data supporting an association between periodontal disease and atherosclerotic cardiovascular disease (ASCVD) and updates the Association’s 2012 scientific statement. ACSVD, the leading cause of death globally, is caused by buildup of arterial plaque (fatty deposits in the arteries) and refers to conditions that include coronary heart disease, stroke, peripheral artery disease and aortic aneurysms.
“Your mouth and your heart are connected,” said Chair of the scientific statement writing group Andrew H. Tran, M.D., M.P.H., M.S., FAHA, a pediatric cardiologist and the director of the preventive cardiology program at Nationwide Children's Hospital in Columbus, Ohio. “Gum disease and poor oral hygiene can allow bacteria to enter the bloodstream, causing inflammation that may damage blood vessels and increase the risk of heart disease. Brushing, flossing and regular dental checkups aren’t just about a healthy smile—they’re an important part of protecting your heart.”
Highlights of the statement include:
Periodontal disease is a chronic inflammatory condition affecting over 40% of U.S. adults over age 30. The earliest stage is gingivitis (inflammation of the gums due to buildup of oral plaque). If left untreated, gingivitis may progress to periodontitis, where the gums begin to pull away from the teeth, forming small pockets that can trap bacteria and lead to infection. The most advanced stage, severe periodontitis, involves extensive damage to the bones supporting the teeth; teeth may become loose and fall out. This stage often requires surgical intervention.
Periodontal disease is more common in individuals with poor oral hygiene and other cardiovascular disease risk factors, such as high blood pressure, overweight or obesity, diabetes and smoking. The prevalence of periodontal disease is also higher among men, older adults, individuals with low physical activity and people affected by adverse social determinants of health, such as lower socioeconomic status, food insecurity and/or lack of access to health care including dental care.
Although periodontal disease and ASCVD share common risk factors, emerging data indicates there is an independent association between the two conditions. Potential biological mechanisms linking periodontal disease with poor cardiovascular outcomes include direct pathways such as bacteria in the blood and vascular infections, as well as indirect pathways such as chronic systemic inflammation.
Numerous studies have found that periodontal disease is associated with an increased risk of heart attack, stroke, atrial fibrillation, heart failure, peripheral artery disease, chronic kidney disease and cardiac death. Although periodontal disease clearly contributes to chronic inflammation that is associated with ASCVD, a cause-and-effect relationship has not been confirmed.
There is also no direct evidence that periodontal treatment will help prevent cardiovascular disease. However, treatments that reduce the lifetime exposure to inflammation appear to be beneficial to reducing the risk of developing ASCVD. The treatment and control of periodontal disease and associated inflammation may contribute to the prevention and improved management of ASCVD.
People with one or more cardiovascular disease risk factors are considered to be at higher risk and may benefit from regular dental screenings and targeted periodontal care to address chronic inflammation. Previous studies have found that more frequent tooth brushing is associated with lower 10-year ASCVD risk (13.7% for once-daily or less brushing vs. 7.35% for brushing three or more times per day) and reduced inflammatory markers.
More research, including long-term studies and randomized controlled trials, is needed to determine whether periodontal treatment can impact ASCVD progression and outcomes.
In addition, the role of socioeconomic status, access to dental care and other social factors that adversely affect health should be explored to develop targeted prevention and treatment strategies that can help reduce the prevalence and adverse outcomes of periodontal disease and ASCVD.
Representative images and heatmaps illustrate how human fetal tooth germs from the upper and lower jaws, although morphologically similar at the cap stage, already display distinct gene expression signatures. Maxillary tooth germs show higher expression of morphogenesis-related genes, while mandibular tooth germs are enriched for mineralization- and calcium homeostasis-related genes, highlighting early regional specialization in tooth development.
Credit: Oral Science and Homeostatic Medicine / Beijing Stomatological Hospital, Capital Medical University & Peking University School and Hospital of Stomatology
The interaction between genetics and tissue environment shapes how individual teeth form in different regions of the jaw. While most experimental studies have focused on mandibular (lower jaw) teeth, little was known about how human maxillary (upper jaw) and mandibular teeth diverge at the molecular level during early development.
