Sukirth Murthy Ganesan

Background: The tissue-resident microbiome of oral epithelial lesions remains incompletely characterized, with most prior studies relying on saliva or surface sampling. This study aimed to characterize intralesional microbial communities across histopathologic categories of tongue lesions using formalin-fixed paraffin-embedded (FFPE) tissue. Methods: This cross-sectional study characterized the intralesional microbiome of 63 formalin-fixed, paraffin-embedded tongue tissues, including fibroma ( n = 15), low malignant potential dysplasia (LMP; n = 24), high malignant potential dysplasia (HMP; n = 24), and additional OSCC samples. Amplicon sequencing of the V3–V4 16S rRNA region was used to assess taxonomic composition, alpha and beta diversity, phylogenetic structure, predicted functional pathways (PICRUSt2), and machine-learning–based discrimination of lesion categories. Results: Microbial community profiles differed significantly across histopathologic groups. Non-dysplastic tissues exhibited higher richness and greater representation of commensal genera such as Streptococcus , Rothia , and Veillonella . Dysplastic tissues demonstrated reduced diversity and increased abundance of stress-adapted Proteobacteria including Bosea , Novosphingobium , Sphingomonas , and Pseudomonas . Beta diversity analyses revealed distinct community structures between fibroma, LMP, and HMP categories. Predicted functional profiles suggested differences in inferred metabolic potential, including pathways related to carbohydrate metabolism and xenobiotic degradation in dysplastic lesions. A supervised classifier demonstrated separation between groups (AUC 0.83–1.00), with several taxa contributing to classification; however, these findings should be interpreted cautiously given the sample size. Conclusion: Intralesional microbial communities differ across fibroma, dysplasia, and OSCC of the tongue in both taxonomic composition and predicted functional profiles. These findings describe lesion-associated microbial signatures within tissue and provide a foundation for future studies incorporating longitudinal designs and multi-omics approaches to clarify their biological and clinical relevance.

Background: Peri‐implantitis is a destructive disease affecting the tissues surrounding dental implants. Biomaterials may be applied during surgical treatment to reconstruct bony defects and support soft tissue healing. However, current evidence is unclear if these treatments increase the likelihood of peri‐implantitis resolution. Methods: A systematic review and meta‐analysis was performed on randomized controlled trials (RCTs) comparing surgical treatment with addition of reconstructive biomaterials (intervention) versus surgical treatment of peri‐implantitis alone (comparison) with follow‐up periods of at least 12 months. Resolution of peri‐implantitis, defined as a reduction of probing pocket depth (PPD) to ≤5 mm, absence bleeding on probing (BOP), and stable or decreasing radiographic defect level (RDL), was selected as the primary outcome. Secondary outcomes included RDL reduction, buccal mucosal recession (REC), and patient‐related outcome measures (PROMs). Risk of bias and quality of evidence were calculated using established guidelines. Results: Seven studies reporting on 402 patients with 405 implants met inclusion criteria. Wide variations in outcome reporting prevented the synthesis and quantitative comparison of peri‐implantitis disease resolution between intervention and comparison groups. Individual meta‐analyses showed a weighted mean difference (WMD) in PPD reduction of 0.28 mm [95% confidence interval (CI) ‐0.30, 0.86] and a relative risk (RR) for absence of BOP of 1.11 (95% CI 0.78, 1.59) for the inclusion of biomaterials (intervention) over access flap alone (comparison). For RDL reduction, a WMD of 1.08 mm (95% CI 0.41, 1.74) with significant heterogeneity (Q p ‐val: < 0.01, I ² : 85%) and for REC, a WMD of ‐0.38 (95% CI −0.66, −0.11) was found, both in favor of the intervention. Analysis of the heterogeneity affecting RDL identified a positive effect on RDL when hydrogen peroxide but not rotary titanium brushes were used as an adjunct for implant surface debridement. Conclusion: Current evidence suggests that incorporating reconstructive biomaterials into surgical treatment may not definitively enhance the likelihood of peri‐implantitis disease resolution. However, this lack of effect may be due to other factors such as implant surface treatments which may also affect clinical outcomes. Overall, this work highlights the critical need for standardizing the reporting of composite outcomes for the resolution of peri‐implantitis disease and controlling for implant surface treatment effects when assessing reconstructive biomaterials. Plain language summary: Peri‐implantitis is a destructive disease affecting tissues around dental implants. We studied whether adding reconstructive biomaterials (i.e., biomaterials used to improve the likelihood of new bone formation or bone defect fill) to surgical treatments improves the clinical condition, meaning no further bone loss, probing pocket depths (PPD) ≤5 mm, and no bleeding on probing (BOP). We reviewed randomized controlled trials (RCTs) comparing surgery with biomaterials to surgery alone with at least 12 months of follow‐up. The main outcomes measured were PPD reduction, absence of BOP, and radiographic defect level (RDL). Secondary outcomes included RDL change, buccal mucosal recession (REC), and patient‐related outcomes (PROMs). Seven studies with 402 patients and 405 implants were analyzed. Due to variations in outcome reporting, it was challenging to compare the effectiveness of treatments. However, some individual analyses showed a small improvement in PPD and BOP with biomaterials. For RDL reduction, biomaterials showed better results, but with significant variability. REC also improved slightly with biomaterials. The analysis also suggested that using hydrogen peroxide, but not rotary titanium brushes, for implant cleaning could positively affect bone levels. The study concluded that adding biomaterials to surgical treatment does not definitively improve peri‐implantitis resolution, possibly due to other factors like implant surface treatments. This study emphasized the need for standardized reporting and considering these factors in future research.

