AIM:This cross-sectional study aimed to compare the endodontic microbiome assessed from root canals of teeth associated with either symptomatic or asymptomatic apical periodontitis and analysed by 16S rDNA gene sequencing. METHODOLOGY:60 teeth presenting clinical and radiographic signs of symptomatic or asymptomatic apical periodontitis (n = 30) were included in this cross-sectional study after participants had given their written informed consent. After isolation with rubber dam, disinfection and access cavity preparation, glide paths were prepared using C-Pilot Files and K-Files under electronic root canal length control. Microbial samples were collected from a total of 120 root canals (symptomatic apical periodontitis, SAP: n = 62, asymptomatic apical periodontitis, AAP: n = 58) each with a sterile file (size 20/0.06) in a single length technique. Only one specimen per tooth was included in the analysis; in multi-rooted teeth, the specimen with highest sequencing depth. After DNA extraction, the hypervariable region V4 of the bacterial 16 S rRNA gene was amplified and sequenced (Illumina MiSeq). Taxonomy was assigned based on the expanded Human Oral Microbiome Database (eHOMD). Statistical analysis of diversity parameters comprised Mann-Whitney U tests and PERMANOVA. Compositional differences were evaluated by differential abundance analyses using DESeq2, LinDA, and ANCOM-BC2 methods. RESULTS:No differences were observed in richness and diversity (Shannon diversity index) on the genus or ASV level (p > 0.05). According to PERMANOVA, SAP and AAP microbiomes did not differ significantly both on genus and ASV levels (p > 0.05). Among highly abundant genera, Fusobacterium was indicated to be more abundant in SAP samples whereas Actinomyces was more abundant in AAP samples. CONCLUSIONS:The expression of clinical symptoms in apical periodontitis does not appear to be determined by specific microorganisms but may instead reflect shifts of the relative abundance of the microbial community.

OBJECTIVES:This study assessed whether periodontitis stage and grade are associated with long-term implant survival in periodontally compromised patients. METHODS:A retrospective analysis was conducted among 362 periodontitis patients who received 1106 implants at the University Clinic Münster, Germany, with a median follow-up of 85.5 months (range: 3.6-236.4). Periodontitis stage and grade were assessed based on clinical and radiographic data at the first clinical visit. Kaplan-Meier curves and Cox regression models were used to analyze implant survival. RESULTS:A total of 85 implants (7.69%) failed, with nearly half of these losses occurring within the first six months (failed osseointegration). Cumulative survival rates were 95.8% at 60 months, 91.1% at 120 months, and 82.6% at 180 months. Grading, but not staging, was significantly associated with implant loss. Patients classified as grade C had a higher risk of implant loss at any given time during follow-up than patients with grade A or B (hazard ratio = 2.78; 95% confidence interval: 1.18-6.54). CONCLUSIONS:Our findings demonstrate that periodontitis, particularly in terms of grading as defined by the current classification, is a significant risk factor for implant loss, even in patients undergoing periodontal therapy. Both clinicians and patients should consider these risk factors during treatment planning, as they can substantially impact implant survival. Nevertheless, dental implants remain a reliable and predictable therapeutic option, even for patients with severe periodontitis.

BACKGROUND AND OBJECTIVE:Periodontitis is a chronic inflammatory disease driven by immune dysfunction and microbial imbalance. This study aims to identify circulating druggable proteins causally linked to the disease. MATERIALS AND METHODS:We integrated proteomics data from deCODE genetics with periodontitis genome-wide association studies (GWAS) from the Million Veteran Program to identify proteins associated with periodontitis. Findings were replicated using GWAS data from the Gene-Lifestyle Interactions in Dental Endpoints consortium. Causal associations were validated using genetic and statistical methods, and the identified proteins were assessed for biological relevance and druggability. RESULTS:Among the 2088 evaluated proteins, three showed robust evidence of causal association with periodontitis: FGF2 (fibroblast growth factor 2) (odds ratio [OR]: 1.06, 95% confidence interval [CI] 1.032-1.082), AZGP1 (zinc-alpha-2-glycoprotein) (OR: 1.12, 95% CI 1.058-1.189) and BTC (betacellulin) (OR: 0.86, 95% CI 0.789-0.942). Replication analysis confirmed associations for 18 proteins, with 16 showing high colocalisation. Further evaluation of drug target databases revealed indirect links between the identified proteins and approved therapies for inflammatory conditions, suggesting potential therapeutic relevance. CONCLUSION:This study identifies three circulating proteins-FGF2, AZGP1 and BTC-as causally associated with periodontitis, highlighting their potential as therapeutic targets. These results provide a foundation for future research into targeted therapies for periodontitis.

