Consensus report of the second European Consensus Workshop on Education in Periodontology.

BACKGROUND: The second European Consensus Workshop on Education in Periodontology was commissioned, as a result of the changes in the discipline and the advances in educational methods/technology, to update the 2009 Consensus report of the first European Federation of Periodontology (EFP) Workshop on the same topic that was jointly authored by the Association for Dental Education in Europe. AIM: To identify and propose changes necessary in periodontal education at three levels, namely undergraduate, specialist and continuing professional development (CPD), with respect to learning outcomes, competencies and methods of learning/training and evaluation. METHODS: Four working groups (WGs) considered education in periodontology at the undergraduate, specialist and CPD levels, and education methods. Four commissioned position papers, one per WG, summarized the relevant information. Workshop participants gathered at an in-person consensus meeting to discuss the individual reviews, and this consensus report summarizes the conclusions. RESULTS: The learning outcomes for undergraduate and specialist education in periodontology have been updated, and a proposal for learning outcomes for CPD programmes was made. Learning/teaching/training and evaluation methods were proposed for each level of education, which included face-to-face, virtual and blended learning methods. CONCLUSION: Developments in oral/dental medicine and in contemporary educational technologies have been translated into updated learning outcomes and learning/teaching/ training/evaluation methods relevant to education in periodontology.

Dietary nitrate intake and net nitrite-generating capacity of the oral microbiome interact to enhance cardiometabolic health: Results from the Oral Infections Glucose Intolerance and Insulin Resistance Study (ORIGINS).

Background: We investigated the association between dietary nitrate intake and early clinical cardiometabolic risk biomarkers, and explored whether the oral microbiome modifies the association between dietary nitrate intake and cardiometabolic biomarkers. Methods: Cross-sectional data from 668 (mean [SD] age 31 [9] years, 73% women) participants was analyzed. Dietary nitrate intakes and alternative healthy eating index (AHEI) scores were calculated from food frequency questionnaire responses and a validated US food database. Subgingival 16S rRNA microbial genes (Illumina, MiSeq) were sequenced, and PICRUSt2 estimated metagenomic content. The Microbiome Induced Nitric oxide Enrichment Score (MINES) was calculated as a microbial gene abundance ratio representing enhanced net capacity for NO generation. Cardiometabolic risk biomarkers included systolic and diastolic blood pressure, HbA1c, glucose, insulin, and insulin resistance (HOMA-IR), and were regressed on nitrate intake tertiles in adjusted multivariable linear models. Results: Mean nitrate intake was 190[171] mg/day. Higher nitrate intake was associated with lower insulin, and HOMA-IR but particularly among participants with low abundance of oral nitrite enriching bacteria. For example, among participants with a low MINES, mean insulin[95%CI] levels in high vs. low dietary nitrate consumers were 5.8[5.3,6.5] vs. 6.8[6.2,7.5] (p=0.004) while respective insulin levels were 6.0[5.4,6.6] vs. 5.9[5.3,6.5] (p=0.76) among partcipants with high MINES (interaction p=0.02). Conclusion: Higher dietary nitrate intake was only associated with lower insulin and insulin resistance among individuals with reduced capacity for oral microbe-induced nitrite enrichment. These findings have implications for future precision medicine-oriented approaches that might consider assessing the oral microbiome prior to enrollment into dietary interventions or making dietary recommendations.

ACES: A new framework for the application of the 2018 periodontal status classification scheme to epidemiological survey data.

AIM: To propose a framework for consistently applying the 2018 periodontal status classification scheme to epidemiological surveys (Application of the 2018 periodontal status Classification to Epidemiological Survey data, ACES). PROPOSED FRAMEWORK: We specified data requirements and workflows for either completed or planned epidemiological surveys, utilizing commonly collected measures of periodontal status (clinical attachment levels [CAL], probing depths, bleeding on probing), as well as additional necessary variables for the implementation of the 2018 periodontal status classification (tooth loss due to periodontitis and complexity factors). Following detailed instructions and flowcharts, survey participants are classified as having periodontal health, gingivitis or periodontitis. Rates of edentulism must also be reported. In cases of periodontitis, instructions on how to compute the stage and extent are provided. Assessment of grade can be derived from CAL measurements (or from radiographic alveolar bone loss data) in relation to root length and the participant's age. CONCLUSIONS: ACES is a framework to be used in epidemiological studies of periodontal status that (i) have been completed, and in which stage and grade according to the 2018 classification are inferred retroactively, or (ii) are being planned. Consistent use of the proposed comprehensive approach will facilitate the comparability of periodontitis prevalence estimates across studies.

