Association between periodontitis and non-alcoholic fatty liver disease in community-dwelling adults: a systematic review and meta-analysis

Abstract

Both non-alcoholic fatty liver disease (NAFLD) and periodontitis are prevalent chronic conditions. While prior research indicates a possible connection between these diseases, the conclusions in the existing literature are highly variable and the findings are inconsistent. Consequently, there is an urgent need for a comprehensive evaluation of this relationship. This study conducted a systematic search of the PubMed, Embase, Scopus, and Web of Science databases, encompassing research published up to June 25, 2025, to assess the association between NAFLD and periodontitis. The review incorporated cross-sectional, case-control, and cohort studies. A meta-analysis was performed utilizing a random effects model, with subgroup and sensitivity analyses conducted to investigate potential sources of heterogeneity. From 628 initially identified records, 11 studies (8 cross-sectional, 3 cohort) involving a total of 225,091 participants were included. The meta-analysis of cross-sectional studies demonstrated a significant positive association between periodontitis and NAFLD (OR:1.34, 95% CI:1.13,1.58), albeit with substantial heterogeneity (I² =68%). Subgroup analysis revealed that studies using clinical attachment loss (CAL) for periodontitis diagnosis showed a stronger and more robust association (OR: 1.38, 95% CI: 1.19, 1.60) with low heterogeneity (I² = 25%), unlike those using probing depth. The limited cohort studies suggested a potential bidirectional relationship, but heterogeneity precluded quantitative synthesis, highlighting the need for more high-quality prospective studies. Current evidence confirms a significant association between periodontitis and NAFLD, which is strongest and most consistent when periodontitis is defined by CAL, a marker of cumulative tissue destruction. These findings underscore the importance of standardized, tissue-based periodontitis diagnosis in future research and suggest potential implications for interdisciplinary patient management between dental and hepatology practices.

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-026-42308-2.

Introduction

Periodontitis is a chronic inflammatory condition resulting from the dysregulation of the subgingival microbiota. It affects approximately 40–75% of the global adult population and is recognized as the sixth most prevalent disease among humans^1–3. The defining characteristic of this condition is the destruction of the dental supporting structures, encompassing the gums, periodontal ligament, and alveolar bone⁴. In addition to adversely affecting oral health, the dysregulation of the host’s immune inflammatory response, as mediated by periodontitis, results in the systemic release of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), as well as bacterial endotoxins like lipopolysaccharides (LPS)⁵. A growing body of evidence suggests a significant association between periodontitis and various systemic diseases, including cardiovascular diseases, diabetes, and respiratory diseases^6–8. Consequently, the consideration of periodontitis as a potential risk factor for overall health has garnered increasing scholarly attention.

Liver diseases are another major global health challenge, causing 44,000 deaths in the United States each year and 2 million deaths worldwide annually⁹. Chronic liver diseases are a group of diseases that affect the liver and cause its function to gradually decline over at least 6 months. The most common causes include chronic hepatitis B virus, hepatitis C virus, alcohol-related liver disease, and non-alcoholic fatty liver disease (NAFLD)⁹. The liver, as a front-line immune organ, is easily invaded by pathogenic substances from the intestine and circulating inflammatory factors through the portal vein system¹⁰. Compensatory hepatocyte proliferation and the gradual replacement of liver components by fibrous tissue are two pathological processes that can lead to end-stage liver diseases, including cirrhosis and hepatocellular carcinoma^11,12. Chronic liver diseases not only cause significant morbidity and mortality but also impose a huge economic burden on the healthcare system¹³. Therefore, understanding the risk factors of liver diseases and potential prevention strategies is crucial for reducing their public health impact. Globally, NAFLD is a common trigger for long-term liver diseases. According to statistics, the prevalence of NAFLD among adults worldwide is as high as 32%¹⁴. Histologically, NAFLD is defined as the presence of more than 5% of liver cells with fatty degeneration when other causes of chronic liver diseases (excessive alcohol consumption, viral, autoimmune hepatitis, etc.) are excluded. It covers a range of liver diseases, from simple fatty degeneration (non-alcoholic fatty liver) to non-alcoholic steatohepatitis¹⁵. It is reported that NAFLD is related to lifestyle, and the increase in the prevalence of obesity and type 2 diabetes further exacerbates the disease burden of NAFLD¹⁶.