Background: The pathogenesis and etiology of peri‐implantitis demand a deeper understanding to lead to successful treatment modalities. Animal models of peri‐implantitis pathogenesis offer unique insights but their translational impact requires consideration of implant biomaterials science. This systematic review, sanctioned by the International Association for Dental Research (IADR) Implantology Research Group, aimed to systematically review animal models in peri‐implant disease research. Experts deliberated on merits, limitations, and optimization of various models to guide researchers in selecting suitable platforms for investigations. Methods: A pre‐registered review (ID: CRD42023399976) was performed guided by the PICO question: Population (P): Laboratory animals with dental implants or surrogate biomaterials placed in the oral cavity; Intervention (I): Induction of peri‐implant inflammation; Control (C): Animals without induced inflammation or those subjected to a placebo treatment only; Outcome (O): Parameters including bone loss, histopathology of peri‐implant tissues, tissue inflammatory response, and microbiological outcomes. Results: Searches identified 158 articles, with 96 meeting inclusion criteria following a 2‐step systematic review (inter‐reviewer agreement: kappa = 0.72; 0.68, respectively for each phase). Most studies were on large animal models, mainly dogs ( n = 66); the majority employed ligature‐induced peri‐implant defect models. These models often reported delayed implant placement after teeth extraction followed by active breakdown via ligatures of various types, and a chronicity progression period without the ligatures to assimilate chronic inflammatory lesions. Primate studies ( n = 6) were published from the late 1990s to early 2000s. Murine models in mice ( n = 16) focused on disease establishment and biomolecular aspects, while rat models ( n = 6) addressed diabetes, xerostomia, and inflammation suppression. Murine models invariably required custom implant devices due to volume limitations, which often did not have implant surface modifications limiting their translational potential. Mini‐pig models ( n = 2) delved into microbiological shifts and the impact of soft tissue management on peri‐implant infection. Conclusion: Comprehensive overview of animal models in peri‐implant disease research offered insights into their strengths, challenges, and findings. The ongoing shift toward non‐animal alternatives and future horizons in peri‐implantitis research is highlighted. Plain Language Summary: This commissioned systematic review provides a comprehensive overview of animal models in peri‐implant disease research, offering insights into their strengths, challenges, and findings. Further, this article summarizes the consensus proceedings of the IADR IRG Peri‐Implantitis Best Evidence Consensus and provides guidance for future use of animals in peri‐implantitis research.