Introduction: The aim was to evaluate the suitability of paper points or endodontic nickel- titanium files to sample microorganisms for in vivo investigation of endodontic microbiota by 16S ribosomal DNA (rDNA) sequencing. Methods: Forty-five patients presenting clinical and radiological signs of apical periodontitis were recruited for sampling, giving their written informed consent. Glide paths were assessed using C-Pilot Files and K-Files under electronic root canal length control under aseptic conditions. Microbial samples were taken from 84 root canals in duplicate, the first sample with a sterile paper point (size 15), the second with a sterile file (size 20/.06). After DNA extraction, the hypervariable region V4 of the bacterial 16S rRNA gene was amplified and sequenced (Illumina MiSeq). Sequencing data were trimmed with Cutadapt and exact amplicon sequence variants generated by DADA2. Taxonomy was assigned based on the Human Oral Microbiome Database (eHOMD). Statistical analysis of diversity parameters comprised Wilcoxon signed-rank tests and permutational analysis of variance (PERMANOVA). Compositional differences were evaluated by differential abundance analysis (DESeq2). Microbial contamination during the sampling process and analysis were evaluated. Results: Concerning alpha diversity, richness and dissimilarity differed nonsignificantly between paper point and instrument samples (P> .05), whereas a significant difference was observed in the Shannon index (P < .05). Regarding beta diversity, paper point and instrument samples presented with similar microbial community compositions (P 5 1.0, PERMANOVA). Paper point controls contained significantly higher proportions of Pseudomonadales (P < .05). Conclusions: Paper point and endodontic instrument sampling generate valid specimens for 16S rDNA community profiling. Endodontic instrument sampling is easier to execute and, therefore, could be the technique of choice. (J Endod 2025;51:164-171.)

AIM:To investigate whether exhaled carbon monoxide (CO) is dose-dependently associated with subgingival polymicrobial clusters before and after non-surgical periodontal therapy. MATERIAL AND METHODS:We followed 163 adults with periodontitis, measuring CO before and at 2, 14 and 26 months after therapy. Subgingival plaque samples were analysed using 16S rRNA gene sequencing. We applied topic models and regression analysis, adjusted for age, sex, treatment group, pocket probing depth and plaque levels. RESULTS:Smokers had generally higher mean CO levels at every visit and showed significant declines at 14 and 26 months after therapy (p < 0.01). Before therapy, CO was not associated with dysbiosis; after therapy, higher levels were positively associated. In sensitivity analyses, self-reported smoking status explained more variance in dysbiosis than CO alone, with only marginal gains when both were combined. Among smokers, a distinct polymicrobial cluster dominated by Fusobacterium and Prevotella increased with higher exhaled CO. Every 10 parts per million increase in CO was associated with an estimated 16% increase in cluster abundance (95% confidence interval: 8%-26%). CONCLUSION:Exhaled CO may help monitor persistent dysbiosis and select an anaerobe-dominated subgingival community after periodontal therapy among smokers.