As previously discussed, the oral microenvironment has the potential to influence the physiological state of other organs. Recent studies have increasingly elucidated a complex relationship between the oral cavity and the liver. Some researchers have introduced the concept of the oral-gut-liver axis to explain the potential connection between oral diseases, particularly periodontitis, and liver diseases^17,18. The liver is located in a unique anatomical position and thus has a dual blood supply. At present, two pathways have been proposed to explain the connection between periodontal disease and liver pathology, namely the systemic and intestinal dissemination of hepatotoxic components¹⁹. The first pathway, systemic dissemination via the bloodstream, involves the direct release of periodontal pathogens, endotoxins, and pro-inflammatory mediators into the circulatory system, thereby reaching the liver without an obligatory intestinal passage. This is due to the excessive permeability of the internal surface of pocket epithelium and the micro-ulcers in the periodontal inflamed tissues, as well as the inflammatory mediators and microorganisms that are caused by the inflammatory process and are transported through the circulatory system²⁰. For instance, in patients with periodontitis, the levels of reactive oxygen species and inflammatory cytokines in the serum increase, suggesting the presence of a mild chronic inflammatory condition throughout the body²¹. Another possible pathway connecting the mouth and the liver is that oral bacteria are transported through the gastrointestinal tract, resulting in abnormal intestinal microbiota²². Chronic inflammation and dysbiosis are common features that contribute to the clinical pathology of both periodontitis and NAFLD¹⁷. Despite progress in understanding the relevant mechanisms, the clinical epidemiological evidence remains fragmented, and the research findings are still contentious, lacking a unified conclusion. In light of this, the present study aims to conduct a meta-analysis of existing literature to systematically evaluate the association between periodontitis and NAFLD, thereby providing a scientific basis for their clinical treatment and early intervention.

Methods

Protocol and registration

Systematic reviews and meta-analyses were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, as well as the standards for meta-analysis of observational epidemiological studies. In instances where discrepancies arise between the two reviewers during the processes of study selection, data extraction, or methodological quality assessment, resolution was achieved through consensus or, if necessary, consultation with a third reviewer. The study protocol had been registered with PROSPERO database (CRD420251102841).

Database and retrieval strategy

We conducted a comprehensive literature search across multiple databases, including PubMed, Scopus, Embase, and the Web of Science, for studies published up to June 2025. Search was done using the following MeSH terms: (Periodontitis OR Periodontal Diseases) AND (Non-alcoholic Fatty Liver Disease OR NAFLD). Detailed search terms are provided in the appendix.

Eligibility criteria

Two independent authors conducted a review of the titles and/or abstracts to identify full-text articles potentially meeting the PECOS criteria (Participants comprised adult humans without hepatic comorbidities; Exposure required clinically verified periodontitis; Controls included matched periodontally healthy subjects; Outcomes necessitated objective NAFLD confirmation; Study designs encompassed observational or interventional approaches with adequate sample sizes). The inclusion criteria were as follows: (1) studies investigating the association between periodontitis and NAFLD; (2) studies that provide diagnostic criteria for NAFLD; (3) studies that clarify and report diagnostic criteria for periodontitis; and (4) studies that include or are suitable for calculating outcome indicators such as risk estimates (odds ratio [OR], relative risk [RR], or hazard ratio [HR]) or secondary outcome measurements like clinical attachment loss (CAL) or pocket probing depth (PPD); (5) studies published in English or studies written in other languages but accompanied by an English abstract or full-text translation were included. The exclusion criteria were: (1) inability to quantify outcome indicators; (2) unavailability of full-text articles; (3) documents such as systematic reviews, clinical case reports, letters, commentaries, abstracts, conference proceedings, meta-analyses, animal studies, and other similar publications; and (4) duplicate publications. We focused on community-dwelling adults aged ≥ 18 years with no known hepatic comorbidities (exclusion of viral hepatitis B/C, autoimmune liver disease, Wilson’s disease, alcoholic liver disease or previous liver surgery). Studies restricted to special sub-populations (pregnant women, dialysis patients, organ-transplant recipients or individuals with malignant tumors) were not considered.