In a new study published in Oral Science and Homeostatic Medicine, a collaborative team from Beijing Stomatological Hospital, Capital Medical University, and Peking University School and Hospital of Stomatology performed a RNA-sequencing analysis of human fetal tooth germs at the cap stage (11–12 post-conception weeks). They compared gene expression profiles between pooled maxillary and mandibular tooth germs and validated key findings with quantitative PCR and immunofluorescence staining.
Upper and lower tooth germs show distinct transcriptomic profiles at the cap stage
Morphologically, both upper and lower tooth germs displayed typical cap-stage features, but principal component analysis of the RNA-seq data revealed a clear separation between maxillary and mandibular samples, indicating distinct transcriptional signatures despite their similar morphology.
The team identified 14,267 genes that were highly expressed in both regions, enriched in pathways related to extracellular matrix organization, TGF-β, WNT, NOTCH and BMP signaling, reflecting a shared core program for epithelial–mesenchymal interactions and early odontogenesis.
Upper tooth germs are enriched for morphogenesis-related genes, whereas lower tooth germs are enriched for mineralization-related genes.
Beyond this common framework, 687 genes were differentially expressed between the two regions: 282 were upregulated in maxillary tooth germs and 405 in mandibular tooth germs.
Maxillary-enriched genes, including GATA3, SHOX2 and PAX3, were associated with embryonic organ morphogenesis, regulation of FGF and BMP signaling, and extracellular matrix remodeling. These genes have been previously implicated in craniofacial patterning, palatal development and upper jaw formation.
In contrast, mandibular-enriched genes such as HAND2, DLX6, NKX2-3, PHEX and DMP1 were linked to actin-based movement, calcium ion transport and homeostasis, dentinogenesis and cytokine secretion—processes that support mineralized tissue formation and mechanical function.
“Even though the tooth germs in the upper and lower jaws look very similar at the cap stage, their gene expression patterns are diverging,” said Ran Zhang, corresponding author of the study.
Protein–protein interaction network analysis highlighted several hub regulators, including IHH, HAND2, PAX3 and SP7, that connect multiple signaling pathways and may orchestrate region-specific tooth germ differentiation.
Validation at RNA and protein levels
To confirm the RNA-seq results, the investigators selected 18 representative genes for RT-qPCR. Most showed significant and consistent regional differences, with SHOX2, CHRDL1, GATA3, SP7 and PAX3 higher in maxillary tooth germs, and DMP1, NKX2-3, PHEX, HAND2 and DLX6 higher in mandibular tooth germs.
Immunofluorescence staining additionally showed that DLX6 and PHEX were strongly expressed in mandibular tooth germs, whereas SHOX2 was predominantly expressed in the maxillary tooth germs, revealing both regional and compartment-specific expression across epithelium and mesenchyme.
“These region-specific regulatory programs likely contribute to the distinct eruption timing, crown morphology and functional specialization of maxillary and mandibular teeth,” said corresponding author Songlin Wang.
Implications and next steps
Human embryonic samples at this stage are extremely rare, so the authors acknowledge the modest sample size as a limitation but emphasize the value of obtaining direct human data rather than extrapolating solely from animal models. They suggest that functional studies in model organisms, guided by the identified hub genes and pathways, will be needed to decode how these transcriptional programs translate into jaw-specific tooth morphology.
The RNA-seq data from this study have been deposited in the CNGB Sequence Archive (accession CNP0008028) to facilitate reuse by the dental research community.
A new article published in the Journal of Dental Research explores the development an integrated data-cleaning and subtype discovery pipeline using unsupervised machine learning for comprehensive analysis and visualization of data patterns in the National Health and Nutrition Examination Survey (NHANES) database.
Authored by Alena Orlenko, Cedars-Sinai Medical Center, Los Angeles, CA, USA, et al., “Uncovering Dental Caries Heterogeneity in NHANES Using Machine Learning” addresses the limitations of the NHANES, one of the largest curated repositories of nationally representative population-level health-related indicators, by establishing a data-cleaning pipeline with a novel outlier detection algorithm and unsupervised machine learning to identify phenotype subtypes within NHANES dental caries data.
“By bringing the power of machine learning to a large national data set, the authors identify key clusters of factors linked to caries in children or seniors,” said Nick Jakubovics, Editor-in-Chief of Journal of Dental Research. “The next challenge is to build on this information and find more effective methods to prevent caries in different groups of people.”
