Fusobacterium nucleatum subsp. nucleatum RadD binds Siglec-7 and inhibits NK cell-mediated cancer cell killing.

Fusobacterium nucleatum is an oral commensal bacterium that can colonize extraoral tumor entities, such as colorectal cancer and breast cancer. Recent studies revealed its ability to modulate the immune response in the tumor microenvironment (TME), promoting cancer progression and metastasis. Importantly, F. nucleatum subsp. animalis was shown to bind to Siglec-7 via lipopolysaccharides, leading to a pro-inflammatory profile in human monocyte-derived dendritic cells. In this study, we show that F. nucleatum subsp. nucleatum RadD binds to Siglec-7 on NK cells, thereby inhibiting NK cell-mediated cancer cell killing. We demonstrate that this binding is dependent on arginine residue R124 in Siglec-7. Finally, we determine that this binding is independent of the known interaction of RadD with IgA. Taken together, our findings elucidate the targeting of Siglec-7 by F. nucleatum subsp. nucleatum RadD as a means to modulate the NK cell response and potentially promoting immune evasion and tumor progression.

Antagonistic interaction between two key endodontic pathogens Enterococcus faecalis and Fusobacterium nucleatum.

Background: Endodontic infections are known to be caused by pathogenic bacteria. Numerous previous studies found that both Fusobacterium nucleatum and Enterococcus faecalis are associated with endodontic infections, with Fusobacterium nucleatum more abundant in primary infection while Enterococcus faecalis more abundant in secondary infection. Little is known about the potential interactions between different endodontic pathogens. Objective: This study aims to investigate the potential interaction between F. nucleatum and E. faecalis via phenotypical and genetic approaches. Methods: Physical and physiological interactions of F. nucleatum and E. faecalis under both planktonic and biofilm conditions were measured with co-aggregation and competition assays. The mechanisms behind these interactions were revealed with genetic screening and biochemical measurements. Results: E. faecalis was found to physically bind to F. nucleatum under both in vitro planktonic and biofilm conditions, and this interaction requires F. nucleatum fap2, a galactose-inhibitable adhesin-encoding gene. Under our experimental conditions, E. faecalis exhibits a strong killing ability against F. nucleatum by generating an acidic micro-environment and producing hydrogen peroxide (H2O2). Finally, the binding and killing capacities of E. faecalis were found to be necessary to invade and dominate a pre-established in vitro F. nucleatum biofilm. Conclusions: This study reveals multifaceted mechanisms underlying the physical binding and antagonistic interaction between F. nucleatum and E. faecalis, which could play a potential role in the shift of microbial composition in primary and secondary endodontic infections.

Correlation between Streptococcus mutans levels in dental plaque and saliva of children.

PURPOSE: This study was designed to compare the levels of Streptococcus mutans (S. mutans) in saliva with those in occlusal plaque on posterior teeth at different stages of dentition, and to explore the correlation with caries experience to determine the most suitable source of S. mutans for research. METHODS: Samples of saliva and occlusal plaque were collected from 83 patients (aged 3-17 years) over three months. S. mutans levels were determined by culture-based selective plating, morphological identification, and S.mutans-specific monoclonal antibody labeling. RESULTS: The mean age of the participants was 8.8 (±3.7) years, and 74.7% of them were Hispanic. Mean caries experience for children with primary, mixed, and permanent dentition was 5.2 (±4.7), 4.0 (±3.3), and 0.8 (±1.3), respectively. Children with primary and mixed dentition had a higher caries experience than children with permanent dentition (P < 0.01), despite having similar S. mutans levels and total bacteria. A positive correlation was observed between S. mutans levels in plaque and those in saliva, but not between S. mutans levels and caries experience. It was noteworthy that plaque samples harbored higher S. mutans levels (>105 CFU/mL) than saliva samples. CONCLUSION: Both plaque and saliva samples are useful sources for S. mutans isolation. S. mutans levels from both sources were not significantly correlated with caries experience, but occlusal plaque had greater sensitivity for quantification of high S. mutans levels.