Literature screening and data extraction

Initially, all studies retrieved from the relevant databases are imported into EndNote X9 software to remove duplicates. Prior to formal screening, the two independent reviewers (H.L. and M.S.) underwent a calibration process by jointly reviewing a pilot set of 30 studies. Inter-reviewer agreement was assessed using Cohen’s kappa statistic, which was 0.78 for both title/abstract screening and full-text assessment, indicating excellent agreement. Subsequently, an initial screening is performed based on the titles and abstracts. For articles necessitating further review, the full texts are examined, and those meeting the established criteria are selected. Finally, the fundamental characteristics of the qualifying studies are extracted, which include: (1) Research information: the first author’s name, publication date, geographical area, and study design; (2) Baseline data: sample size, gender, age, and diagnostic criteria for periodontitis; (3) Result data: OR/RR/HR and the corresponding 95% confidence interval (CI).

Evaluation of literature quality

The quality of the literature was assessed using the Newcastle-Ottawa Scale (NOS)²³ and the evaluation criteria recommended by the Agency for Healthcare Research and Quality (AHRQ)²⁴. The NOS appraises cohort studies based on three dimensions: the selection of exposed and unexposed cohorts, the comparability of these cohorts, and the outcomes. It employs a 9-point scale, categorizing studies as low-quality (0–4 points), medium-quality (5–6 points), and high-quality (> 7 points). In contrast, the AHRQ criteria for cross-sectional studies encompass 11 items, yielding a total score of 11 points. Studies are classified as low-quality (0–3 points), medium-quality (4–7 points), and high-quality (8–11 points) based on their scores.

Statistical analysis

The relationship between NAFLD and periodontitis was analyzed using RevMan software version 5.3 (Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). The OR/RR/HR values and their 95% CI were calculated as measures of the association between periodontitis and NAFLD. Heterogeneity tests were conducted on the data from the final included studies, and the I² statistic was used to analyze the heterogeneity. The heterogeneity of the studies was classified based on the I² value. The larger the I² value, the greater the heterogeneity. If I² was less than 50%, it indicated a lower heterogeneity and the fixed-effect model was applied. In contrast, if I² was greater than or equal to 50%, it indicated greater heterogeneity, and the random-effect model was applied. Further sensitivity analysis was conducted, and the publication bias test was evaluated by visual inspection of the funnel plot.

Results

Study selection

A systematic search of four databases (PubMed, Embase, WOS, and Scopus) initially identified 628 records. After the removal of 313 duplicates, 315 unique records underwent a systematic screening process. The titles and abstracts of these records were screened against the predefined eligibility criteria, leading to the exclusion of 291 records for not meeting the study objectives. Following this, the full texts of the remaining 24 articles were thoroughly assessed for eligibility, from which 11 studies (8 cross-sectional and 3 cohort) were ultimately included in the systematic review and meta-analysis. The complete selection process is outlined in the PRISMA flow diagram (Fig. 1).

Fig. 1.

Study flow chart.

Study characteristics

The general characteristics of the eight cross-sectional studies are presented in Table 1. Collectively, these studies encompassed a total of 225,091 adult participants, with individual study sample sizes ranging from 1,226 to 132,529. All studies included both male and female participants, aged between 18 and 74 years, thus encompassing a broad age spectrum. Geographically, these studies were conducted in the United States, South Korea, Japan, and Israel. The majority of the studies diagnosed periodontitis based on the degree and extent of clinical attachment loss. The other two studies used the probing depth as the diagnostic criterion^25,26.

Table 1.

Main characteristics of included studies.

