Host-Microbiome-Immune Disequilibrium: A New Framework for Understanding and Treating Oral Diseases
核心洞察
Oral diseases including periodontitis (搜索), dental caries (搜索), and OSCC are best understood as disorders of host-microbiome-immune disequilibrium rather than isolated infections, according to a comprehensive narrative review.
Dysbiosis disrupts oral homeostasis by promoting pathobiont expansion, amplifying inflammatory responses, and contributing to tissue injury through self-reinforcing cycles.
Emerging therapeutic strategies including probiotics, bacteriophage therapy, CRISPR-Cas antimicrobials, host-modulatory agents, and immune checkpoint inhibitors aim to restore ecological balance rather than simply eliminate pathogens.
The oral cavity harbors one of the most diverse and densely inhabited microbial ecosystems in the human body, yet traditional models of oral disease have focused narrowly on specific pathogens. A structured narrative review published in Frontiers in Immunology now argues that oral diseases—including periodontitis (搜索), dental caries (搜索), and oral squamous cell carcinoma (搜索) (OSCC)—should be reframed as disorders of host-microbiome-immune disequilibrium, a systems-level perspective with profound implications for prevention, diagnosis, and treatment.
Drawing on evidence from PubMed/MEDLINE, Web of Science, Embase, and Scopus, the review synthesizes current understanding of how coordinated interactions among commensal microbial communities, epithelial and salivary barriers, and immune surveillance maintain oral homeostasis—and how their disruption drives disease.
The ecological foundation of oral health
Under healthy conditions, the oral microbiome is dominated by bacterial phyla including Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Fusobacteria, and Spirochaetes, with commonly observed genera such as Streptococcus, Actinomyces, Veillonella, Neisseria, and Corynebacterium. These commensal species contribute to ecological equilibrium by generating bacteriocins and alkaline metabolites via arginine and urea metabolism, protecting enamel and inhibiting pathogenic colonization.
Oral epithelial cells form a multilayered barrier and produce antimicrobial peptides and cytokines that restrict microbial invasion. In parallel, innate and adaptive immune cells continuously monitor microbial communities. Salivary secretory Immunoglobulin A (sIgA) limits microbial adhesion to mucosal surfaces, while neutrophils—comprising more than 95% of leukocytes in saliva—restrict pathogenic colonization through phagocytosis, protease release, oxidative burst, and neutrophil extracellular trap formation.
Dysbiosis as a driver of oral disease
When this equilibrium is disrupted, dysbiosis creates ecological and immunological conditions favoring pathobiont expansion, altered microbial metabolism, and dysregulated host responses. The review identifies distinct dysbiotic patterns across major oral diseases.
In periodontitis (搜索), a self-reinforcing inflammatory cycle emerges in which host inflammation reshapes the local periodontal environment. The subgingival niche becomes enriched with proteolytic and inflammophilic anaerobes including Porphyromonas gingivalis (搜索), Tannerella forsythia, Treponema denticola, and Fusobacterium nucleatum (搜索). Neutrophil hyperactivation, macrophage polarization, and elevated levels of IL-1β, IL-6, TNF-α, IL-17, MMPs, and RANKL (搜索) promote connective tissue degradation and osteoclast-mediated bone resorption. Tissue destruction then releases additional inflammatory nutrients, creating a feed-forward loop.
Dental caries (搜索), by contrast, represents an acid-driven ecological collapse. Frequent consumption of fermentable carbohydrates drives repeated acidification in dental plaque, selecting for aciduric and acidogenic taxa including Streptococcus mutans, Lactobacillus spp., and Candida albicans. As the biofilm becomes progressively more acidic, the microbial community shifts toward species capable of thriving in low-pH environments.
In OSCC, microbial remodeling interacts with tumor-promoting inflammation. Tissues and saliva from OSCC patients often contain elevated levels of F. nucleatum and P. gingivalis, while typical commensals are relatively depleted. F. nucleatum may promote epithelial proliferation and immune evasion partly through β-catenin activation, while P. gingivalis can modulate IL-6/STAT3, NF-κB, and anti-apoptotic signaling.
Therapeutic recalibration of the oral ecosystem
The review organizes emerging therapies into ecological restoration, pathogen-selective suppression, host-inflammatory modulation, and immune regulation.
Probiotic strains including Lactobacillus reuteri, L. casei, L. rhamnosus, Bifidobacterium spp., and Streptococcus salivarius K12 have demonstrated modest but significant improvements in gingival inflammation and bleeding scores as adjuncts to periodontal therapy. Meta-analyses report that adjunctive Lactobacillus and Bifidobacterium probiotics lower gingival bleeding and decrease P. gingivalis counts in plaque.
For pathogen-selective suppression, bacteriophage therapy has shown preclinical efficacy against Aggregatibacter actinomycetemcomitans, F. nucleatum, and P. gingivalis, though further validation in multispecies biofilms and clinical settings is needed. CRISPR-Cas systems offer precision targeting of antibiotic resistance genes, biofilm formation, and virulence factors, with demonstrated success against colistin resistance genes on MCR-1 plasmids.
Host-directed strategies include low-dose doxycycline (20 mg daily), which in a randomized controlled trial of 30 chronic periodontitis (搜索) patients significantly reduced MMP-8 levels in gingival crevicular fluid at 6 months while improving probing depth and gingival index over 12 months. Resolvin E1, a pro-resolving lipid mediator derived from omega-3 eicosapentaenoic acid, has demonstrated the ability to regenerate pathologically lost tissues including bone by resolving inflammation in preclinical models—the first report of a naturally occurring lipid mediator achieving such regeneration.
In OSCC, immune checkpoint inhibitors have become an important treatment option. KEYNOTE-048 established pembrolizumab, alone or with chemotherapy, as first-line standard of care for recurrent or metastatic head and neck squamous cell carcinoma, particularly in PD-L1-positive tumors. Long-term follow-up confirmed durable survival benefit. CheckMate 141 established nivolumab as effective treatment for platinum-refractory disease with improved survival and lower toxicity.
Toward precision oral medicine
Multi-omics integration is increasingly recognized as essential for moving beyond descriptive profiling. Califf et al. applied a meta-omics workflow combining 16S rRNA sequencing, shotgun metagenomics, and tandem mass spectrometry to subgingival and supragingival biofilms, finding that metabolite diversity significantly correlated with maximum pocket depth (rho = 0.21, P = 0.008), and that patients who did not improve showed greater taxonomic instability than responders (UniFrac distance: t = −3.59, P = 0.002).
AI-driven approaches are also advancing the field. Feher et al. used a Random Forest model integrating demographic, clinical, microbiological, and treatment-related data from 414 patients to predict individual periodontal treatment responses at one year, achieving an internal AUROC of 0.93 and an external AUROC of 0.76 in an independent cohort of 78 patients.
The review emphasizes that oral diseases should be understood as context-dependent failures of the integrated host-microbiome-immune system, and that effective treatment must restore ecological balance and recalibrate host responses rather than simply reduce pathogenic burden.