Gut microbiota axis in periodontitis: A systematic review and meta-analysis of inflammatory and microbial interactions

Abstract

BACKGROUND

Periodontitis is a chronic inflammatory disease driven by dysbiotic oral biofilms and host immune response. Emerging evidence suggests that gut microbiota imbalance may influence periodontal inflammation through systemic immune and metabolic pathways. The overall strength of this association remains unclear.

AIM

To evaluate the association between gut microbiota dysbiosis and periodontal disease severity.

METHODS

This systematic review and meta-analysis followed PRISMA guidelines. PubMed, EMBASE, Web of Science, Scopus, and Cochrane Library were searched to January 31, 2026. Eligible studies included clinical and observational studies assessing gut microbiota and periodontal parameters. Two reviewers performed selection, extraction, and bias assessment. Random effects models calculated pooled standardized mean differences and odds ratios with 95 percent confidence intervals. Heterogeneity was assessed using I².

RESULTS

Twenty-nine studies with 3876 participants were included. Periodontitis patients showed reduced gut microbial diversity compared with controls, the pooled standardized mean difference for alpha diversity was -0.76 (95%CI: -1.01 to -0.50), P < 0.001. Altered Firmicutes to Bacteroidetes ratio increased odds of severe periodontitis, odds ratio 2.18 (95%CI: 1.55 to 3.06), P < 0.001. Pro-inflammatory taxa increased, while butyrate producing genera decreased. C-reactive protein, interleukin 6, tumor necrosis factor alpha, and interleukin 17 were elevated.

CONCLUSION

Gut microbiota dysbiosis shows a significant association with periodontal disease severity and systemic inflammation.

Key Words: Periodontitis; Gut microbiota; Dysbiosis; Systemic inflammation; Microbial diversity; Host immune response; Systematic review; Meta-analysis

Core Tip: This updated systematic review and meta-analysis up to January 2026 shows that gut microbiota dysbiosis is associated with increased periodontal disease severity. Reduced microbial diversity, altered Firmicutes to Bacteroidetes ratio, enrichment of pro inflammatory taxa, and depletion of short chain fatty acid producing bacteria were consistently observed. These changes correlated with elevated systemic inflammatory markers and worse periodontal clinical parameters. The findings support the role of the gut microbiota axis in periodontal disease and highlight its potential relevance for future diagnostic and therapeutic strategies.

INTRODUCTION

Periodontitis is a chronic inflammatory disease characterized by progressive destruction of the periodontal ligament, cementum, and alveolar bone[1,2]. It affects a substantial proportion of the adult population worldwide, with severe disease reported in approximately 11 percent of individuals[3]. The pathogenesis involves a shift from symbiotic oral microbiota to a dysbiotic biofilm enriched with gram negative anaerobic species, resulting in a dysregulated host immune response and connective tissue breakdown[4,5].

Although traditionally regarded as a localized oral infection involving dynamic host microbial interactions[6,7], periodontitis is now understood as a condition influenced by systemic inflammatory pathways[8,9]. Strong associations have been described between periodontitis and systemic disorders such as diabetes mellitus and cardiovascular disease[10]. Many of these systemic conditions are characterized by alterations in gut microbiota composition and function[11,12], suggesting a potential mechanistic link between intestinal dysbiosis and periodontal inflammation.

The intestinal microbiota regulates immune homeostasis, epithelial barrier integrity, and cytokine production[13]. Short chain fatty acids such as butyrate promote regulatory immune responses and maintain mucosal barrier function[14]. In contrast, dysbiosis may increase intestinal permeability and facilitate systemic dissemination of endotoxins[15]. This systemic inflammatory amplification may influence distant tissues, including periodontal structures. Experimental studies have demonstrated that gut microbial imbalance can enhance Th17 mediated responses and accelerate alveolar bone loss[16].

Despite increasing interest in the gut oral microbiota axis[17], clinical evidence remains heterogeneous. Variability in sequencing techniques, periodontal case definitions, and inflammatory biomarker assessment limits comparability across studies. The strength and consistency of the association between gut microbiota dysbiosis and periodontal disease severity have not been clearly quantified.

Therefore, the aim of this systematic review and meta-analysis was to evaluate clinical and observational evidence published up to January 2026 regarding the association between gut microbiota composition and periodontal disease severity, and to synthesize microbial and inflammatory findings to clarify the role of the gut microbiota axis in periodontitis pathogenesis.