Background:This study examines the relationship between supragingival plaque control and subgingival microbiota during periodontal therapy, focusing on microbial clusters associated with plaque levels. Methods:Data were drawn from a 26-month multicenter, double-blinded, randomized, placebo-controlled trial. Supragingival plaque was measured using the O'Leary index, and subgingival microbiota were profiled via Illumina 16S rRNA gene sequencing. A novel topic modelling approach using cross-validated Latent Dirichlet Allocation (LDA) identified microbial clusters, and negative binomial mixed models evaluated their association with plaque levels. Results:Supragingival plaque was positively associated with bleeding on probing (BOP) and microbial diversity, but not with dysbiosis. A specific subgingival microbial cluster dominated by Selenomonas and Leptotrichia was linked to elevated plaque levels and increased in abundance following both antibiotic and placebo treatments. The odds ratio for plaque associated with this cluster was 1.20 (95% CI: 1.07-1.35). Stratified analyses showed this association was reduced in the antibiotic group but remained in the placebo group. Conclusion:Ineffective supragingival plaque control correlates with increased BOP and microbial diversity, though not necessarily with dysbiosis. Adjunctive antibiotics may promote a more cariogenic subgingival microbiota by disrupting the association between plaque accumulation and the abundance of acidogenic taxa such as Selenomonas and Leptotrichia.

AimAn excessively activated or dysregulated complement system has been proven to be a vital contributor to the pathogenesis of periodontitis. It has been previously hypothesized that inhibiting the activity of complement component C5 by targeting the C5a receptor is a powerful candidate for treating periodontitis. Here, we apply the drug target instrumental variable (IV) approach to investigate the therapeutic effect of genetically proxied inhibition of C5 on periodontitis.MethodIn our primary analysis, we used 26 independent ‘cis’ single nucleotide polymorphisms as IVs from the vicinity of the encoding locus of C5 that are associated with plasma C5 levels. In a secondary analysis, we assess the validity of our primary findings, exploring the involvement of alternative downstream biomarkers, interleukin 17 (IL-17), interleukin 1β (IL-1β), and tumor necrosis factor (TNF). Summary statistics of plasma levels (C5, IL-17, IL-1β, and TNF) were obtained from a genome-wide association study (GWAS) of 35,559 European descent individuals. We extracted association statistics from a GWAS of 17,353 clinical periodontitis cases and 28,210 European controls. Wald ratios were combined using inverse-variance weighted meta-analysis.ResultsIn our primary approach, inhibiting C5 reduced the risk of periodontitis (Odds ratio 0.89 per 1 standard deviation reduction in C5; 95% confidence Interval 0.80–0.98, p value=0.022). Our secondary analysis suggests an involvement of IL-17 within the potential causal pathway, but was inconclusive for other biomarkers.ConclusionsThe findings from our study suggest that C5 inhibition may reduce the risk of periodontitis, prioritizing C5 inhibitors as a potential adjunctive therapeutic intervention in this disease.

Periodontitis, a prevalent chronic inflammatory disease, offers insights into the broader landscape of chronic inflammatory conditions. The progression and treatment outcomes of periodontitis are closely related to the oral microbiota’s composition. Adjunctive systemic Amoxicillin 500 mg and Metronidazole 400 mg, often prescribed thrice daily for 7 days to enhance periodontal therapy’s efficacy, have lasting effects on the oral microbiome. However, the precise mechanism through which the oral microbiome influences clinical outcomes in periodontitis patients remains debated. This investigation explores the pivotal role of the oral microbiome's composition in mediating the outcomes of adjunctive systemic antibiotic treatment. Subgingival plaque samples from 10 periodontally healthy and 163 periodontitis patients from a randomized clinical trial on periodontal therapy were analyzed. Patients received either adjunctive amoxicillin/metronidazole or a placebo after mechanical periodontal treatment. Microbial samples were collected at various intervals up to 26 months post-therapy. Using topic models, we identified microbial communities associated with normobiotic and dysbiotic states, validated with 86 external and 40 internal samples. Logistic regression models evaluated the association between these microbial communities and clinical periodontitis parameters. A Directed Acyclic Graph (DAG) determined the mediating role of oral microbiota in the causal path of antibiotic treatment effects on clinical outcomes. We identified clear distinctions between dysbiotic and normobiotic microbial communities, differentiating healthy from periodontitis subjects. Dysbiotic states consistently associated with below median