Clinical attachment loss is cross-sectionally associated with elevated glucose among adults without diabetes.

AIM: We investigated whether periodontal measures are cross-sectionally associated with prediabetes and cardiometabolic biomarkers among non-diabetic younger adults. MATERIALS AND METHODS: One thousand seventy-one participants (mean age = 32.2 years [SE = 0.3]; 73% female) from the Oral Infections, Glucose Intolerance and Insulin Resistance Study were enrolled. Full-mouth clinical attachment loss (fm-CAL), probing depth (fm-PD) and bleeding on probing were ascertained. Interproximal CAL (i-CAL) and probing depths (i-PD) served as our primary exposures. Glucose, HbA1c, insulin and insulin resistance (HOMA-IR) outcomes were assessed from fasting blood. Prediabetes was defined per American Diabetes Association guidelines. Prediabetes prevalence ratios (PR [95% CI]) and mean [SE] cardiometabolic biomarkers were regressed on periodontal variables via multivariable robust variance Poisson regression or multivariable linear regression. RESULTS: Prevalence of prediabetes was 12.5%. Fully adjusted prediabetes PR in Tertiles 3 versus 1 of mean i-CAL was 2.42 (1.77, 3.08). Fully adjusted fasting glucose estimates across i-CAL tertiles were 83.29 [0.43], 84.31 [0.37], 86.48 [0.46]; p for trend <.01. Greater percent of sites with i-PD ≥3 mm showed elevated natural-log-HOMA-IR after adjustment (0%-12% of sites = 0.33 [0.03], 13%-26% of sites = 0.39 [0.03], ≥27% of sites = 0.42 [0.03]; p for trend = .04). CONCLUSIONS: i-CAL (vs. fm-CAL) was associated with elevated fasting glucose and prediabetes, whereas i-PD (vs. fm-PD) was associated with insulin resistance. Future studies are needed to examine periodontal disease and incident prediabetes.

Periodontitis and brain magnetic resonance imaging markers of Alzheimer's disease and cognitive aging.

INTRODUCTION: We examined the association of clinical, microbiological, and host response features of periodontitis with MRI markers of atrophy/cerebrovascular disease in the Washington Heights Inwood Columbia Aging Project (WHICAP) Ancillary Study of Oral Health. METHODS: We analyzed 468 participants with clinical periodontal data, microbial plaque and serum samples, and brain MRIs. We tested the association of periodontitis features with MRI features, after adjusting for multiple risk factors for Alzheimer's disease/Alzheimer's disease-related dementia (AD/ADRD). RESULTS: In fully adjusted models, having more teeth was associated with lower odds for infarcts, lower white matter hyperintensity (WMH) volume, higher entorhinal cortex volume, and higher cortical thickness. Higher extent of periodontitis was associated with lower entorhinal cortex volume and lower cortical thickness. Differential associations emerged between colonization by specific bacteria/serum antibacterial IgG responses and MRI outcomes. DISCUSSION: In an elderly cohort, clinical, microbiological, and serological features of periodontitis were associated with MRI findings related to ADRD risk. Further investigation of causal associations is warranted.

Experimentally Induced Peripheral Venous Congestion Exacerbates Inflammation, Oxidative Stress, and Neurohormonal and Endothelial Cell Activation in Patients With Systolic Heart Failure.