Objective: Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by inflammation, demyelination, and neurological impairment. While the gut microbiota's role in MS is extensively studied, the association between the oral microbiota and MS remains underexplored, particularly in North American cohorts. This study aimed to investigate the microbiota (bacterial) composition as well as functional pathways and immune profiles of the oral cavity in 60 patients with relapsing–remitting MS (RRMS), stratified by treatment status, compared to 44 healthy controls (HC). Methods: Unstimulated saliva was collected for genomic DNA extraction and salivary cytokine quantification. Oral bacterial composition and diversity were analyzed using 16S rRNA sequencing, with functional pathways inferred using PICRUSt2. Salivary cytokine levels were measured via multiplex immunoassays. LEfSe and random forest models identified key discriminatory taxa, and correlations between microbiota and cytokines were assessed using Spearman's rank analysis. Results: RRMS patients exhibited distinct microbial communities compared to HC and a higher Bacteroidota to Firmicutes ratio. Key taxa such as Campylobacter, Lachnoanaerobaculum , and Porphyromonas were enriched in RRMS. Functional profiling revealed 49 differentially abundant pathways, including the enrichment of lipopolysaccharide biosynthesis in MS. Elevated levels of IFN‐γ, IL‐6, and other cytokines correlated with the altered microbiome. IL‐21, elevated in HC, correlated with anti‐inflammatory pathways, suggesting a protective role in immune homeostasis. Interpretation: This study provides, for the first time, insights into oral microbiome‐host interactions in North American RRMS patients, underscoring the interplay between microbial dysbiosis, functional pathways, and immune dysregulation. The oral microbiome shows potential as a biomarker for MS‐related immune alterations.

Chronic graft-versus-host disease (cGVHD) frequently follows allogeneic hematopoietic stem cell transplantation and impacts the mucosa. This atlas study highlights the role of exhausted-like effector CD8 ⁺ T cells (T _EXEF ) in oral mucosal cGVHD pathogenesis. Biopsies from the oral mucosa were collected at oral cGVHD onset or at six months post-transplant and analyzed using single-cell RNA sequencing and other modalities. At cGVHD onset, in addition to changes in the myeloid compartment, two distinct populations of CD8 ⁺ T cells with a T _EXEF phenotype were prevalent: an inflammatory CD8T cell cluster (CD8T_4) expressing CCL4 , CD69 , and TNFSF9 , and an exhausted CD8T cell cluster (CD8T_5) characterized by the expression of CXCL13 , HIF1A , and HLA-DRA, both correlated with clinical disease severity. Pseudo-time analysis suggests a transition from the inflammatory pre-exhausted CD8T_4 cluster to the cytolytic, terminally exhausted CD8T_5 cluster. The CXCL9-CXCR3 interactions among CD8 ⁺ T cells, fibroblasts and myeloid cells are implicated in tissue damage. Onset of cGVHD despite frequent oral mucosal FOXP3⁺ regulatory CD4⁺T cells suggests potential impaired Treg function or CD8 ⁺ T cell dysfunction. These findings highlight T _EXEF cells as key contributors to oral cGVHD pathology and potential therapeutic targets for mitigating sustained tissue injury in cGVHD.