The study demonstrates a robust data-cleaning–subtype discovery pipeline that could be applied to investigate other health conditions using NHANES and similar databases for machine learning predictive modeling. Applying a comprehensive bioinformatics pipeline to NHANES data successfully identified substantial age-driven heterogeneity in dental caries, suggesting stratification is crucial for future predictive modeling.
This integrative approach systematically addresses data quality issues and facilitates exploratory analysis to reveal data patterns associated with subtypes and variables associated with the clinical heterogeneity of caries. It uncovered novel associations between caries status, lead/pollutant exposure, specific laboratory markers and food types, as well as sleep patterns, reflecting additional disease markers in susceptible populations. This demonstrates the value of integrating data science techniques with large-scale observational data to gain deeper insights into complex, multifactorial diseases.
About the Journal of Dental Research
The IADR/AADOCR Journal of Dental Research (JDR) is a multidisciplinary journal dedicated to the dissemination of new knowledge in all sciences relevant to dentistry and the oral cavity and associated structures in health and disease. The JDR Editor-in-Chief is Nicholas Jakubovics, Newcastle University, England. Follow the JDR on Twitter at @JDentRes.
About IADR/AADOCR
IADR is a nonprofit organization with a mission to drive dental, oral, and craniofacial research for health and well-being worldwide. IADR represents the individual scientists, clinician-scientists, dental professionals, and students based in academic, government, non-profit, and private-sector institutions who share our mission. AADOCR is the largest division of IADR. Learn more at www.iadr.org.
Journal
Journal of Dental Research
Article Title
Uncovering Dental Caries Heterogeneity in NHANES Using Machine Learning
Researchers from The University of Osaka find that migration of blood sugar to saliva in individuals with type 2 diabetes causes an imbalance in the oral microbiome, affecting cavity development
Credit: Akito Sakanaka, Kuboniwa Laboratory, The University of Osaka
Osaka, Japan – Individuals with type 2 diabetes often have a higher incidence of tooth decay, but the underlying mechanisms remain unclear. Recent evidence indicates that hyperglycemia could lead to the overwhelming presence of sugars not only in urine but also in saliva, yet its contribution to the development, or pathogenesis, of tooth decay is still unknown.
Researchers have now been able to demonstrate that this is directly influenced by blood sugar migration to saliva, changing the bacterial populations in the mouth to promote cavity development. In a study recently published in Microbiome, researchers from The University of Osaka have revealed that blood sugar migration to saliva, induced by hyperglycemia, caused shifts in the oral microbiome that fueled cavity-associated bacteria. This migration of blood sugar was increased in individuals with dental caries, commonly known as cavities, and more dental plaque, but reduced with improved blood sugar control.
“We developed a novel method for untargeted metabolomic profiling of gland-derived saliva that preserves intact metabolite profiles before modification by the oral microbiome,” explains Masae Kuboniwa, senior author of the study. “This allowed us to understand the changes in these metabolites between the blood and saliva, and their subsequent changes after exposure to the oral microbiome.”
The team compared gland-derived saliva metabolite profiles, which provides information about an individual’s metabolic status without bacteria present, against whole saliva and plasma samples from individuals living with and without type 2 diabetes. It was found that the migration of fructose and glucose from blood to saliva was induced by hyperglycemia. Through microbial sequencing, they were then able to see the effect that this migration had on the oral microbiome.
“The increase of these metabolites in saliva fueled changes in the oral microbiome, enriching cariogenic bacteria such as Streptococcus mutans and reducing the abundance of health-associated species like Streptococcus sanguinis, shifting oral biofilm metabolism toward glycolysis and carbohydrate degradation,” says Akito Sakanaka, lead author. “This shift in the microbial population increases acid production, which erodes tooth enamel and strongly links diabetes to dental caries.”
Importantly, the team found that improved glycemic control reduces the plasma-to-saliva transfer of sugars, particularly fructose, reversing this microbiome imbalance and reducing the risk of tooth decay. In fact, a co-culture biofilm experiment with S. mutans and S. sanguinis demonstrated that the proportion of S. mutans markedly increased in a nutrient-rich medium containing fructose, indicating that the combination of glucose and fructose favors S. mutans under co-culture conditions. Together, these findings help to reveal the role of blood sugar migration to saliva in the pathogenesis of tooth decay and plaque buildup in individuals with type 2 diabetes. The findings indicate that glycemic control could be an effective strategy to reduce the risk of not only periodontal disease, an established oral comorbidity, but also tooth decay, helping to improve oral health and quality of life.