BACKGROUND: Venous congestion (VC) is a hallmark of symptomatic heart failure (HF) requiring hospitalization; however, its role in the pathogenesis of HF progression remains unclear. We investigated whether peripheral VC exacerbates inflammation, oxidative stress and neurohormonal and endothelial cell (EC) activation in patients with HF with reduced ejection fraction (HFrEF). METHODS AND RESULTS: Two matched groups of patients with HFrEF and with no peripheral VC vs without recent HF hospitalization were studied. We modeled peripheral VC by inflating a cuff around the dominant arm, targeting ∼ 30 mmHg increase in venous pressure (venous stress test [VST]). Blood and ECs were sampled before and after 90 minutes of VST. We studied 44 patients (age 53 ± 12 years, 32% female). Circulating endothelin-1, tumor necrosis factor-α, interleukin-6, isoprostane, angiotensin II (ang-2), angiopoietin-2, vascular cell adhesion molecule-1, and CD146 significantly increased after the VST. Enhanced endothelin-1 and angiopoietin-2 responses to the VST were present in patients with vs without recent hospitalization and were prospectively associated with incident HF-related events; 6698 messenger ribonucleic acid (mRNA probe sets were differentially expressed in ECs after VST. CONCLUSIONS: Experimental VC exacerbates inflammation, oxidative stress, neurohormonal and EC activation and promotes unfavorable transcriptome remodeling in ECs of patients with HFrEF. A distinct biological sensitivity to VC appears to be associated with high risk for HF progression.

Essential Domains, Core Outcome Sets, and Measurements to Capture the Benefits and Harms of Implant Dentistry Interventions: The ID-COSM Initiative.

Consensus on a valid and comprehensive set of outcomes to capture the full benefits and harms of implant dentistry interventions is key for progressing toward better clinical guidelines and policy. In this field, research remains fragmented and uses too many different outcomes. Studies are unable to cover the full breadth necessary to properly evaluate benefits, harms, and costs. Best-practice examples inspired the Implant Dentistry Core Outcome Set and Measurements (ID-COSM) initiative that identified four core outcome domain areas (pathophysiology, implant/prosthesis lifespan, life impact, and access to care), five essential outcomes mandatory for all trials, and six outcomes mandatory in specific circumstances. This innovative multistep approach combined input from scientific evidence, patients from multiple countries, methodologists, and industry representatives. The ID-COSM consensus aspires to contribute to better adoption of relevant and valid outcomes in trials and enable their results to be combined in high-quality meta-analyses to support better-informed care and policy.

Prevention and treatment of peri-implant diseases-The EFP S3 level clinical practice guideline.

BACKGROUND: The recently published Clinical Practice Guidelines (CPGs) for the treatment of stages I-IV periodontitis provided evidence-based recommendations for treating periodontitis patients, defined according to the 2018 classification. Peri-implant diseases were also re-defined in the 2018 classification. It is well established that both peri-implant mucositis and peri-implantitis are highly prevalent. In addition, peri-implantitis is particularly challenging to manage and is accompanied by significant morbidity. AIM: To develop an S3 level CPG for the prevention and treatment of peri-implant diseases, focusing on the implementation of interdisciplinary approaches required to prevent the development of peri-implant diseases or their recurrence, and to treat/rehabilitate patients with dental implants following the development of peri-implant diseases. MATERIALS AND METHODS: This S3 level CPG was developed by the European Federation of Periodontology, following methodological guidance from the Association of Scientific Medical Societies in Germany and the Grading of Recommendations Assessment, Development and Evaluation process. A rigorous and transparent process included synthesis of relevant research in 13 specifically commissioned systematic reviews, evaluation of the quality and strength of evidence, formulation of specific recommendations, and a structured consensus process involving leading experts and a broad base of stakeholders. RESULTS: The S3 level CPG for the prevention and treatment of peri-implant diseases culminated in the recommendation for implementation of various different interventions before, during and after implant placement/loading. Prevention of peri-implant diseases should commence when dental implants are planned, surgically placed and prosthetically loaded. Once the implants are loaded and in function, a supportive peri-implant care programme should be structured, including periodical assessment of peri-implant tissue health. If peri-implant mucositis or peri-implantitis are detected, appropriate treatments for their management must be rendered. CONCLUSION: The present S3 level CPG informs clinical practice, health systems, policymakers and, indirectly, the public on the available and most effective modalities to maintain healthy peri-implant tissues, and to manage peri-implant diseases, according to the available evidence at the time of publication.