Cancer therapies impact the oral cavity. Oral microbial changes occur following cancer therapy, but the nature, duration, and implications of these shifts are not well understood. Exposure to radiation, chemotherapy or cellular therapies has been associated with oral microbiome shifts toward dysbiosis and increased frequency of pathogenic species in the microbiome. Despite these findings, much remains unknown about cancer-therapy-related changes in the oral microbiome following specific therapies, and what the associated long-term oral health implications may be for cancer survivorship. We therefore conducted a scoping review of oral microbiome studies in patients undergoing cancer therapy to broadly synthesize the literature on the oral microbiome in the context of cancer therapy, categorize findings, and identify research gaps to inform future projects. This scoping review of the literature describes substantial changes in the oral microbiome during cancer treatment, specifically chemotherapy, radiation therapy, and stem cell transplantation. Across 62 studies, chemotherapy, radiation therapy, and stem cell transplantation were associated with substantial changes in oral microbial communities. Among studies that assessed alpha diversity, the richness of species that comprised the oral microbiome often increased, encompassing more microbial taxa, while the evenness of species decreased, suggesting that community change was dominated by a few species. Frequently observed changes included decreases in commensal taxa such as Streptococcus and Prevotella and increases in opportunistic organisms such as Candida albicans and Staphylococcus aureus. While mucositis was often studied, consistent microbial predictors of this outcome were not identified The present study lays the groundwork for future research on the unique oral microenvironment and health needs in cancer survivors. The alterations in microbiome composition associated with specific cancer treatment categories add to our limited understanding of the key role of cancer therapy modalities on the oral microbiome.

The prevalence of childhood metabolic syndrome (MetS) and obesity is rising, with emerging evidence suggesting these conditions negatively affect oral health. However, the underlying molecular determinants are unclear. This study investigated the oral microbiome, inflammatory markers, and metabolites in children with obesity and MetS to explore the interrelationships between systemic disease and oral health. We recruited 76 periodontally healthy, caries-free individuals aged 10 to 17 y into 3 groups: MetS (29), metabolically healthy obesity (MHO) (30), and normal-weight healthy (NWH) controls (17). Unstimulated saliva was collected. Bacterial DNA was isolated, V3–V4 regions amplified, and 16S sequencing performed on the Illumina MiSeq platform. Sequences were annotated against the HOMD database. Multiplex assays quantified adipokines and cytokines, with significance determined by Tukey honestly significant difference. Gas chromatography/mass spectrometry identified metabolite peaks that were annotated against the Small Molecule Pathway Database, with enrichment analysis determining significance. Integrated multiomics analysis was performed using multiblock sparse partial least squares regression discriminant analysis. The MHO and MetS groups demonstrated lower abundances of Streptococcus , Actinomyces , and Schaalia and higher levels of Aggregatibacter , Campylobacter , Alloprevotella , Prevotella , Leptotrichia , and Porphyromonas compared with NWH, despite similar clinical oral status in all cohorts. MetS and MHO also had increased leptin, tumor necrosis factor–α, interleukin (IL)–1β, and IL-15 and decreased adiponectin levels versus NWH. Disease-associated metabolites, including glutamate, cholesterol, isoleucine, tyrosine, phenylalanine, serine, and indoleacetic acid, were significantly enriched in the MetS and MHO groups. Integrated multiomic analysis identified key correlations in the saliva of subjects with metabolic health or disease. Decreases in health-associated species and increases in proinflammatory cytokines and disease-associated metabolites in the saliva of MetS and obese adolescents with clinical oral health indicate an “at-risk” environment, potentially explaining their elevated risk for oral diseases. Increased salivary leptin and decreased adiponectin levels highlight the potential of saliva as a noninvasive biomarker source for childhood MetS.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a treatment modality for cancers and hematopoietic disorders. The number of allo-HCT survivors is increasing in the United States. Allo-HCT is associated with oral health problems that can affect the quality of posttransplantation life. We characterize clinical and patient-reported oral health outcomes from the time of allo-HCT through 2 y following transplantation among a contemporary cohort of patients transplanted between 2019 and 2022. This prospective cohort study analyzed data from participants enrolled in a contemporary allo-HCT natural history study (ClinicalTrials.gov ID: NCT03602599). Clinical characteristics and patient-reported outcomes were captured at 3, 6, 12, 18, and 24 mo post-HCT. Descriptive and bivariable statistics were calculated. Sixty HCT participants were included in the final analysis. Differences were observed in oral pain, oral dryness, diet quality, difficulty swallowing, taste disturbances, and feelings of embarrassment from time of transplantation through the follow-up period. At 2 y, 47.5% of participants reported oral pain, and 44.1% reported xerostomia. Quality-of-life reductions related to taste, pain, and uncomfortable chewing were also observed after 2 y. Oral health problems and reductions in oral health–related quality of life were reported 2 y after allo-HCT. These findings support a tailored approach to oral health care among recipients of allo-HCT. Providing comprehensive and sustained oral health care for this patient population is essential. Knowledge Transfer Statement: This study found time-specific changes in patient-reported symptoms, oral health status, and quality of life that persisted 2 y after allo-HCT. It also suggests that specific attention to long-term oral health care among this patient population remains warranted.