PURPOSE:To help fill the knowledge gaps regarding the long-term effectiveness of peri-implantitis therapy, this retrospective study of soldiers with treated severe periodontitis (stage III gen. / IV) who had been undergoing adherent SPT for at least 20 years aimed to determine the frequency of peri-implantitis and patient-related risk factors for this, as well as the 10-year survival rates of dental implants under peri-implantitis therapy. MATERIALS AND METHODS:The observation period was between 1993 and 2023. All patients were referred by their military dentists for specialist dental training and underwent systematic periodontal therapy. A multi-stage peri-implantitis treatment concept was used. RESULTS:In 86 (31%) of 276 patients (total treatment time 23.6 ± 2.8 years, 53.1 ± 20.4 SPT sessions), 296 implant restorations were performed to close gaps or lengthen rows of teeth. In 29 (33%) of the implant patients, peri-implantitis developed on 25% of the implants. As a result, 11% of all implants were lost within 10 years due to peri-implantitis. Peri-implantitis led to implant loss in 59% of affected patients and 45% of implants. The survival time of implants lost later was 8.4 ± 6.2 years. Peri-implantitis and implant loss rates increased statistically significantly in stage IV periodontitis as well as in heavy smokers. Patients with implant loss and peri-implantitis had received systemic antibiotics due to periodontitis recurrence statistically significantly more frequently than patients without peri-implantitis and without implants during the ≥ 20-year SPT (p 0.05). CONCLUSIONS:Based on the present results, the early extraction of teeth during SPT in patients with treated generalised periodontitis stage III and stage IV plus replacement with implants is not advantageous.

Aims: To explore the influence of gender on periodontal treatment outcomes in a dataset of eight RCTs conducted in Brazil, United States, and Germany. Methods: Clinical parameters were compared between men and women with stages III/IV grades B/C generalized periodontitis at baseline and 1-year post-therapy, including scaling and root planing with or without antibiotics. Results: Data from 1042 patients were analyzed. Men presented a tendency towards higher probing depth (p = .07, effect size = 0.11) and clinical attachment level (CAL) than women at baseline (p = .01, effect size = 0.16). Males also presented statistically significantly lower CAL gain at sites with CAL of 4-6 mm at 1-year post-therapy (p = .001, effect size = 0.20). Among patients with Grade B periodontitis who took antibiotics, a higher frequency of women achieved the endpoint for treatment (i.e., <= 4 sites PD >= 5 mm) at 1 year than men (p < .05, effect size = 0.12). Conclusion: Men enrolled in RCTs showed a slightly inferior clinical response to periodontal therapy in a limited number of sub-analyses when compared to women. These small differences did not appear to be clinically relevant. Although gender did not dictate the clinical response to periodontal treatment in this population, our findings suggest that future research should continue to explore this topic.

AIM:Assessment of treatment response after systemic amoxicillin/metronidazole adjunctive to subgingival instrumentation (SI) according to stages and grades of the 2018 classification of periodontal diseases.MATERIALS AND METHODS:We carried out exploratory re-analysis of the placebo-controlled, multi-centre ABPARO trial (52; 45/60 years of age; 205 males, 114 active smokers). Patients were randomized to SI with systemic amoxicillin 500 mg/metronidazole 400 mg (three times a day for 7 days, n = 205; ANTI) or placebo (n = 200; PLAC) and maintenance therapy every 3 months. Patients were reclassified according to the 2018 classification (stage/extent/grade). Treatment effect was the percentage of sites per patient with new attachment loss ≥1.3 mm (PSAL ≥ 1.3 mm) at 27.5 months post-baseline/randomization.RESULTS:All patients were assigned according to the stage (n = 49 localized stage III, n = 206 generalized stage III, n = 150 stage IV). Because of missing radiographs, only 222 patients were assigned to grades (n = 73 B, n = 149 C). Treatment (PLAC/ANTI) resulted in PSAL ≥ 1.3 mm (median; lower/upper quartile) in localized stage III (PLAC: 5.7; 3.3/8.4% vs. ANTI: 4.9; 3.0/8.3%; p = .749), generalized stage III (8.0; 4.5/14.3% vs. 4.7; 2.4/9.0%; p < .001), stage IV (8.5; 5.1/14.4% vs. 5.7; 3.3/10.6%; p = .008), grade B (4.4; 2.4/6.7% vs. 3.6; 1.9/4.7%; p = .151) and grade C (9.4; 5.3/14.3% vs. 4.8; 2.5/9.4%; p < .001).CONCLUSIONS:In generalized periodontitis stage III/grade C, a clinically relevant lower percentage of disease progression after adjunctive systemic amoxicillin/metronidazole was observed compared to placebo (PLAC: 9.7; 5.8/14.3% vs. ANTI: 4.7; 2.4/9.0%; p < .001).