Relevant domains, core outcome sets and measurements for implant dentistry clinical trials: The Implant Dentistry Core Outcome Set and Measurement (ID-COSM) international consensus report.

AIM: Lack of consistently reported outcomes limits progress in evidence-based implant dentistry and quality of care. The objective of this initiative was to develop a core outcome set (COS) and measurements for implant dentistry clinical trials (ID-COSM). MATERIALS AND METHODS: This Core Outcome Measures in Effectiveness Trials (COMET)-registered international initiative comprised six steps over 24 months: (i) systematic reviews of outcomes reported in the last 10 years; (ii) international patient focus groups; (iii) a Delphi project with a broad range of stakeholders (care providers, clinical researchers, methodologists, patients and industry representatives); (iv) expert group discussions organizing the outcomes in domains using a theoretical framework and identifying the COSs; (v) identification of valid measurement systems to capture the different domains and (vi) final consensus and formal approval involving experts and patients. The methods were modified from the best practice approach following the Outcome Measures in Rheumatoid Arthritis Clinical Trial and COMET manuals. RESULTS: The systematic reviews and patient focus groups identified 754 (665 + 89, respectively) relevant outcome measures. After elimination of redundancies and duplicates, 111 were formally assessed in the Delphi project. By applying pre-specified filters, the Delphi process identified 22 essential outcomes. These were reduced to 13 after aggregating alternative assessments of the same features. The expert committee organized them into four core outcome areas: (i) pathophysiology, (ii) implant/prosthesis lifespan, (iii) life impact and (iv) access to care. In each area, core outcomes were identified to capture both the benefits and harms of therapy. Mandatory outcome domains included assessment of surgical morbidity and complications, peri-implant tissue health status, intervention-related adverse events, complication-free survival and overall patient satisfaction and comfort. Outcomes deemed mandatory in specific circumstances comprised function (mastication, speech, aesthetics and denture retention), quality of life, effort for treatment and maintenance and cost effectiveness. Specialized COSs were identified for bone and soft-tissue augmentation procedures. The validity of measurement instruments ranged from international consensus (peri-implant tissue health status) to early identification of important outcomes (patient-reported outcomes identified by the focus groups). CONCLUSIONS: The ID-COSM initiative reached a consensus on a core set of mandatory outcomes for clinical trials in implant dentistry and/or soft tissue/bone augmentation. Adoption in future protocols and reporting on the respective domain areas by currently ongoing trials will contribute to improving evidence-informed implant dentistry and quality of care.

With Teeth, Broken, or Fixed: The Challenges of Linking Periodontitis, Neuroepidemiology, and Biomarkers of Disease.

Periodontitis is a chronic inflammatory, bacterially-driven disease of the tooth-supporting tissues that shares several risk factors and elements of host response with Alzheimer's disease and related dementias (ADRD). Epidemiological studies have identified relatively consistent associations between adverse oral health conditions and ADRD. In this issue of the journal, a large study from the UK Biobank further explores these relationships along with MRI cognitive biomarkers. Despite its strength due to the large sample size, challenges in the study of periodontitis and neuroepidemiology markers include potential sampling bias, appropriate assessment of exposures, and the possibility of reverse causality.

Relevant domains, core outcome sets and measurements for implant dentistry clinical trials: The Implant Dentistry Core Outcome Set and Measurement (ID-COSM) international consensus report.