Oral microbial extracellular DNA initiates periodontitis through gingival degradation by fibroblast-derived cathepsin K in mice.

Periodontitis is a highly prevalent disease leading to uncontrolled osteoclastic jawbone resorption and ultimately edentulism; however, the disease onset mechanism has not been fully elucidated. Here we propose a mechanism for initial pathology based on results obtained using a recently developed Osteoadsorptive Fluogenic Sentinel (OFS) probe that emits a fluorescent signal triggered by cathepsin K (Ctsk) activity. In a ligature-induced mouse model of periodontitis, a strong OFS signal is observed before the establishment of chronic inflammation and bone resorption. Single cell RNA sequencing shows gingival fibroblasts to be the primary cellular source of early Ctsk. The in vivo OFS signal is activated when Toll-Like Receptor 9 (TLR9) ligand or oral biofilm extracellular DNA (eDNA) is topically applied to the mouse palatal gingiva. This previously unrecognized interaction between oral microbial eDNA and Ctsk of gingival fibroblasts provides a pathological mechanism for disease initiation and a strategic basis for early diagnosis and treatment of periodontitis.

Effect of Calcium Ion Supplementation on Oral Microbial Composition and Biofilm Formation In Vitro.

The oral cavity contains a variety of ecological niches with very different environmental conditions that shape biofilm structure and composition. The space between the periodontal tissue and the tooth surface supports a unique anaerobic microenvironment that is bathed in the nutrient-rich gingival crevicular fluid (GCF). During the development of periodontitis, this environment changes and clinical findings reported a sustained level of calcium ion concentration in the GCF collected from the periodontal pockets of periodontitis patients. Here, we report the effect of calcium ion supplementation on human oral microbial biofilm formation and community composition employing an established SHI medium-based in vitro model system. Saliva-derived human microbial biofilms cultured in calcium-supplemented SHI medium (SHICa) exhibited a significant dose-dependent increase in biomass and metabolic activity. The effect of SHICa medium on the microbial community composition was evaluated by 16S rRNA gene sequencing using saliva-derived microbial biofilms from healthy donors and periodontitis subjects. In this study, intracellular microbial genomic DNA (iDNA) and extracellular DNA (eDNA) were analyzed separately at the genus level. Calcium supplementation of SHI medium had a differential impact on iDNA and eDNA in the biofilms derived from healthy individuals compared to those from periodontitis subjects. In particular, the genus-level composition of the eDNA portion was distinct between the different biofilms. This study demonstrated the effect of calcium in a unique microenvironment on oral microbial complex supporting the dynamic transformation and biofilm formation.

Exploitation of a Bacterium-Encoded Lytic Transglycosylase by a Human Oral Lytic Phage To Facilitate Infection.

Bacteriophages (phages) are an integral part of the human oral microbiome. Their roles in modulating bacterial physiology and shaping microbial communities have been discussed but remain understudied due to limited isolation and characterization of oral phage. Here, we report the isolation of LC001, a lytic phage targeting human oral Schaalia odontolytica (formerly known as Actinomyces odontolyticus) strain XH001. We showed that LC001 attached to and infected surface-grown, but not planktonic, XH001 cells, and it displayed remarkable host specificity at the strain level. Whole-genome sequencing of spontaneous LC001-resistant, surface-grown XH001 mutants revealed that the majority of the mutants carry nonsense or frameshift mutations in XH001 gene APY09_05145 (renamed ltg-1), which encodes a putative lytic transglycosylase (LT). The mutants are defective in LC001 binding, as revealed by direct visualization of the significantly reduced attachment of phage particles to the XH001 spontaneous mutants compared that to the wild type. Meanwhile, targeted deletion of ltg-1 produced a mutant that is defective in LC001 binding and resistant to LC001 infection even as surface-grown cells, while complementation of ltg-1 in the mutant background restored the LC001-sensitive phenotype. Intriguingly, similar expression levels of ltg-1 were observed in surface-grown and planktonic XH001, which displayed LC001-binding and nonbinding phenotypes, respectively. Furthermore, the overexpression of ltg-1 failed to confer an LC001-binding and -sensitive phenotype to planktonic XH001. Thus, our data suggested that rather than directly serving as a phage receptor, ltg-1-encoded LT may increase the accessibility of phage receptor, possibly via its enzymatic activity, by cleaving the peptidoglycan structure for better receptor exposure during peptidoglycan remodeling, a function that can be exploited by LC001 to facilitate infection. IMPORTANCE The evidence for the presence of a diverse and abundant phage population in the host-associated oral microbiome came largely from metagenomic analysis or the observation of virus-like particles within saliva/plaque samples, while the isolation of oral phage and investigation of their interaction with bacterial hosts are limited. Here, we report the isolation of LC001, the first lytic phage targeting oral Schaalia odontolytica. Our study suggested that LC001 may exploit the host bacterium-encoded lytic transglycosylase function to gain access to the receptor, thus facilitating its infection.