Observational studies suggested an inverse association between physical activity and periodontitis. However, observational studies might be subject to unobserved confounding and reverse causation bias. We conducted an instrumental variable study to strengthen the evidence on the relationship between physical activity and periodontitis. We used genetic variants associated with self-reported and accelerometer-assessed physical activity in 377,234 and 91,084 UK Biobank participants, respectively, as instruments. For these instruments, genetic associations with periodontitis were obtained from 17,353 cases and 28,210 controls in the GeneLifestyle Interactions in Dental Endpoints consortium. We found no evidence for effects of self-reported moderate-to-vigorous physical activity, self-reported vigorous physical activity, accelerometry “average accelerations,” and “fraction of accelerations > 425 milli-gravities” on periodontitis. For example, the odds ratio for self-reported moderate-to-vigorous physical activity was 1.07 (95

Aim Evidence from a phase IIa trial showed that a complement C3-targeted drug reduced gingival inflammation in patients with gingivitis. We investigated the therapeutic effect of genetically proxied C3 inhibition on periodontitis using drug target Mendelian randomization (MR). Materials and methods We used multiple ‘cis’ instruments from the vicinity of the encoding loci of C3 that are associated with serum C3. We selected three independent single nucleotide polymorphisms (rs141552034, rs145406915, rs11569479) from a genome-wide association study (GWAS) of 5,368 European descent individuals. We extracted association statistics from a GWAS of 17,353 clinical periodontitis cases and 28,210 European controls. Wald ratios were combined using inverse-variance weighted meta-analysis. Results MR analysis revealed that the inhibition of C3 reduces the risk of periodontitis (Odds ratio 0.91 per 1 standard deviation reduction in C3; 95% Confidence Interval 0.87–0.96, P-value=0.0003). Conclusions Findings from MR analysis showed that C3 blockade protects against periodontitis. Scientific rationale for study Mounting evidence suggests that the complement system is dysregulated in periodontitis. First human randomized clinical trials demonstrated promising effects mediated via the blockade of C3, a key factor of the complement system. Results from drug target MR analysis can provide compelling evidence to predict the efficacy of pharmacological C3 blockage in future clinical trials in periodontitis patients. Principle findings Genetically proxied C3 inhibition reduced periodontitis risk. Practical implications Our MR analysis provides genetic evidence that C3-targeted drugs might be an efficient adjunct therapy in periodontitis. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Summary genetic data for complement C3 protein are deposited at the GWAS Catalog with accession ID: GCST90088016. The periodontitis summary data are available at

BackgroundThe purpose of the study was to examine the association between total body bone mineral density (BMD) and periodontitis using Mendelian randomization (MR) analysis. Methods and materialsWe used 81 single nucleotide polymorphisms (SNPs) associated with BMD at a p-value of < 5 x 10(-8) from a genome-wide association study (GWAS) of 66,628 individuals of European descent. The GWAS for periodontitis was derived from a meta-analysis of seven cohort studies that included 17,353 cases and 28,210 controls of European ancestry. ResultsMR showed no association between BMD and periodontitis (odds ratio per standard deviation increment in genetically predicted BMD = 1.00; 95% confidence interval: 0.92-1.08). Leave-one-out analyses and pleiotropy-robust methods did not indicate any bias. ConclusionsThe MR study provided no evidence that BMD might be causally linked to periodontitis. Hence it may be concluded as the key finding that BMD depletion does not increase the risk of periodontitis.