AIM: Lack of consistently reported outcomes limits progress in evidence-based implant dentistry and quality of care. The objective of this initiative was to develop a core outcome set (COS) and measurements for implant dentistry clinical trials (ID-COSM). MATERIALS AND METHODS: This Core Outcome Measures in Effectiveness Trials (COMET)-registered international initiative comprised six steps over 24 months: (i) systematic reviews of outcomes reported in the last 10 years; (ii) international patient focus groups; (iii) a Delphi project with a broad range of stakeholders (care providers, clinical researchers, methodologists, patients and industry representatives); (iv) expert group discussions organizing the outcomes in domains using a theoretical framework and identifying the COSs; (v) identification of valid measurement systems to capture the different domains and (vi) final consensus and formal approval involving experts and patients. The methods were modified from the best practice approach following the Outcome Measures in Rheumatoid Arthritis Clinical Trial and COMET manuals. RESULTS: The systematic reviews and patient focus groups identified 754 (665 + 89, respectively) relevant outcome measures. After elimination of redundancies and duplicates, 111 were formally assessed in the Delphi project. By applying pre-specified filters, the Delphi process identified 22 essential outcomes. These were reduced to 13 after aggregating alternative assessments of the same features. The expert committee organized them into four core outcome areas: (i) pathophysiology, (ii) implant/prosthesis lifespan, (iii) life impact and (iv) access to care. In each area, core outcomes were identified to capture both the benefits and harms of therapy. Mandatory outcome domains included assessment of surgical morbidity and complications, peri-implant tissue health status, intervention-related adverse events, complication-free survival and overall patient satisfaction and comfort. Outcomes deemed mandatory in specific circumstances comprised function (mastication, speech, aesthetics and denture retention), quality of life, effort for treatment and maintenance and cost effectiveness. Specialized COSs were identified for bone and soft-tissue augmentation procedures. The validity of measurement instruments ranged from international consensus (peri-implant tissue health status) to early identification of important outcomes (patient-reported outcomes identified by the focus groups). CONCLUSIONS: The ID-COSM initiative reached a consensus on a core set of mandatory outcomes for clinical trials in implant dentistry and/or soft tissue/bone augmentation. Adoption in future protocols and reporting on the respective domain areas by currently ongoing trials will contribute to improving evidence-informed implant dentistry and quality of care.

Essential domains, core outcome sets, and measurements to capture benefits and harms of implant dentistry interventions: The ID-COSM initiative.

Consensus on a valid and comprehensive set of outcomes to capture the full benefits and harms of implant dentistry interventions is key for progress towards better clinical guidelines and policy. In this field, outcome research remains fragmented and uses too many different outcomes. Accordingly, such efforts are still unable to cover the full breadth necessary to properly evaluate benefits, harms, and costs. Best practice examples from medicine have inspired the Implant Dentistry Core Outcome Set and Measurements (ID-COSM) initiative that identified four core outcome domain areas (pathophysiology, implant/prosthesis lifespan, life impact, and access to care) and five essential outcomes mandatory for all trials, plus six others that are mandatory in specific circumstances. The innovative multistep approach has combined input from scientific evidence, patients from multiple countries, methodologists, and industry representatives. It is an important step. The ID-COSM consensus aspires to contribute to better adoption of relevant and valid outcomes in trials and enable combining their results in high-quality meta-analyses to support better informed care and policy.

Genome-Wide Analysis of Periodontal and Peri-implant Cells and Tissues.

-Omics analyses, including the systematic cataloging of messenger RNA and microRNA sequences or DNA methylation patterns in a cell population, organ, or tissue sample, are powerful means of generating comprehensive genome-level data sets on complex diseases. We have systematically assessed the transcriptome, microbiome, miRNome, and methylome of gingival and peri-implant tissues from human subjects and further studied the transcriptome of primary cells ex vivo, or in vitro after infection with periodontal pathogens.Our data offer new insight on the pathophysiology underlying periodontal and peri-implant diseases, a possible route to a better and earlier diagnosis of these highly prevalent chronic inflammatory diseases and thus, to a personalized and efficient treatment approach.Herein, we outline the laboratory steps required for the processing of periodontal cells and tissues for -omics analyses using current microarrays or next-generation sequencing technology.

Differential Expression, Functional and Machine Learning Analysis of High-Throughput -Omics Data Using Open-Source Tools.