Tooth-Specific Streptococcus mutans Distribution and Associated Microbiome.

Dental caries is multifactorial and polymicrobial in nature and remains one of the most common oral diseases. While caries research has focused on Streptococcus mutans as the main etiological pathogen, its impact at the tooth level is not fully understood. In this cross-sectional study, the levels and distribution of S. mutans in the posterior teeth at different dentition stages were investigated along with the corresponding tooth-specific microbiome. Occlusal plaque samples of 87 individual posterior teeth were collected from thirty children in three dentition stages (primary, mixed, and permanent). The S. mutans levels in the occlusal plaque of individual posterior teeth were quantified with qPCR, and those with preferential colonization were selected for tooth-specific microbiome analysis using 16S rRNA sequencing. Results: Quantification of S. mutans levels in the occlusal plaque confirmed the preferential colonization on the first primary and permanent molars. These teeth were selected for further tooth-specific microbiome sequencing, as they also displayed high caries experience. There were significant differences in the relative abundance of the four most abundant genera: Neisseria, Streptococcus, Rothia, and Veillonella. Furthermore, the tooth-level caries experience was correlated with a reduction in the microbiome diversity. Analyzing the different tooth-associated microbial communities, distinct tooth-specific core microbiomes were identified. Conclusions: Our findings suggest that caries susceptibility at the tooth level, depending on tooth type and dentition stage, is influenced by individual species as well as plaque community.

A Denture Use Model Associated with Candida spp. in Immunocompetent Male and Female Rats.

Denture stomatitis (DS) is a common infection in denture wearers, especially women. This study evaluated the induction of DS using acrylic devices attached to the palate of rats combined with inoculation of Candida spp. Immunocompetent male and female rats received a carbohydrate-rich diet. Impressions were taken from the rats' palate to individually fabricate acrylic devices. Mono- and multispecies biofilms of C. albicans, C. glabrata, and C. tropicalis were grown on the devices, which were then cemented on posterior teeth and kept in the rats' palate for four weeks. Microbial samples from the palate and the device were quantified. Oral microbiome of rats inoculated with C. albicans was analyzed by 16S rRNA gene sequencing. Log10(CFU/mL) were analyzed by mixed or two-way MANOVA (α = 0.05). Candida spp. and acrylic device did not induce palatal inflammation macroscopically nor microscopically. Although there was an increase (p < 0.001) of the total microbiota and female rats demonstrated higher (p = 0.007) recovery of Candida spp. from the palate, the gender differences were not biologically relevant. The microbiome results indicate an increase in inflammatory microbiota and reduction in health-associated micro-organisms. Although Candida spp. and acrylic device did not induce DS in immunocompetent rats, the shift in microbiota may precede manifestation of inflammation.

Effect of Cigarette and E-Cigarette Smoke Condensates on Candida albicans Biofilm Formation and Gene Expression.