AimInterleukin 6 (IL-6) is considered to play a role in the dysbiotic host response in the development of periodontitis. While the inhibition of the IL-6 receptor using monoclonal antibodies is a well-established therapy for some diseases, so far, its potential benefit in patients with periodontitis has not been examined. We tested the association of genetically proxied downregulation of IL-6 signaling with periodontitis to explore whether downregulation of IL-6 signaling could represent a viable treatment target for periodontitis, Materials and methodsAs proxies for IL-6 signaling downregulation, we selected 52 genetic variants in close vicinity of the gene encoding IL-6 receptor that were associated with lower circulating C-reactive protein (CRP) levels in a genome-wide association study (GWAS) of 575 531 participants of European ancestry from the UK Biobank and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Associations with periodontitis were tested with inverse-variance weighted Mendelian randomization in a study of 17 353 cases and 28 210 controls of European descent in the Gene-Lifestyle Interactions in Dental Endpoints (GLIDE) consortium. In addition, the effect of CRP reduction independent of the IL-6 pathway was assessed. ResultsGenetically proxied downregulation of IL-6 signaling was associated with lower odds of periodontitis (odds ratio (OR) = 0.81 per 1-unit decrement in log-CRP levels; 95% confidence interval (CI): [0.66;0.99]; P = 0.0497). Genetically proxied reduction of CRP independent of the IL-6 pathway had a similar effect (OR = 0.81; 95% CI: [0.68; 0.98]; P = 0.0296). ConclusionIn conclusion, genetically proxied downregulation of IL-6 signaling was associated with lower odds of periodontitis and CRP might be a causal target for the effect of IL-6 on the risk of periodontitis.

AimTo investigate the effect of genetically proxied inhibition of tumor necrosis factor receptor 1 (TNFR1) on the risk of periodontitis.Materials and methodsGenetic instruments were selected from the vicinity of TNFR superfamily member 1A (TNFRSF1A) gene (chromosome 12; base pairs 6,437,923–6,451,280 as per GRCh37 assembly) based on their association with C-reactive protein (N= 575,531). Summary statistics of these variants were obtained from a genome-wide association study (GWAS) of 17,353 periodontitis cases and 28,210 controls to estimate the effect of TNFR1 inhibition on periodontitis using a fixed-effects inverse method.ResultsConsidering rs1800693 as an instrument, we found no effect of TNFR1 inhibition on periodontitis risk (Odds ratio (OR) scaled per standard deviation increment in CRP: 1.57, 95% confidence interval (CI): 0.38;6.46). Similar results were derived from a secondary analysis that used three variants (rs767455, rs4149570, and rs4149577) to index TNFR1 inhibition.ConclusionsWe found no evidence of a potential efficacy of TNFR1 inhibition on periodontitis risk.

Objectives Periodontitis (PD) can cause systematic inflammation and is associated with various metabolic processes in the body. However, robust serum markers for these relationships are still lacking. This study aims to identify novel circulating inflammation-related proteins associated with PD using targeted proteomics. Materials and methods We used population-based, cross-sectional data from 619 participants of the Polish Longitudinal University Study (Bialystok PLUS). Mean pocket probing depth (mPPD) and proportion of bleeding on probing (pBOP) served as exposure variables. Fifty-two inflammation-related proteins were measured using the Olink Target 96 Cardiovascular III and the Olink Target 96 Immune Response panels. Associations between periodontal measures and proteins were tested using covariate-adjusted linear regression models. Results At a false discovery rate of < 0.05, we identified associations of mPPD and pBOP with platelet-endothelial cell adhesion molecule-1 (PECAM-1) and tripartite motif–containing protein 21 (TRIM21). Conclusion This study revealed novel associations between PD and serum levels of PECAM-1 and TRIM21. Our results suggest that these proteins might be affected by molecular processes that take place in the inflamed periodontium. Clinical relevance Novel associations of PECAM-1 and TRIM21 with PD indicate promising serum markers for understanding the disease’s pathophysiological processes and call for further biomedical investigations.