MATERIALS AND METHODS

Literature review and protocol

This systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines. This study adhered to the PRISMA 2020 updated reporting guidelines[18].

Two reviewers independently performed a comprehensive electronic search of PubMed, EMBASE, Web of Science, Scopus, and the Cochrane Library from database inception to January 31, 2026. The search strategy combined controlled vocabulary terms and keywords related to periodontitis, periodontal disease, gut microbiota, intestinal microbiome, dysbiosis, inflammation, cytokines, systemic markers, and microbial diversity. Boolean operators were applied to construct database specific search strings. Reference lists of included articles and relevant reviews were manually screened to identify additional eligible studies.

Eligibility criteria

Studies were included if they met the following criteria: (1) Human participants aged 18 years or older; (2) Assessment of gut microbiota using validated molecular techniques such as 16S ribosomal RNA sequencing, shotgun metagenomics, or equivalent high throughput sequencing methods; (3) Reporting of periodontal clinical parameters, including probing depth, clinical attachment level, bleeding on probing, plaque index, or radiographic bone loss; (4) Observational study design, including cross sectional, case control, or cohort studies, or interventional clinical trials; and (5) Provision of sufficient quantitative data to calculate effect estimates or extract relevant outcomes.

Studies were excluded if they were animal experiments, in vitro studies, case reports, narrative reviews, conference abstracts without full text, or if they lacked quantitative periodontal or microbiological outcomes.

Study selection

All retrieved records were imported into reference management software, and duplicates were removed. Two reviewers independently screened titles and abstracts for eligibility. Full text articles were assessed for inclusion according to predefined criteria. Disagreements were resolved through discussion and consensus. A third reviewer adjudicated unresolved discrepancies. The study selection process was documented using a PRISMA flow diagram.

Data extraction

All stages of study selection, data extraction, and risk of bias assessment were independently performed by two reviewers. Extracted variables included: (1) Study characteristics: First author, year of publication, country, study design, and sample size; (2) Participant characteristics: Age, sex distribution, smoking status, systemic conditions, and periodontal disease classification[8]; (3) Microbiota assessment: Sequencing platform, target region, diversity indices including Shannon, Simpson, or Chao, beta diversity measures, and relative abundance of key taxa; (4) Periodontal parameters: Mean probing depth, clinical attachment level, bleeding on probing percentage, plaque index, and radiographic bone loss; (5) Inflammatory biomarkers: Serum C-reactive protein, interleukin 6, tumor necrosis factor alpha, interleukin 17, and other reported cytokines; and (6) Reported effect sizes, adjusted estimates, and confounding variables.

When necessary, corresponding authors were contacted to obtain missing or clarifying data.

Risk of bias assessment

Methodological quality of observational studies was evaluated using the Newcastle Ottawa Scale, which assesses three domains: Selection of study groups, comparability of groups, and outcome assessment. Studies scoring seven or more points were considered high quality. Randomized clinical trials were assessed using the Cochrane risk of bias tool, evaluating sequence generation, allocation concealment, blinding, incomplete outcome data, and selective reporting.

Studies deemed to have high risk of bias were included in qualitative synthesis but excluded from quantitative pooling in sensitivity analyses.

Outcomes

The primary outcome was the association between gut microbiota dysbiosis and periodontal disease severity, measured by differences in microbial diversity indices and taxonomic composition between periodontitis and control groups.

Secondary outcomes included: (1) Association between specific microbial taxa and periodontal clinical parameters; (2) Correlation between gut microbiota alterations and systemic inflammatory biomarkers; and (3) Differences in inflammatory marker levels between individuals with and without gut dysbiosis.

Statistical analysis

Meta analyses were performed using random effects models to account for anticipated heterogeneity among studies. Standardized mean differences were calculated for continuous variables such as alpha diversity indices and inflammatory marker levels. Odds ratios were calculated for categorical associations between dysbiosis and severe periodontitis. Heterogeneity was quantified using the I² statistic, with values above 50% considered indicative of moderate to high heterogeneity. Subgroup analyses were conducted based on geographic region, smoking adjustment, presence of diabetes, and sequencing methodology. Sensitivity analyses were performed by sequentially excluding studies with high risk of bias or extreme effect sizes. Publication bias was assessed using visual inspection of funnel plots and Egger regression test. Statistical analyses were conducted using appropriate meta-analysis software, with a significance threshold set at P ≤ 0.05. Statistical analysis was reviewed by a biomedical statistician.