Smoking triggers environmental changes in the oral cavity and increases the risk of mucosal infections caused by Candida albicans such as oral candidiasis. While cigarette smoke has a significant impact on C. albicans, how e-cigarettes affect this oral pathogen is less clear. Here, we investigated the effect of cigarette and e-cigarette smoke condensates (CSC and ECSC) on C. albicans growth, biofilm formation, and gene expression. Whereas pure nicotine (N) at the minimum inhibitory concentration (MIC, 4 mg/mL) prevented C. albicans growth, enhanced biofilm formation was observed at 0.1 mg/mL. In contrast, at this nicotine sub-MIC (0.1 mg/mL) concentration, CSC and ECSC had no significant effect on C. albicans biofilm formation. Additionally, N, CSC, and ECSC increased the expression of HWP1 and SAP2 genes. The ECSC group exhibited elevated expression levels of the EAP1 and ALS3 genes, compared to the nicotine-free ECSC (-) control. Moreover, our in vitro study illustrated that the antifungal drugs, fluconazole and amphotericin B, alleviated the effect of nicotine on C. albicans gene expression. Overall, the results of the study indicated nicotine from different sources may affect the pathogenic characteristics of C. albicans, including hyphal growth, biofilm formation, and particularly the expression of virulence-related genes.

The Microbiome in Periodontitis and Diabetes.

Objectives: To perform a comprehensive and integrative review of the available literature on the potential changes in the microbiome of healthy and individuals with diabetes under periodontal health and disease. Materials and Methods: The review was conducted by two independent reviewers. Indexed electronic databases (PubMed/Medline, Cochrane Library, Web of Science and Scopus) were searched, including articles published in English and dated from 5 years ago until December 2021. A manual search also was performed to identify co-related articles. Following the removal of duplicates and eligibility criteria, the articles were included in tables for analysis and described in the manuscript. Results: According to this review, diabetes mellitus was associated with significant changes in the subgingival and salivary microbiome, either in its association with periodontitis or in cases of periodontal health. In addition to affecting microbial diversity in terms of taxonomy, metagenomic studies have shown that this endocrine disorder may also be directly related to increased pathogenicity in the oral microbiome. Conclusion: Although the reviewed studies demonstrate important differences in the subgingival and salivary microbiome composition because of diabetes mellitus, further studies are needed to clarify the real effects of hyperglycemia on oral microbial profiles and support new diagnostic approaches and innovative treatments.

Oral Microbiome: Streptococcus mutans/Caries Concordant-Discordant Children.

Dental caries remains the most common chronic disease in children, and the respective etiology is not fully understood. Though Streptococcus mutans is an important factor in the initiation and progression of caries, its presence is not always associated with the disease. The existence of caries discordant populations, in which S. mutans counts do not correlate with caries experience, poses a challenging problem. This study explored the possible correlation of S. mutans and other microorganism levels on caries-associated ecology of caries-concordant and discordant populations. A total of forty-seven children were analyzed in this study and stratified into four clinical groups based on their S. mutans levels in saliva (HS/LS: High/low S. mutans) and caries experience. Streptococcus mutans levels were determined by culture-based selective plating. The salivary microbiome of caries concordant and discordant populations was investigated by 16S rRNA gene sequencing and downstream bioinformatics analysis. The salivary microbial communities significantly clustered based on S. mutans levels and independent of their caries experience. In addition to S. mutans levels, significant differences in the abundance of other species were observed between HS and LS groups. Interestingly, disease-associated species such as Veillonella dispar, Streptococcus spp., and Prevotella spp. were significantly increased in HS groups and may contribute, in combination with S. mutans, to the caries progression. Furthermore, health-associated species exhibited higher abundance in the LS groups, such as Veillonella rogosae, Haemophilus sp., and Alloprevotella spp. but their possible contribution to the caries process remains to be elucidated. This study provides evidence that S. mutans may play a role in shaping the salivary microbial community. Our results highlight that future caries research should consider additional species as health/disease microbial markers in conjunction with S. mutans to improve diagnosis and caries management of the caries-discordant population.