AIM:To explore whether adjunctive antibiotics can relevantly influence long-term microbiota changes in stage III-IV periodontitis patients.MATERIALS AND METHODS:This is a secondary analysis of a randomized clinical trial on periodontal therapy with adjunctive 500 mg amoxicillin and 400 mg metronidazole or placebo thrice daily for 7 days. Subgingival plaque samples were taken before and 2, 8, 14 and 26 months after mechanical therapy. The V4-hypervariable region of the 16S rRNA gene was sequenced with Illumina MiSeq 250 base pair paired-end reads. Changes at the ribosomal sequence variant (RSV) level, diversity and subgingival-microbial dysbiosis index (SMDI) were explored with a negative binomial regression model and non-parametric tests.RESULTS:Overall, 50.2% of all raw reads summed up to 72 RSVs (3.0%) that were generated from 163 stage III-IV periodontitis patients. Of those, 16 RSVs, including Porphyromonas gingivalis, Tannerella forsythia and Aggregatibacter actinomycetemcomitans, changed significantly over 26 months because of adjunctive systemic antibiotics. SMDI decreased significantly more in the antibiotic group at all timepoints, whereas the 2-month differences in alpha and beta diversity between groups were not significant at 8 and 14 months, respectively.CONCLUSIONS:Mechanical periodontal therapy with adjunctive antibiotics induced a relevant and long-term sustainable change towards an oral microbiome more associated with oral health.

BACKGROUND:Circulating levels of interleukin-17 (IL-17) are associated with the presence and severity of periodontitis. However, whether IL-17 is causal for disease development is unknown. We investigated the effect of genetically proxied IL-17 on periodontitis using instrumental variable analysis. METHODS:We identified 12 genetic variants from genome-wide association study (GWAS) of 7760 European descent individuals, used these variants as instrumental variables for IL-17, and linked them to a GWAS of 17,353 clinical periodontitis cases and 28,210 European controls. Generalized weighted least squares analysis accounted for linkage disequilibrium of variants. RESULTS:We found an inverse association of genetically proxied IL-17 and periodontitis (odds ratio, 0.84; 95% confidence interval: 0.75-0.94; p = 0.003), which was corroborated after sensitivity analysis for horizontal pleiotropy. CONCLUSION:The findings suggest that IL-17 protects against initial periodontitis.

AIM:Evidence from a Phase IIa trial showed that a complement C3-targeted drug reduced gingival inflammation in patients with gingivitis. Using drug-target Mendelian randomization (MR), we investigated whether genetically proxied C3 inhibition alters the risk of periodontitis.MATERIALS AND METHODS:We used multiple 'cis' instruments from the vicinity of the encoding loci of C3. Instrument selection was restricted to the drug target encoding loci (chromosome 19; 6,677,715-6,730,573 (GRCh37/hg19)). We selected three uncorrelated single-nucleotide polymorphisms (rs141552034, rs145406915, rs11569479) that were associated with serum C3 levels (p value <1 × 10-4 ) from a genome-wide association study (GWAS) of 5368 European descent individuals. We extracted association statistics from a GWAS of 17,353 clinical periodontitis cases and 28,210 European controls. Wald ratios were combined using inverse-variance weighted meta-analysis to estimate the odds ratio (OR) of the genetically proxied inhibition of C3 in relation to periodontitis.RESULTS:MR analysis revealed that the inhibition of C3 reduces the odds of periodontitis (OR 0.91 per 1 standard deviation reduction in C3; 95% confidence interval 0.87-0.96, p value = .0003).CONCLUSIONS:Findings from our MR analysis suggest a potential protective effect of C3 blockade against periodontitis.