We tested the hypothesis that e-cigarette aerosol is metabolized by the indigenous oral microbiome, leading to structural and functional alterations. We combined untargeted metabolomics of in vitro commensal-rich and pathogen-rich biofilms with metatranscriptomics and fluorescent microscopy and verified the results in human samples. Spectral deconvolution of 4215 peaks identified 969 exposomal and endogenous metabolites that mapped to 23 metabolic pathways. The metabolites clustered by both aerosol characteristics and biofilm composition; and several were verified in human saliva of vapers. E-cigarette exposure upregulated xenobiotic degradation, capsule, peptidoglycan biosynthesis, organic carbon-compound metabolism, antimicrobial resistance, and secretion systems. E-cigarette exposure also altered biofilm architecture characterized by low surface-area to biovolume ratio, high biomass, and diffusion distance. In conclusion, our data suggest that bacterial metabolism of e-cigarette aerosol triggers a quorum-sensing-regulated stress response which mediates the formation of dense, exopolysaccharide-rich biofilms in health-compatible communities and antibiotic resistance and virulence amplification in disease-associated communities.

The peri-implant mucosal barrier is a unique microenvironment where host-microbiome interactions take place on the surface of an implanted biomaterial. Therefore, peri-implant immunity not only is quintessential to oral health but also contributes to the maintenance of the biomaterial-tissue equilibrium in health. This review delves into the intricate interplay between host factors, biomaterial properties, and the microbiome with a focus on the mechanisms underlying peri-implant dysbiosis. Investigations into this complex milieu have led to the emerging understanding of titanium particles released from the implant as significant exposomes. When biomaterial breakdown occurs, implant degradation products form particles that are released in the peri-implant crevice, exerting profound effects on the local immune surveillance. Comparative analyses with natural dentition highlight the distinct immune responses elicited by titanium particles, thereby implicating them as a key modulator of peri-implant dysbiosis that differentiates peri-implant from periodontal inflammation. Nonetheless, disruptions in the homeostatic balance of host-biomaterial interactions are linked to pathogenic shifts of the peri-implant microbiome that are correlated with titanium particles in humans. Collectively, it is now well established that to elucidate the mechanisms governing peri-implant dysbiosis, this triangle of host-microbiome-biomaterial has to be conjointly investigated. This review highlights findings from studies that have underscored the multifaceted nature of peri-implant dysbiosis, emphasizing the intricate crosstalk between host immunity, biomaterial characteristics, and microbial ecology. These findings suggest that the titanium particle exposome may alter key inflammatory cascades in the peri-implant tissues including toll-like receptor activation and inflammasome and complement signaling, which lead to nonresolving destructive inflammation. The presence of abiotic danger signals in the form of implant degradation products in peri-implant tissues may make antimicrobial monotherapies largely ineffective for managing peri-implantitis. In turn, the future of peri-implantitis therapy seems to lie in the development of targeted host modulatory interventions against titanium-mediated inflammatory pathways.