Clinical evaluation of Er,Cr:YSGG laser therapy used as an adjunct to non-surgical treatment of periodontitis: Twelve-month results from a pilot study.

BACKGROUND: The purpose of this study was to evaluate the results of adjunctive Er,Cr:YSGG laser therapy with scaling and root planing (SRP) as compared with SRP alone in the treatment of moderate to severe periodontitis. METHODS: Fifteen adults (aged 27 to 65 years) with 90 nonadjacent sites probing ≥ 5 mm were treated in split-mouth design with SRP and laser therapy versus SRP alone. Probing pocket depth (PPD), gingival recession (GR), clinical attachment level (CAL), plaque, and bleeding on probing were collected at baseline, 1, 3, 6, 9, and 12 months. Patient reported outcomes were measured to assess pain, sensitivity, and satisfaction. RESULTS: Clinical improvements were similar for test and control sites with no statistically significant difference. At 12 months, the average PPD reduced from 6.1 to 4.2 mm for test and 6.2 to 4.3 mm for control sites. GR increased by 0.4 mm at test and control sites. CAL increased from 6.8 to 5.3 mm for test and 6.9 to 5.5 mm for control sites. Clinical outcomes were stratified by baseline PPD ( = 5, = 6 and ≥7 mm) and analyzed for number of sites that reduced (≤4 mm). No significant difference was observed when the baseline PPD was 5 or 6 mm. Test sites with baseline PPD ≥7 mm demonstrated a statistically significant difference in the percentage of reduced sites when compared with controls at nine (P = 0.001) and 12 months (P = 0.044). CONCLUSIONS: Adjunctive Er,Cr:YSGG laser therapy with SRP provides similar clinical improvement in the treatment of moderate-severe periodontitis as SRP alone and may offer some advantage for deeper (≥7 mm) pockets.

The impact of fixed orthodontic appliances and clear aligners on the oral microbiome and the association with clinical parameters: A longitudinal comparative study.

INTRODUCTION: Orthodontic treatment interferes with oral hygiene and promotes plaque retention, which leads to gingival inflammation and enamel demineralization. Although removable clear aligners (CAs) are designed to improve oral hygiene compared with fixed appliances (FAs), comprehensive studies comparing their respective effects on the oral microbiome are limited. This longitudinal study investigated the microbial changes during orthodontic treatment with FA and CA in correlation with clinical parameters. METHODS: Clinical parameters and supragingival plaque were collected from 12 study participants for the FA or CA treatment groups at baseline and at least twice at the 1, 3, 6, and 12-month follow-up appointments. The plaque was also harvested from the aligner tray for the CA group. Microbiome composition was determined via 16S rRNA gene sequencing, compared between groups, and correlated with clinical parameters. RESULTS: Plaque (PI) and gingival indexes (GI) increased significantly in the FA but not the CA group. Beta but not alpha diversities of the microbial communities were distinct between the 2 treatment groups, even though genus-level differences were not significant except for Leptotrichia. The CA tray harbors a unique plaque community. Elevated PI and GI in the FA group correlated with a higher abundance of disease-related genera. CONCLUSIONS: Orthodontic treatments trigger appliance-related plaque community shifts from baseline, and the CA tray environment attracts distinct microbial communities. In comparison with FA, the use of CA resulted in better oral health index outcomes, which is reflected by the corresponding PI and GI-associated oral microbial communities.

Fusobacterium nucleatum secretes amyloid-like FadA to enhance pathogenicity.