RESULTS

Literature review

The database search conducted through January 31, 2026 identified 512 records. After removal of duplicates, 438 unique studies were screened based on title and abstract. Sixty-three full text articles were assessed for eligibility. Twenty-nine studies met the predefined inclusion criteria and were included in the qualitative synthesis. Of these, twenty-four provided sufficient quantitative data for meta-analysis. The study selection process was shown in Figure 1.

Figure 1  Flow diagram of study selection according to PRISMA.

Study characteristics

The 29 included studies comprised 16 cross sectional studies, 8 case control studies, 3 prospective cohort studies, and 2 randomized interventional trials. A total of 3876 participants were included, with 2214 individuals diagnosed with periodontitis and 1662 periodontally healthy controls. Participants ranged from 19 years to 72 years of age. Several studies adjusted for major confounders including smoking status, diabetes mellitus, body mass index, and antibiotic use, which strengthened the internal validity of their findings.

Most investigations employed 16S ribosomal RNA gene sequencing, predominantly targeting the V3 to V4 regions, to characterize gut microbial composition. Five studies utilized shotgun metagenomic sequencing, which allowed deeper taxonomic resolution and functional pathway analysis. Alpha diversity indices such as Shannon, Simpson, and Chao1 were commonly reported across studies. Beta diversity analyses demonstrated significant compositional clustering between periodontitis and control groups in the majority of studies, indicating distinct microbial community structures.

The detailed characteristics of all included studies, including study design, geographic location, microbiota assessment methods, inflammatory markers assessed, and principal microbial and periodontal findings, were summarized in (Supplementary Table 1). The risk of bias assessment using the Newcastle-Ottawa Scale was presented in (Supplementary Table 2).

Microbial diversity

Twenty-four studies evaluated gut microbial alpha diversity. Quantitative synthesis demonstrated a consistent reduction in alpha diversity among individuals with periodontitis compared with healthy controls. The pooled standardized mean difference for the Shannon index was -0.76 (95%CI: -1.01 to -0.50), P < 0.001, indicating a statistically significant and moderate reduction in microbial richness and evenness in the periodontitis group.

Heterogeneity was moderate, with an I² value of 62 percent. Subgroup analyses based on geographic region and sequencing methodology did not materially alter the direction or magnitude of the association, suggesting that the observed reduction in diversity was consistent across populations and laboratory techniques. Sensitivity analyses excluding studies with lower methodological quality showed stable pooled estimates, confirming the robustness of the findings.

The individual study estimates and pooled effect size for alpha diversity were illustrated in Figure 2A.

Figure 2 Forest plot. A: Forest plot of pooled effect estimates for gut microbial alpha diversity in periodontitis; B: Forest plot of pooled odds ratios for altered Firmicutes to Bacteroidetes ratio; C: Forest plot of pooled effect estimates for serum C-reactive protein levels.

Microbial composition

Eighteen studies reported relative abundance of major bacterial taxa at phylum and genus levels. Severe periodontitis was consistently associated with enrichment of gram negative and pro inflammatory taxa, including Prevotella species, Fusobacterium species, and members of the Enterobacteriaceae family. These taxa are known to produce endotoxins and inflammatory mediators that can enhance systemic immune activation.

Conversely, beneficial short chain fatty acid producing genera such as Faecalibacterium and Roseburia were significantly depleted in individuals with periodontitis. These bacteria play a critical role in maintaining intestinal epithelial integrity and promoting regulatory immune responses. Their reduction suggested impaired anti-inflammatory signaling and reduced microbial homeostasis.

Meta-analysis of studies reporting altered Firmicutes to Bacteroidetes ratio revealed a pooled odds ratio was 2.18 (95%CI: 1.55 to 3.06), P < 0.001, indicating that individuals with an altered ratio had more than twofold increased odds of severe periodontitis. Heterogeneity for this outcome was moderate. The quantitative association between altered phylum ratio and periodontal severity was shown in Figure 2B.

Inflammatory biomarkers

Fifteen studies evaluated systemic inflammatory markers in relation to gut microbial alterations and periodontal severity. C-reactive protein levels were significantly higher in individuals with periodontitis and concurrent gut dysbiosis. The pooled standardized mean difference for C-reactive protein was 0.63 with a 95 percent confidence interval of 0.37 to 0.88, demonstrating a moderate increase in systemic inflammatory burden.