Today, -omics analyses, including the systematic cataloging of messenger RNA and microRNA sequences or DNA methylation patterns in a cell population, organ or tissue sample, allow for an unbiased, comprehensive genome-level analysis of complex diseases, offering a large advantage over earlier "candidate" gene or pathway analyses. A primary goal in the analysis of these high-throughput assays is the detection of those features among several thousand that differ between different groups of samples. In the context of oral biology, our group has successfully utilized -omics technology to identify key molecules and pathways in different diagnostic entities of periodontal disease.A major issue when inferring biological information from high-throughput -omics studies is the fact that the sheer volume of high-dimensional data generated by contemporary technology is not appropriately analyzed using common statistical methods employed in the biomedical sciences. Furthermore, machine learning methods facilitate the detection of additional patterns, beyond the mere identification of lists of features that differ between groups.Herein, we outline a robust and well-accepted bioinformatics workflow for the initial analysis of -omics data using open-source tools. We outline a differential expression analysis pipeline that can be used for data from both arrays and sequencing experiments, and offers the possibility to account for random or fixed effects. Furthermore, we present an overview of the possibilities for a functional analysis of the obtained data including subsequent machine learning approaches in form of (i) supervised classification algorithms in class validation and (ii) unsupervised clustering in class discovery.

Periodontal Status, C-Reactive Protein, NT-proBNP, and Incident Heart Failure: The ARIC Study.

BACKGROUND: Periodontal disease (PD), resulting from inflammatory host response to dysbiotic subgingival microbiota, has been linked to cardiovascular disease; however, its relationship to heart failure (HF) and its subtypes (heart failure with reduced ejection fraction [HFrEF] and heart failure with preserved ejection fraction [HFpEF]) is unexplored. OBJECTIVES: The authors hypothesize that the presence of PD is associated with increased risk of incident HF, HFpEF, and HFrEF. METHODS: A total of 6,707 participants (mean age 63 ± 6 years) of the ARIC (Atherosclerosis Risk In Communities) study with full-mouth periodontal examination at visit 4 (1996-1998) and longitudinal follow-up for any incident HF (visit 4 to 2018), or incident HFpEF and HFrEF (2005-2018) were included. Periodontal status was classified as follows: healthy, PD (as per Periodontal Profile Classification [PPC]), or edentulous. Multivariable-adjusted Cox proportional hazards models were used to calculate HRs and 95% CIs for the association between PPC levels and incident HF, HFpEF, or HFrEF. Additionally, biomarkers of inflammation (C-reactive protein [CRP]) and congestion (N-terminal brain natriuretic peptide [NT-proBNP]) were assessed. RESULTS: In total, 1,178 incident HF cases occurred (350 HFpEF, 319 HFrEF, and 509 HF of unknown type) over a median of 13 years. Of these cases, 59% had PD, whereas 18% were edentulous. PD was associated with an increased risk for HFpEF (HR: 1.35 [95% CI: 0.98-1.86]) and significantly increased risk for HFrEF (HR: 1.69 [95% CI: 1.18-2.43]), as was edentulism: HFpEF (HR: 2.00 [95% CI: 1.37-2.93]), HFrEF (HR: 2.19 [95% CI: 1.43-3.36]). Edentulism was associated with unfavorable change in CRP and NT-proBNP, whereas PD was associated only with CRP. CONCLUSIONS: Periodontal status was associated with incident HF, HFpEF, and HFrEF, as well as unfavorable changes in CRP and NT-proBNP.

Treatment of stage IV periodontitis: The EFP S3 level clinical practice guideline.