Study	Country	Year	Sample (NAFLD/non-NAAFLD)	Age	Gender	Diagnosis of periodontitis	Diagnosis of NAFLD	Adjusted factors
Alazawi26	USA	2017	8172(2930/5242)	20-74	46.5% men	2 sites with PPD ≥3 mm from different sextants or 1 site with PPD≥5 mm in any sextant	the presence ofmild, moderate or severe steatosis in the absence ofserum hepatitis B surface antigen or hepatitis C antibody positivity, serum transferrin saturation>50%, pregnancy and elevated alcohol consumption (>2 drinks/day for women or >3 drinks/day for men)	sex, age groups, ethnicity, PIR, education, diet, smoking, diabetes, hypertension, cholesterol, BMI groups
Akinkugbe28	USA	2018	11,914	18-74	not mention	the extent (none, <30%, ≥30%) of periodontal sites with clinical attachment level (CAL) of ≥3 mm or probing pocket depth (PD) of ≥4 mm	having alanine aminotransferase (ALT) >40 IU/L or aspartate aminotransferase (AST) >37 IU/L for men and ALT >31 IU/L or AST >31 IU/L for women	abdominal obesity, smoking, diabetes, physical activity, education and acculturation score
Iwasaki5	Japan	2018	1226(339/887)	40-59	63.0% men	PPD≥4 mm	ultrasonography-diagnosed	gender, age, Brinkman index, regular exercise habits, body mass index, number of teeth present, blood pressure, and serum parameters
Weintraub27	USA	2019	5421(1030/4391)	21-74	47.9% men	≥2 teeth with loss of attachment ≥6 mm at interproximal sites and ≥1 teeth with pocket depth ≥5 mm at interproximal sites	USON examination	age, sex, education, race/ethnicity, and marital status
Kim32	Korea	2020	4272	>19	42.2% men	CPI(3 and 4)	FLI	age, sex, smoking, alcohol consumption, physical exercise, household income, and education level, tooth brushing frequency and periodic dental checkup
Shin31	Korea	2020	4061(413/3648)	>19	36.3% men	CPI(3 and 5)	FLI>60 and HSI>36	age, income level, education level, smoking status, alcohol consumption, physical activity, diabetes mellitus, obesity, hypertension, hypercholesterolemia
Ram30	Israel	2022	132,529(938/131591)	18-50	75.1% men	periodontitis was defined according to the American Academy of Periodontology guidelines	2015 ICD-9-CM Diagnosis Code 571.8	age, sex, locality of residence, socioeconomic status, smoking, diabetes type 2,BMI
Wilensky29	Israel	2023	57,496	18-51	73.9% men	periodontitis was defined according to the American Academy of Periodontology guidelines	2015 ICD-9-CM Diagnosis Code 571.9	age, sex, education, residency location, socioeconomic status, birth country, smoking, obesity

Evaluation of literature quality

This study conducted a quality assessment of the nine included cross-sectional studies utilizing the AHRQ scale (Table 2), while the three cohort studies were evaluated using the NOS scale (Table 3). The evaluation results summarized that the literature selected for this study demonstrated moderate to high quality. Overall, there was no significant difference in the quality of the included studies. There were no obvious biases in the selection of the study population and the measurement of the results. However, none of the multiple studies reported whether there were any missing data and the related handling. Cross-sectional studies generally did not describe the tracking and analysis situations, which may lead to doubts about the reliability of the results and make the source of heterogeneity unclear.

Table 2.

Agency for healthcare research and quality scores of cross-sectional studies.

Study	1	2	3	4	5	6	7	8	9	10	11	Total
Alazawi 2017	Y	Y	Y	Y	Y	U	Y	Y	Y	Y	U	9
Akinkugbe 2018	Y	Y	Y	Y	Y	U	N	Y	Y	Y	U	8
Iwasaki 2018	Y	Y	Y	Y	U	Y	Y	Y	N	Y	U	8
Weintraub 2019	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	U	10
Kim 2020	Y	Y	Y	Y	Y	Y	Y	Y	U	Y	U	9
Shin 2020	Y	Y	Y	Y	Y	Y	N	Y	Y	Y	U	9
Ram 2022	Y	Y	Y	Y	U	Y	N	U	U	Y	U	6
Wilensky 2023	Y	Y	Y	Y	Y	Y	Y	Y	U	Y	U	9

Notes: 1: Are the sources clear? 2: Are the inclusion and exclusion criteria for the two groups clear? 3: Is the time to identify patients clear? 4: Are the subjects continuous? 5: Is the evaluator isolated from other objective measures of the patient? 6: Has quality assurance been assessed? 7: Are excluded objects analyzed? 8: Are confounding factors assessed? 9: Is there any processing of the lost data? 10: Is the data complete? 11: Is there follow-up and analysis? Y: Yes; N: No; U: Unclear.

Table 3.

Quality assessment of cohort studies according to the modified NOS.

