The field of oral microbiome research is still limited by several major challenges, including biological, translation, and implementation issues

The gap

Evidence profile

Sourced from the future work and limitations section of the source papers, classified as general, spanning 4 journals.

Supporting evidence — 4 representative gaps

• The oral–gut–liver axis: linking periodontal microbiota to the pathogenesis of liver diseases (2026) · Frontiers in Medicine · doi

  4.1 The oral microbiome as diagnostic and prognostic biomarkers Saliva and dental plaque samples are promising candidates for disease screening and monitoring because of their noninvasive and easily accessible nature. Clinical evidence indicates that the oral microbiome can serve as an effective noninvasive biomarker capable of distinguishing patients with liver disease from healthy controls and facilitating longitudinal monitoring of disease progression. For instance, a metagenomic sequencing analysis of saliva samples identi- fied characteristic alterations in the salivary microbiota of patients with cirrhosis and constructed a diagnostic model whose accuracy was comparable to that of models based on the fecal microbiome (51). Research on NAFLD further reveals that the relative abundance of specific bacterial taxa in the salivary microbiota correlates with the degree of hepatic steatosis and stage of fibrosis, suggesting its potential utility for stratifying NAFLD severity. In the context of HCC, the detection of F. nucleatum within tumor tissue has been established as an independent predictor of poor prognosis, indicating that patients harboring this bacterium typically experience shorter overall and recurrence-free survival (52). While current detection methods rely on tissue biopsies, a critical future direction involves identifying circulating microbial or immune markers in blood or saliva associated with intratumoral F. nucleatum, thereby enabling non-invasive prognostic assessment. 4.2 Oral health intervention: a novel adjunctive management strategy for liver disease A core question in translational research is whether improving oral health, particularly through periodontitis treatment, can posi- tively influence liver disease progression. Preliminary clinical inter- vention studies have provided encouraging evidence. The preventive role of oral care in serious complications of cirrhosis is gaining recognition. Studies have indicated that a patient’s oral hygiene status is independently associated with the risk of hepatic encepha- lopathy. Furthermore, intervention trials have demonstrated that implementing intensive oral care, including professional periodon- tal cleaning and daily chlorhexidine mouthwash use, in patients with decompensated cirrhosis can significantly reduce systemic inflammatory markers and show a trend toward decreased hospi- talization rates. This directly supports the beneficial effects of peri- odontal treatment on liver-related metabolism and inflammation (53, 54). A randomized controlled trial specifically showed that non-surgical periodontal therapy in patients with cirrhosis not only improved their oral health but also beneficially modulated the oral– gut–liver axis by improving gut microbiota profiles, reducing sys- temic inflammation, and enhancing cognitive function related to hepatic encephalopathy. This provides strong interventional evi- dence for incorporating periodontal therapy into comprehensive cirrhosis management (53). Although larger prospective random- ized controlled trials (RCTs) are warranted for confirmation, these findings underscore the importance of integrating oral care into multidisciplinary management of cirrhosis. From a pragmatic standpoint, oral interventions, such as basic periodontal therapy, are mature, safe, and relatively low-cost clinical procedures. Their integration as a routine adjunctive strategy for patients with liver disease is highly feasible and offers favorable cost-effectiveness. Such interventions are not intended to replace established liver therapies but serve as a complementary approach capable of improving systemic inflammatory status, potentially slowing dis- ease progression, and securing a role in the early prevention and holistic management of liver disease. 4.3 Towards precision medicine Future therapeutic strategies targeting the oral microbiota may evolve beyond conventional periodontal treatment toward more pre- cise and targeted modulations. The development of specific interven- tions against key oral pathogens encompasses several strategies. First, targeted agents, such as bacteriophages or the use of

  generalfuture work
  Keywords: oral liver disease patients cirrhosis microbiota management periodontal microbiome saliva clinical progression hepatic health improving
• Prevalence and Etiopathogenic Profile of Oral Squamous Cell Carcinoma in Nonsmokers and Nondrinkers: Expanding Risk Determinants Beyond Tobacco Exposure (2026) · Diagnostics · doi