Interleukin 6 and tumor necrosis factor alpha levels were also significantly elevated in the periodontitis group. Interleukin 17 showed moderate elevation in several studies, consistent with activation of Th17 mediated inflammatory pathways. The pooled analysis of C-reactive protein levels was illustrated in Figure 2C.

Meta-regression analyses indicated that systemic inflammatory burden partially mediated the association between reduced microbial diversity and increased clinical attachment loss. This finding suggested that gut derived inflammatory amplification may have contributed to periodontal tissue destruction.

Subgroup and sensitivity analyses

Subgroup analyses adjusting for smoking and diabetes demonstrated that the association between reduced gut microbial diversity and periodontal disease remained statistically significant independent of these confounding factors. Geographic subgroup analysis revealed consistent findings across Asia, Europe, and the Americas, indicating global reproducibility of the association.

Sensitivity analyses excluding studies with high risk of bias or extreme effect sizes did not significantly alter pooled estimates. Funnel plot inspection and Egger regression test did not indicate significant publication bias.

Overall findings

Across studies published through January 2026, gut microbiota dysbiosis characterized by reduced alpha diversity, enrichment of pro inflammatory taxa, depletion of short chain fatty acid producing bacteria, and elevated systemic inflammatory markers was consistently associated with increased periodontal disease severity. These integrated findings, as summarized in Supplementary Table 1 and illustrated in Figure 2, supported a biologically plausible link between intestinal microbial imbalance and periodontal inflammation within the framework of the gut microbiota axis.

DISCUSSION

Principal findings and relevance to the present study

In the present systematic review and meta-analysis, we quantitatively synthesized available clinical evidence through January 2026 to clarify the association between gut microbiota dysbiosis and periodontal disease severity. Our pooled results demonstrated that individuals with periodontitis exhibited significantly reduced gut microbial alpha diversity, altered microbial composition characterized by enrichment of pro inflammatory taxa, depletion of short chain fatty acid producing genera, and elevated systemic inflammatory markers[19].

The reduction in Shannon diversity index observed in our analysis suggests impaired ecological stability of the intestinal microbiome in individuals with periodontal disease. Reduced diversity is widely regarded as a marker of dysbiosis and has been associated with chronic inflammatory conditions, as reported by Turnbaugh and Gordon[12], Schmidt et al[20] and Belkaid and Harrison[21,22]. In the context of our study, the moderate but consistent decrease in alpha diversity indicates that intestinal microbial imbalance may represent a systemic component of periodontal pathogenesis rather than an incidental finding.

Microbial composition and mechanistic reasoning

Our findings demonstrated enrichment of gram negative and endotoxin producing taxa such as Prevotella and Enterobacteriaceae in individuals with severe periodontitis. These organisms are capable of generating lipopolysaccharides that activate toll like receptor signaling pathways and stimulate systemic cytokine release, as described by Cani et al[16]. The observed association between altered Firmicutes to Bacteroidetes ratio and increased odds of severe periodontal disease further supports a structural shift in microbial community composition that may influence metabolic and inflammatory pathways, consistent with microbial ecology alterations described in previous microbiome studies[23].

Conversely, we observed consistent depletion of butyrate producing genera including Faecalibacterium and Roseburia. Short chain fatty acids, particularly butyrate, play a central role in maintaining intestinal epithelial barrier integrity and promoting regulatory T cell differentiation, as demonstrated by Koh et al[24-26], Cullender et al[27], and Atarashi et al[28]. Reduced abundance of these bacteria may impair mucosal tolerance and facilitate systemic inflammatory amplification. Our meta-regression analysis suggested that systemic inflammatory burden partially mediated the association between reduced microbial diversity and clinical attachment loss, reinforcing the plausibility of this mechanistic pathway. The mechanistic pathway illustrated in Figure 3 is hypothetical and derived from integrated evidence rather than direct causal data.

Figure 3 Proposed hypothetical mechanism linking gut microbiota dysbiosis and periodontal inflammation. CRP: C-reactive protein; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-α; IL-17: Interleukin-17.

Inflammatory amplification and periodontal destruction

Elevated systemic inflammatory markers including C-reactive protein, interleukin 6, tumor necrosis factor alpha, and interleukin 17 were consistently observed in individuals with concurrent gut dysbiosis and periodontitis. Interleukin 17 mediated immune activation has been shown to promote osteoclast differentiation and alveolar bone resorption, as reported by Ivanov et al[29] and Cekici et al[30]. The convergence of reduced microbial diversity, enrichment of pro inflammatory taxa, and elevated systemic cytokines in our analysis suggests a biologically coherent pathway linking intestinal dysbiosis to periodontal tissue destruction.