Study	Study population selection				Comparability between groups	Outcome measurement			Total
	1	2	3	4	5	6	7	8
Akinkugbe 2017	1	1	1	1	2	1	0	1	8
Shin 2022	1	1	1	1	2	1	1	1	9
Joo 2024	1	1	1	1	2	1	0	1	8

Notes: 1: Representativeness of the exposed group. 2: Selection of non-exposed groups. 3: Identification of exposure factors. 4: No outcome indicators were available before the study began. 5: Comparability of the resulting cohort based on design and analysis. 6: Methods of evaluating outcome events. 7: Whether the follow-up time was sufficient. 8: Integrity of follow-up.

Meta-analysis

In the cross-sectional study (n = 8), the presence of NAFLD was significantly associated with a higher prevalence of periodontitis (OR = 1.34; 95% CI:1.13,1.58), however, the estimated values showed moderate heterogeneity (I² = 68%, p < 0.001) (Fig. 2).

Fig. 2.

Meta-analysis forest plot of the correlation between periodontitis and NAFLD (cross-sectional study).

As previously discussed, the diagnostic criteria for periodontitis and NAFLD may present a fundamental contradiction. We performed a subgroup analysis to explore the impact of differing diagnostic criteria for these two conditions (Table 4). In the assessment of periodontitis, six studies utilized CAL as the diagnostic criterion, and two studies employed PPD. CAL is defined as the distance from the enamel-dental pulp junction to the base of the periodontal pocket, serving as a direct and critical measure of the irreversible loss of periodontal supporting tissues, including gingival connective tissue and alveolar bone. It is recognized as the most significant indicator of periodontal tissue destruction. In contrast, PPD is measured as the distance from the gingival margin to the base of the periodontal pocket. PPD can be influenced not only by the loss of connective tissue attachment (true periodontal pocket) but also by gingival inflammation and edema (false periodontal pocket). Consequently, CAL is regarded as a more reliable and objective parameter for diagnosing periodontitis, as it is not directly influenced by variations in the position of the gingival margin, whether due to recession or hyperplasia. Therefore, CAL is considered the gold standard for determining the presence and severity of periodontitis. In a subgroup analysis (n = 6) that utilized CAL as the diagnostic criterion for periodontitis, the strongest evidence of association was observed, yielding a combined odds ratio of 1.38, with heterogeneity reduced to 25%. The criteria for detecting NAFLD contribute to the observed heterogeneity among studies. Although liver biopsy is the gold standard for diagnosing NAFLD, ultrasound is more appropriate for large-scale, population-based research. The limited number of pertinent studies has led to considerable variation in the NAFLD detection criteria used across the included studies. However, the heterogeneity associated with diagnosing NAFLD using ICD-9-CM codes and ultrasound was minimal. In contrast, studies that relied on different biochemical markers, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), exhibited significantly greater heterogeneity. ALT and AST are non-specific indicators of hepatocellular injury and do not consistently elevate in cases of NAFLD, potentially introducing bias into the results.

Table 4.

Subgroup analysis based on NAFLD diagnostic criteria and periodontitis diagnostic criteria.

Diagnostic criteria	NAFLD diagnosis			Periodontitis diagnosis
	ICD-9-CM	ultrasonic testing	Other markers detection	CAL	PPD
n	2	2	4	6	2
I 2	0%	0%	63%	25%	81%
p	0.82	0.51	0.05	0.25	0.02
OR	1.46	1.67	1.18	1.38	1.36
95%CI	[1.21,1.75]	[1.23,2.23]	[0.95,1.46]	[1.19,1.60]	[0.79,2.32]

Due to the substantial methodological differences observed, a sensitivity analysis was performed subsequent to the primary analysis. Upon excluding the two studies^25,26 based on probe depth, the remaining six studies, which employed more consistent diagnostic criteria (primarily CAL), demonstrated that the association between periodontitis and NAFLD remained significantly robust and more stable (OR = 1.38, 95% CI:1.19, 1.60, I² = 25%) (Fig. 3).

Fig. 3.

Funnel plot of the correlation between periodontitis and NAFLD after excluding 3 studies based on probe depth and self-report criteria.

Moreover, research has indicated that gender influences the relationship between the two diseases. Consequently, we performed subgroup analyses based on the gender ratio differences among study participants (Table 5). The findings revealed that in studies where the proportion of male participants exceeded 50% (n = 3), the association between periodontitis and NAFLD was stronger and more consistent (OR = 1.51, 95% CI: 1.27, 1.79, I²=0%). In contrast, in studies where the proportion of male participants was less than 50% (n = 4), the association was weaker and exhibited greater heterogeneity (OR = 1.30, 95% CI: 1.00, 1.68, I²=71%).