Fusobacterium nucleatum (Fn) is a Gram-negative oral commensal, prevalent in various human diseases. It is unknown how this common commensal converts to a rampant pathogen. We report that Fn secretes an adhesin (FadA) with amyloid properties via a Fap2-like autotransporter to enhance its virulence. The extracellular FadA binds Congo Red, Thioflavin-T, and antibodies raised against human amyloid ß42. Fn produces amyloid-like FadA under stress and disease conditions, but not in healthy sites or tissues. It functions as a scaffold for biofilm formation, confers acid tolerance, and mediates Fn binding to host cells. Furthermore, amyloid-like FadA induces periodontal bone loss and promotes CRC progression in mice, with virulence attenuated by amyloid-binding compounds. The uncleaved signal peptide of FadA is required for the formation and stability of mature amyloid FadA fibrils. We propose a model in which hydrophobic signal peptides serve as "hooks" to crosslink neighboring FadA filaments to form a stable amyloid-like structure. Our study provides a potential mechanistic link between periodontal disease and CRC and suggests anti-amyloid therapies as possible interventions for Fn-mediated disease processes.

Omics and interspecies interaction.

Interspecies interactions are key determinants in biofilm behavior, ecology, and architecture. The cellular responses of microorganisms to each other at transcriptional, proteomic, and metabolomic levels ultimately determine the characteristics of biofilm and the corresponding implications for health and disease. Advances in omics technologies have revolutionized our understanding of microbial community composition and their activities as a whole. Large-scale analyses of the complex interaction between the many microbial species residing within a biofilm, however, are currently still hampered by technical and bioinformatics challenges. Thus, studies of interspecies interactions have largely focused on the transcriptional and proteomic changes that occur during the contact of a few prominent species, such as Porphyromonas gingivalis, Streptococcus mutans, Candida albicans, and a few others, with selected partner species. Expansion of available tools is necessary to grow the revealing, albeit limited, insight these studies have provided into a profound understanding of the nature of individual microbial responses to the presence of others. This will allow us to answer important questions including: Which intermicrobial interactions orchestrate the myriad of cooperative, synergistic, antagonistic, manipulative, and other types of relationships and activities in the complex biofilm environment, and what are the implications for oral health and disease?

Fusobacteriumnucleatum Adheres to Clostridioides difficile via the RadD Adhesin to Enhance Biofilm Formation in Intestinal Mucus.

BACKGROUND & AIMS: Although Clostridioides difficile infection (CDI) is known to involve the disruption of the gut microbiota, little is understood regarding how mucus-associated microbes interact with C difficile. We hypothesized that select mucus-associated bacteria would promote C difficile colonization and biofilm formation. METHODS: To create a model of the human intestinal mucus layer and gut microbiota, we used bioreactors inoculated with healthy human feces, treated with clindamycin and infected with C difficile with the addition of human MUC2-coated coverslips. RESULTS: C difficile was found to colonize and form biofilms on MUC2-coated coverslips, and 16S rRNA sequencing showed a unique biofilm profile with substantial cocolonization with Fusobacterium species. Consistent with our bioreactor data, publicly available data sets and patient stool samples showed that a subset of patients with C difficile infection harbored high levels of Fusobacterium species. We observed colocalization of C difficile and F nucleatum in an aggregation assay using adult patients and stool of pediatric patients with inflammatory bowel disease and in tissue sections of patients with CDI. C difficile strains were found to coaggregate with F nucleatum subspecies in vitro; an effect that was inhibited by blocking or mutating the adhesin RadD on Fusobacterium and removal of flagella on C difficile. Aggregation was shown to be unique between F nucleatum and C difficile, because other gut commensals did not aggregate with C difficile. Addition of F nucleatum also enhanced C difficile biofilm formation and extracellular polysaccharide production. CONCLUSIONS: Collectively, these data show a unique interaction of between pathogenic C difficile and F nucleatum in the intestinal mucus layer.

Role of FAD-I in Fusobacterial Interspecies Interaction and Biofilm Formation.