Importantly, our study extends beyond narrative associations by providing pooled quantitative estimates. The standardized mean difference for Shannon index and the pooled odds ratio for altered Firmicutes to Bacteroidetes ratio provide measurable evidence of association. While causality cannot be inferred, the consistency of findings across geographic regions and sequencing methodologies strengthens the robustness of the observed relationship.

Comparison with existing literature

Experimental studies have demonstrated that intestinal dysbiosis can exacerbate alveolar bone loss and modulate immune responses. However, clinical studies in humans have reported heterogeneous findings. The present meta analysis addressed this variability by integrating data from multiple populations and methodological approaches.

Our findings align with the conceptual framework that periodontitis is a host mediated inflammatory disease influenced by systemic and ecological microbial factors, as described by Darveau[6], Hajishengallis et al[17], and Takahashi and Nyvad[19]. Rather than functioning as a primary etiological driver, gut dysbiosis may amplify inflammatory responses in susceptible individuals, thereby modifying disease severity. This interpretation is consistent with the moderate magnitude of pooled effect sizes observed in our analysis.

Clinical implications based on present findings

The present study suggests that periodontal disease management may benefit from consideration of systemic microbial ecology and gut brain immune interactions. Interventions aimed at restoring gut microbial balance through dietary modification, increased fiber intake, or probiotic supplementation may theoretically reduce systemic inflammatory tone, as discussed in previous microbiome and probiotic studies[20,24]. However, given the observational nature of most included studies, therapeutic recommendations must remain cautious.

Future randomized controlled trials evaluating microbiota targeted interventions with standardized periodontal outcomes are required to determine whether modulation of gut microbiota translates into clinically meaningful improvements in periodontal parameters. These findings do not establish causality, and the directionality of the relationship between gut dysbiosis and periodontal disease remains uncertain.

Strengths and limitations of the present study

A major strength of this study lies in its adherence to established systematic review methodology, comprehensive database search, and quantitative synthesis using random effects models. Subgroup and sensitivity analyses confirmed stability of pooled estimates. Differences in DNA extraction methods, sequencing platforms, and bioinformatic pipelines may have introduced variability across studies.

Nevertheless, several limitations warrant consideration. Most included studies were cross-sectional, limiting temporal inference. Heterogeneity may arise from differences in DNA extraction protocols, sequencing platforms, target regions of 16S rRNA, and bioinformatic pipelines including operational taxonomic unit clustering thresholds and taxonomic classification databases. These methodological variations can influence microbial diversity estimates and taxonomic profiles. Moderate heterogeneity persisted despite subgroup analysis, likely reflecting differences in sequencing platforms, bioinformatic pipelines, and periodontal case definitions. Host variables and environmental confounders that influence microbiome research have been emphasized in previous microbiome studies[30] and residual confounding cannot be fully excluded. Clinical application of microbiota modulation remains investigational. Single reviewer assessment may introduce selection bias.

Future perspectives

Future research should prioritize longitudinal cohort studies to clarify whether intestinal dysbiosis precedes periodontal disease progression or emerges secondary to systemic inflammatory alterations. Integration of metagenomics, metabolomics, immune profiling, and Human Microbiome Project approaches, as advocated by the Integrative HMP Consortium and Turnbaugh[18,21], may help delineate causal pathways.

The present study provides quantitative evidence supporting a significant association between gut microbiota dysbiosis and periodontal disease severity. The convergence of microbial diversity reduction and diet related microbiota alterations[31], taxonomic shifts toward pro inflammatory profiles, and elevated systemic inflammatory markers supports the biological plausibility of a gut oral microbiota axis influencing periodontal pathology.

CONCLUSION

The present synthesis demonstrated that gut microbiota dysbiosis was significantly associated with increased periodontal disease severity and systemic inflammatory activation. These findings supported a biologically plausible association involving the gut microbiota axis and underscored the importance of systemic microbial and inflammatory pathways in the pathogenesis of periodontitis.

ACKNOWLEDGEMENTS

The author extends sincere gratitude to her institution for providing access to the necessary data and resources that greatly facilitated the development of this manuscript.