BACKGROUND: The recently published clinical practice guideline (CPG) for the treatment of periodontitis in stages I-III provided evidence-based recommendations for the treatment of periodontitis patients, defined according to the 2018 classification. Stage IV periodontitis shares the severity and complexity characteristics of stage III periodontitis, but includes the anatomical and functional sequelae of tooth and periodontal attachment loss (tooth flaring and drifting, bite collapse, etc.), which require additional interventions following completion of active periodontal therapy. AIM: To develop an S3 Level CPG for the treatment of stage IV periodontitis, focusing on the implementation of inter-disciplinary treatment approaches required to treat/rehabilitate patients following associated sequelae and tooth loss. MATERIALS AND METHODS: This S3 Level CPG was developed by the European Federation of Periodontology (EFP), following methodological guidance from the Association of Scientific Medical Societies in Germany and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) process. A rigorous and transparent process included synthesis of relevant research in 13 specifically commissioned systematic reviews, evaluation of the quality and strength of evidence, the formulation of specific recommendations and a structured consensus process with leading experts and a broad base of stakeholders. RESULTS: The S3 Level CPG for the treatment of stage IV periodontitis culminated in recommendations for different interventions, including orthodontic tooth movement, tooth splinting, occlusal adjustment, tooth- or implant-supported fixed or removable dental prostheses and supportive periodontal care. Prior to treatment planning, it is critically important to undertake a definitive and comprehensive diagnosis and case evaluation, obtain relevant patient information, and engage in frequent re-evaluations during and after treatment. The periodontal component of therapy should follow the CPG for the treatment of periodontitis in stages I-III. CONCLUSIONS: The present S3 Level CPG informs clinical practice, health systems, policymakers and, indirectly, the public on the available and most effective modalities to treat patients with stage IV periodontitis and to maintain a healthy dentition over lifetime, according to the available evidence at the time of publication.

Nitrite Generating and Depleting Capacity of the Oral Microbiome and Cardiometabolic Risk: Results from ORIGINS.

Background The enterosalivary nitrate-nitrite-nitric oxide (NO3-NO2-NO) pathway generates NO following oral microbiota-mediated production of salivary nitrite, potentially linking the oral microbiota to reduced cardiometabolic risk. Nitrite depletion by oral bacteria may also be important for determining the net nitrite available systemically. We examine if higher abundance of oral microbial genes favoring increased oral nitrite generation and decreased nitrite depletion is associated with a better cardiometabolic profile cross-sectionally. Methods and Results This study includes 764 adults (mean [SD] age 32 [9] years, 71% women) enrolled in ORIGINS (Oral Infections, Glucose Intolerance, and Insulin Resistance Study). Microbial DNA from subgingival dental plaques underwent 16S rRNA gene sequencing; PICRUSt2 was used to estimate functional gene profiles. To represent the different components and pathways of nitrogen metabolism in bacteria, predicted gene abundances were operationalized to create summary scores by (1) bacterial nitrogen metabolic pathway or (2) biochemical product (NO2, NO, or ammonia [NH3]) formed by the action of the bacterial reductases encoded. Finally, nitrite generation-to-depletion ratios of gene abundances were created from the above summary scores. A composite cardiometabolic Z score was created from cardiometabolic risk variables, with higher scores associated with worse cardiometabolic health. We performed multivariable linear regression analysis with cardiometabolic Z score as the outcome and the gene abundance summary scores and ratios as predictor variables, adjusting for sex, age, race, and ethnicity in the simple adjusted model. A 1 SD higher NO versus NH3 summary ratio was inversely associated with a -0.10 (false discovery rate q=0.003) lower composite cardiometabolic Z score in simple adjusted models. Higher NH3 summary score (suggestive of nitrite depletion) was associated with higher cardiometabolic risk, with a 0.06 (false discovery rate q=0.04) higher composite cardiometabolic Z score. Conclusions Increased net capacity for nitrite generation versus depletion by oral bacteria, assessed through a metagenome estimation approach, is associated with lower levels of cardiometabolic risk.

Early microbial markers of periodontal and cardiometabolic diseases in ORIGINS.

Periodontitis affects up to 50% of individuals worldwide, and 8.5% are diagnosed with diabetes. The high-comorbidity rate of these diseases may suggest, at least in part, a shared etiology and pathophysiology. Changes in oral microbial communities have been documented in the context of severe periodontitis and diabetes, both independently and together. However, much less is known about the early oral microbial markers of these diseases. We used a subset of the ORIGINS project dataset, which collected detailed periodontal and cardiometabolic information from 787 healthy individuals, to identify early microbial markers of periodontitis and its association with markers of cardiometabolic health. Using state-of-the-art compositional data analysis tools, we identified the log-ratio of Treponema to Corynebacterium bacteria to be a novel Microbial Indicator of Periodontitis (MIP), and found that this MIP correlates with poor periodontal health and cardiometabolic markers early in disease pathogenesis in both subgingival plaque and saliva.