Table 5.

Subgroup analysis based on gender ratio.

n	Men > 50%	Men < 50%
	3	4
I 2	0%	71%
p	0.59	0.01
OR	1.51	1.30
95%Cl	[1.27,1.79]	[1.00,1.68]

Among the three cohort studies analyzed in this article, two studies indicated that periodontitis is associated with an increased risk of NAFLD, with RR of 1.6 (95% CI: 1.05, 2.44)³³ and 1.04 (95% CI: 1.01, 1.07)³¹, respectively (Fig. 4). Another cohort study investigated the incidence of NAFLD as a consequence of chronic periodontitis development³⁴. Due to substantial heterogeneity in study design, definitions of exposure and outcome, and study populations (I² = 75%), a quantitative synthesis was not performed. While these studies suggest a potential association between periodontitis and NAFLD, the variability in study design, diagnostic criteria, and control for confounding factors limits the ability to make firm conclusions.

Fig. 4.

Forest plot of the cohort analysis.

Discussion

The present meta-analysis identifies a clinically significant association between periodontitis and non-alcoholic fatty liver disease (NAFLD), with periodontitis patients exhibiting a 34% increased risk of developing NAFLD (OR = 1.34, 95% CI: 1.13,1.58). While the cohort studies included in this review provide preliminary evidence suggesting a potential association, the findings remain inconclusive due to methodological limitations, such as heterogeneity in study design and insufficient control for key confounders. Previous meta-analyses have reported similar associations. Wijarnpreecha et al. combined five studies (≈ 27,700 subjects) and found a pooled OR = 1.48 for periodontitis in NAFLD patients (though adjusted estimates were not significant)³⁵. Aguiar et al. reported roughly a two - fold increased odds of periodontitis among NAFLD patients (OR = 1.91)³⁶. However, our review incorporates more recent and larger-scale studies, with a total of 225,091 participants, and focuses on adjusted odds ratios, providing a more precise estimate of the association. Furthermore, our review includes both cross-sectional and cohort data, as well as detailed subgroup analyses, thereby offering novel insights into the potential relationship between periodontitis and NAFLD. These unique contributions enhance the understanding of this association, although more homogeneous prospective studies are necessary to further investigate these findings and clarify the underlying mechanisms.

Periodontitis acts as a persistent source of low-grade systemic inflammation, characterized by sustained release of pro-inflammatory cytokines (IL-6, TNF-α) and bacterial endotoxins (e.g., Porphyromonas gingivalis lipopolysaccharide, Pg-LPS) into the bloodstream^37,38. These mediators may fuel NAFLD progression by dual hepatic insults: (i) induction of insulin resistance that augments de novo lipogenesis³⁹, and (ii) activation of Kupffer cells that amplify lobular inflammation and transition from steatosis to steatohepatitis⁴⁰. The subgroup analysis provides critical validation for this paradigm—studies utilizing CAL, a surrogate for cumulative periodontal tissue destruction, demonstrated a stronger association (OR = 1.38, 95% CI: 1.20, 1.58) with lower heterogeneity, compared to studies using probing depth. This divergence underscores that irreversible periodontal damage, rather than transient gingival inflammation, may be a key contributor to this association.

Emerging evidence implicates oral pathobionts in directly modulating hepatic pathophysiology. Porphyromonas gingivalis (Pg), a keystone periodontal pathogen, contributes to NAFLD through multisystemic crosstalk⁴¹. Experimental models reveal that Pg compromises intestinal barrier integrity, enabling translocation of live bacteria and endotoxins into the portal circulation. Subsequent engagement of Toll-like receptors-4 (TLR4) on hepatocytes triggers NF-κB signaling that exacerbates hepatic inflammation and lipotoxicity⁴². Beyond translocation, Pg-derived outer membrane vesicles systemically dysregulate lipid metabolism by upregulating stearoyl-CoA desaturase (SCD-1) while suppressing AMP-activated protein kinase (AMPK) activity^43,44. Furthermore, recent data suggest that Pg-induced Th17/Treg imbalance promotes hepatocyte ferroptosis—an iron-dependent cell death pathway implicated in NASH progression⁴⁵. Intriguingly, NAFLD reciprocally perturbs the oral microbiome through altered lipid metabolism and bile acid circulation, creating a self-perpetuating vicious cycle⁴⁶.