: RadD, a major adhesin of oral fusobacteria, is part of a four-gene operon encoding the small lipoprotein FAD-I and two currently uncharacterized small proteins encoded by the rapA and rapB genes. Previously, we described a role for FAD-I in the induction of human B-defensin 2 (hBD2) upon contact with oral epithelial cells. Here, we investigated potential roles for fad-I, rapA, and rapB in interspecies interaction and biofilm formation. Gene inactivation mutants were generated for each of these genes in the nucleatum and polymorphum subspecies of Fusobacterium nucleatum and characterized for their adherence to partner species, biofilm formation, and operon transcription. Binding to Streptococcus gordonii was increased in all mutant strains with Δfad-I having the most significant effect. This increased adherence was directly proportional to elevated radD transcript levels and resulted in significantly different architecture and height of the biofilms formed by Δfad-I and S. gordonii compared to the wild-type parent. In conclusion, FAD-I is important for fusobacterial interspecies interaction as its lack leads to increased production of the RadD adhesin suggesting a role of FAD-I in its regulation. This regulatory effect does not require the presence of functional RadD.

The subgingival microbiome associated with periodontitis in type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is a systemic disease, predisposing patients to other inflammatory conditions including periodontitis. The subgingival microbiome, a key player in periodontitis pathogenesis, is not well characterized in T2DM population. To better understand whether the subgingival microbiome is different between T2DM and systemically healthy, nondiabetic (ND) subjects, we performed a longitudinal analysis of the subgingival microbiome in T2DM patients (n = 15) compared with ND subjects (n = 16). Using metagenomic shotgun sequencing, we investigated the microbiome in the healthy periodontal state, periodontitis state, and resolved state after treatment. We found that in the periodontitis state, the shift in the subgingival microbiome from the healthy state was less prominent in T2DM compared with ND subjects, yet the clinical signs of disease were similar for both. Furthermore, we revealed highly correlated presence of pathogenic species in relative abundance not only in the periodontitis state, but also in the healthy state in T2DM, suggesting an elevated risk of progression to periodontitis in this cohort. We further investigated the functional potentials of the subgingival microbiome and identified a set of microbial marker genes associated with the clinical states. These genes were significantly enriched in 21 pathways, some of which are associated with periodontitis and some potentially link T2DM and periodontitis. This study identified the longitudinal changes of the subgingival microbiome associated with periodontitis in T2DM and suggests that T2DM patients are more susceptible to shifts in the subgingival microbiome toward dysbiosis, potentially due to impaired host metabolic and immune regulation.

Correction: Shokeen, B., et al. Role of FAD-I in Fusobacterial Interspecies Interaction and Biofilm Formation. Microorganisms 2020, 8, 70.

The authors wish to make the following corrections to this paper [...].

Histone Lys demethylase KDM3C demonstrates anti-inflammatory effects by suppressing NF-κB signaling and osteoclastogenesis.

Histone Lys-specific demethylases (KDMs) play a key role in many biological processes through epigenetic mechanisms. However, the role of KDMs in inflammatory responses to oral bacterial infection is poorly understood. Here, we show a novel regulatory role of KDM3C in inflammatory responses to oral bacterial infection. KDM3C expression is transiently suppressed in human and mouse macrophages exposed to LPS from Porphyromonas gingivalis (Pg LPS). Loss of KDM3C in both human and mouse macrophages led to notable induction of proinflammatory cytokines in response to Pg LPS stimulation. Also, KDM3C depletion led to strong induction of p65 phosphorylation and accelerated nuclear translocation in cells exposed to Pg LPS. Kdm3C knockout (KO) in mice led to increased alveolar bone destruction upon induction of experimental periodontitis or pulp exposure compared with those of the wild-type (WT) littermates. The Kdm3C KO mice also revealed an increased number of osteoclasts juxtaposed to the bony lesions. We also confirmed enhanced osteoclastogenesis by bone marrow-derived macrophages isolated from the Kdm3C KO compared with the WT controls. These findings suggest an anti-inflammatory function of KDM3C in regulating the inflammatory responses against oral bacterial infection through suppression of NF-κB signaling and osteoclastogenesis.-Lee, J. Y., Mehrazarin, S., Alshaikh, A., Kim, S., Chen, W., Lux, R., Gwack, Y., Kim, R. H., Kang, M. K. Histone Lys demethylase KDM3C demonstrates anti-inflammatory effects by suppressing NF-κB signaling and osteoclastogenesis.