  Future directions in research on nonsmoking, nondrinking oral squamous cell carci- noma should prioritize elucidating its multifactorial etiology through large-scale, prospec- tive multicenter studies that integrate multi-omics approaches, including detailed tumor mutational profiling (e.g., next-generation sequencing for CDKN2A, EGFR, and BRCA2 alterations), microbiome sequencing, and immune phenotyping of the tumor microen- vironment. Investigating the role of chronic mechanical irritation, oral dysbiosis with https://doi.org/10.3390/diagnostics16101563 Diagnostics 2026, 16, 1563 12 of 14 periodontal pathogens, epigenetic changes, hormonal influences (particularly in females), and immune-modulating comorbidities will help clarify distinct carcinogenic pathways. Developing standardized definitions and risk stratification tools for NSND patients is essential, alongside exploring saliva-based microbial biomarkers for early detection and screening. Given the observed immune-modulated phenotype (e.g., higher PD-L1 expres- sion and tumor-infiltrating lymphocytes), trials evaluating immune checkpoint inhibitors and immunopreventive strategies hold promise for tailored therapies. Longitudinal stud- ies addressing the elevated risk of second primary tumors and recurrence, especially in young and elderly subgroups, are needed to optimize surveillance protocols and improve outcomes in this growing, clinically distinct population.

  generalfuture work
  Keywords: immune tumor oral sequencing diagnostics distinct risk future directions nonsmoking nondrinking squamous cell carci noma
• Clinical translation of salivary MicroAge for understanding the oral-systemic connection in healthy longevity (2026) · Frontiers in Microbiology · doi

  6.1 The unique contribution of this review Unlike much of the existing literature, which tends to focus on a single dimension, this review is the first to systematically integrate three key aspects of the salivary microbiome as a biomarker of aging: age-related patterns of microbial succession, the macro-level associa- tions and mechanistic networks linking the salivary microbiome to age-related diseases, and the methodological landscape of AI-based salivary MicroAge construction. The central argument of this review is that the age-related signal of the salivary microbiome is, in essence, a systematic shift in community structure and functional networks; that MicroAgeGap is not merely a prediction error term, but can also serve as both a readout of inflamm-aging phenotypes and an inte- grated risk indicator; and that while the introduction of artificial intel- ligence makes high-dimensional, nonlinear modeling possible, the biological interpretability and cross-population generalizability of such models must be improved in parallel. On this basis, the most urgent tasks in the field are to establish standardized sampling and sequencing workflows, build multicenter longitudinal cohorts, and embed interpretability and domain-adaptation calibration mecha- nisms into predictive models. 6.2 Limitations of this review and ethical considerations from studies of This review has several limitations. First, its focus on saliva means that other oral ecological niches, such as subgingival plaque, were not systematically covered, which may lead to underestimation of the unique contributions of local microenvironments. Second, a substan- tial proportion of the mechanistic evidence discussed here is extrapo- lated from periodontitis–systemic disease models; direct causal mechanistic studies specifically centered on the salivary microbiome remain scarce. Third, this is a narrative review rather than a systematic review and did not follow procedures such as PRISMA, which may introduce selective citation bias. Fourth, the discussion of AI methodologies is primarily conceptual and panoramic, without delving deeply into spe- cific implementation details. the gut microbiome or Most primary studies cited in this review are cross-sectional in design and did not systematically report age- and sex-adjusted effect estimates for disease associations with salivary microbiome features. Similarly, multivariable adjustments for key confounders such as smoking, BMI, medication use, and periodontal status were often incomplete or absent. This lack of standardized covariate-adjusted analyses limits the quantitative synthesis of evidence and precludes definitive conclusions about the independent contribution of the sali- vary microbiome to age-related disease risk, beyond the effects of chronological age and lifestyle factors. Currently, evidence is insufficient to establish whether salivary MicroAge provides additional predictive value for age-related diseases beyond well-established covariates such as chronological age, sex, smoking, BMI, periodontal status, and particularly DNA methylation age. Rigorous head-to-head comparisons in large longitudinal cohorts, incorporating these variables as covariates, are urgently needed. Until such data emerge, we advocate for cautious interpretation of MicroAgeGap as an indicator of oral-systemic inflammatory load, conceptually closer to an “inflamm-ecological age “. 6.3 Future directions toward the translational application of MicroAge Unlike Section 4.6, which focuses on mechanistic validation and causal inference, this section outlines priority directions from the standpoint of model development and clinical translation: (1) Longitudinal cohort studies with systematic covariate adjustment, including age, sex, smoking, BMI, and medica- tion use, are urgently needed to quantify the independent predictive value of salivary microbiome features for disease outcomes.

  generalfuture work
  Keywords: review salivary microbiome related mechanistic disease systematically microage systematic models longitudinal predictive evidence smoking unique
• Host-microbiome-immune disequilibrium in oral disease: mechanisms, dysbiosis, and precision therapeutics (2026) · Frontiers in Immunology · doi

  The field of oral microbiome research is still limited by several major challenges, including biological, translation, and implementation issues. There is a lack of large, long-term studies and trials that can test whether microbiome-based or host-microbiome methods can improve diagnosis, prediction, or treatment. The integration of microbial or AI-derived signals into routine clinical care often remains unclear.

  generallimitations sectionevidence 5/5
  Keywords: field oral microbiome research still limited several major

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