The significant heterogeneity observed across the included studies (I²=67%) can largely be attributed to inconsistencies in the methods used to ascertain periodontitis. Studies that employed CAL as the diagnostic criterion—which objectively quantifies the destruction of periodontal connective tissue—produced consistent and reliable risk estimates. In contrast, studies that utilized surrogate measures, such as PPD or self-reported data, generally yielded non-significant associations and exhibited higher levels of heterogeneity. This discrepancy underscores the importance of diagnostic precision in determining the validity of epidemiological findings. It is important to note that CAL alone is not sufficient for diagnosing periodontitis comprehensively. Current guidelines emphasize that CAL should be correlated with PPD, bleeding on probing (BOP), and radiographic bone loss to distinguish between active and stabilized disease states⁴. For instance, patients with stabilized periodontitis may exhibit CAL due to gingival recession without active inflammation or bacterial load, which might not contribute to systemic inflammation⁴⁷. Therefore, future studies should adopt multidimensional diagnostic criteria to accurately capture the periodontitis burden relevant to systemic outcomes like NAFLD.

Furthermore, several studies included in this meta-analysis did not consistently adjust for important lifestyle confounders, such as smoking, alcohol consumption, and physical activity—factors known to influence the risk of both NAFLD and periodontitis⁴⁸. Specifically, only six of the eleven studies controlled for smoking, three adjusted for alcohol consumption, and two accounted for physical activity or dietary patterns. This variability in controlling for key confounders may have introduced residual bias, further contributing to the observed heterogeneity and potentially limiting the accuracy of the reported associations.

The findings of this meta-analysis must be interpreted in the context of its limitations. The primary constraint is the cross-sectional design of most included studies, which prevents causal inference between periodontitis and NAFLD despite the large pooled sample size. Furthermore, the considerable heterogeneity, stemming mainly from variations in the diagnostic criteria for periodontitis, poses a challenge to the interpretation of the pooled estimate. Lastly, the relatively small number of available cohort studies and potential residual confounding highlight the need for more rigorous prospective investigations to verify and extend our findings.

Conclusion

Implications for Clinical Practice

Robust evidence confirms a significant association between periodontitis and NAFLD. Clinicians should recognize this potential association: periodontal patients (especially with CAL-confirmed disease) may be at higher risk for NAFLD, and NAFLD patients should be assessed for periodontitis. It is important to note that while CAL is an objective marker of periodontal tissue destruction, it should not be used in isolation for diagnosis. According to the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions, the diagnosis of periodontitis requires the integration of CAL with other clinical parameters such as probing depth, bleeding on probing, and radiographic bone loss. Promoting oral hygiene and interdisciplinary collaboration between dental and liver health providers is warranted as part of comprehensive patient care.

Implications for Research

Future studies must prioritize standardized and multidimensional diagnostic criteria to reduce heterogeneity. For periodontitis, this includes the use of CAL as a key objective measure of tissue destruction, but it should be correlated with other parameters (e.g., probing depth, bleeding on probing) to accurately capture disease activity and burden. For NAFLD, well-validated methods such as ultrasound or standardized codes (e.g., ICD-9-CM) are recommended. High-quality prospective cohorts with rigorous confounder adjustment are essential to establish causality and directionality. Mechanistic research and trials evaluating periodontal therapy’s impact on NAFLD progression are needed.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

H.L., M.S. and Y.L. contributed to the conception and design of the review and critically revised the manuscript drafts until the final version was approved. R.Y. performed the database searches. H.L. and M.S. conducted assessment of eligibility, data extraction, analysis and interpretation. H.W. and Y.L. contributed to the study through supervision, validation of the methodology and key findings, and acquisition of funding. All authors have made substantive contributions to the article and assume full responsibility for its content. All authors have seen and approved the final version of the manuscript.

Funding

This project was supported by the Gansu Province Joint Research Fund (24JRRA949).

Data availability

Data is provided within the manuscript or supplementary information files.

Declarations

Competing interests

The authors declare no competing interests.