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The article, “Diabetes alters the supragingival microbiome through plasma-to-saliva migration of glucose and fructose,” was published in Microbiome at DOI: https://doi.org/10.1186/S40168-025-02256-X
Schematic overview showing how Porphyromonas gingivalis (Pg) with intact LPS drives periapical bone loss and systemic glucose intolerance through IL-17–mediated inflammation. Pg colonization in teeth induces immune cell infiltration (CD45, CD19, Th17) and adipose tissue inflammation, worsening glucose metabolism in high-fat diet mice. These effects are reduced in mice infected with LPS-deficient Pg or lacking IL-17, highlighting IL-17’s key role in linking oral infection to metabolic dysfunction.
Chronic inflammatory diseases are increasingly recognized as being tied to systemic metabolic dysfunction, overturning the old belief that local infections stay confined. Research now shows that inflammation arising in a single site like the gums or the root of a tooth can send systemic signals that disrupt glucose regulation. Oral diseases, once dismissed as dental issues, have become central to this evolving picture. Among the key culprits is Porphyromonas gingivalis (Pg), a pathogen behind gum disease and periapical lesions. With its atypical lipopolysaccharide (LPS) and strong inflammatory drive, Pg has emerged as a notable link between persistent oral inflammation and broader metabolic imbalance.
The researchers first analyzed periapical tissues from 94 endodontic surgery patients and found Pg to be a predominant pathogen, particularly in severe lesions. Vincent Blasco-Baque explains “To test causation and mechanism, we developed a controlled mouse model in which the endodontic space was monocolonized with Pg. Mice were placed on a high-fat diet to simulate metabolic stress and were assigned to receive either wild-type Pg with intact LPS, a weakened LPS strain, or purified LPS alone.” An additional group lacked IL-17 to determine its role in disease progression. Across all groups, the team evaluated periapical bone loss with micro-CT, profiled immune activation, and assessed adipose inflammation, dysbiosis, and glucose metabolism.
These findings reveal a clear mechanistic link between Pg-induced periapical disease and systemic metabolic dysfunction. As Vincent Blasco-Baque shares, “Mice exposed to Pg with functional LPS showed marked periapical bone loss and a surge in Th17 cells and IL-17.” He further notes, “These effects extended systemically: in high-fat–diet mice, Pg-LPS significantly worsened glucose intolerance, accompanied by adipose dysbiosis, inflammation, and cytokines that disrupt insulin signaling.” In IL-17 knockout mice, however, this cascade largely disappeared. Pg or its LPS failed to induce substantial bone loss, metabolic impairment, or inflammatory activation. Without IL-17, Pg lost much of its capacity to drive local and systemic pathology.
This study offers several key benefits and insights. It highlights a previously underrecognized role of periapical lesions in influencing systemic metabolic health. It also establishes a robust causal model rather than solely correlational evidence. Finally, it identifies IL-17 as a potential therapeutic target, suggesting that modulating Th17 activation or blocking Pg virulence factors, such as gingipains or O-antigen LPS components, may reduce both local tissue destruction and systemic metabolic risk.
“Looking ahead, these findings open opportunities for novel interventions, including IL-17 inhibitors, gingipain blockers, microbiome-modulating approaches, and improved diagnostic biomarkers to assess systemic impact of endodontic infections.” shares Vincent Blasco-Baque. Further research into synergistic interactions with other oral pathogens may also deepen understanding of oral-systemic disease links.
In conclusion, this study demonstrates that Pg and its LPS are potent drivers of both periapical bone destruction and systemic metabolic dysfunction, acting through an IL-17–dependent inflammatory pathway. By unveiling an oral–systemic axis connecting endodontic infection to metabolic disease, the work lays the foundation for new therapeutic strategies aimed at protecting both oral and systemic health.
This study was supported by the Paul Calas Award from the French Society of Endodontics (SFE). The funding body had no role in the study design, data collection, analysis, interpretation, or manuscript writing. Except that, we have not received any funding, grants, or personal benefits from any organization that could affect the objectivity of this study.
