As far as we know, this study is the first to examine the association between dental caries and liver conditions using both bidirectional analyses of the NHANES data and large-scale genetic data. Evidence from observational studies in the U.S. population suggests that UDC is significantly associated with an elevated occurrence of NAFLD, and inversely, NAFLD with a higher potential for UDC in American population. However, MR analyses showed a similar tendency but no significant causal relationship in the observed European population. In addition, we added to the investigation between dental caries and liver conditions including fibrosis, cirrhosis and fibrosis/cirrhosis which remained unexplored before. Despite the significant positive associationof UDC on LSM, a credible figure indicating liver condition severity, MR analyses only displayed a similar tendency without significant results. The robustness of evidence for every causation have all been verified by the sensitivity analyses.
Consumption of highly processed products could lead to increased intake of sucrose, a nutrient demonstrated to mediate the formation and adhesion of cariogenic S. mutans biofilms.(31–33) Dental caries let oral bacteria go inside the bloodstream and spread immune responses and inflammation to organisms all over the body, leading to systematic diseases.(34, 35) An MR analysis conducted in 2023 found various modifiable risk factors genetically associated with NAFLD including alcohol frequency, serum parameters like GGT and AST, and health conditions like fat mass of limbs and trunk and type 2 diabetes.(36) On the other hand, metabolic syndrome including insulin resistance, hyperglycemia and dyslipidemia were found associated with carious teeth.(37) Based on a population-based RPS Cohort, reaearchers found that The Insulin Resistance Phenotype (defined with blood lipid indicators) were associated with the Chronic Oral Disease Burden (latent variable including caries).(38) However, there have been only a few evidence of the causation between dental caries and liver conditions till now. Using data from NHANES, 1988 to 1994, a previous study discussed the connection between NAFLD and several oral disorders including dental caries, in which NAFLD was defined using ultrasonography, Fibrosis Score, Fatty Liver Index, and US Fatty Liver Index. NAFLD was indicated to associate with UDC, but had no significant relevance with overall caries experience.(20) According to our observational analysis using data from NHANES 2017–2020, UDC was found to be relevant with the potential of NAFLD and also liver fibrosis, and the quantified imaging data of liver condition newly-available further added to persuasiveness. On the other side, few studies highlighted the effect of liver conditions on oral disease. Though liver transplantation (LTx), the treatment of end-stage liver conditions was found relevant with increased risk for dental caries in both pre-LTx and post-LTx populations, patients at the pre-LTx stage showed no significant increase in the total amount of UDC.(39) Together with the increasing knowledge of microbiota emerged the therory of oral-gut-liver axis. Its unbalance is speculated to trigger liver inflammation and dysregulated immune response, though most evidence is based on periodontal diseases. A large number of oral microorganisms including Streptococcus were found in the intestinal microbiome in patients with liver cirrhosis,(40) which could participate in metabolic dysregulated mechanism of NAFLD through the oral-gut-liver axis.(41, 42)
As multifactorial diseases, dental caries result from interactions between oral bacteria, fermentable carbohydrates, host factors and time, and they may share something common with liver conditions in terms of pathogenesis, or have an intermediate mechanism. In terms of the relationship to oral-gut-liver axis, gut bacteria can have mutual effects with oral bacteria including the cariogenic S. mutans, therefore aggravating NAFLD and liver fibrosis through systematic and hepatic inflammation response together with elevation of disease susceptibility, but the specific pathways remain unclear.(43, 44) Tan et al. have recently explored the effect of type 1 diabetes and glycemic traits on increasing the risk of dental caries, and the combined GWAS meta-analysis dataset of dental caries was adapted as replication cohort.(45) Aberg et al. have reviewed the bidirectional associations between oral hygiene and liver disorders in 2022,(46) despite the focus mainly on periodontitis. T cell-mediated immunity downregulation after long-period usage of immunosuppressive regimen could contribute to the development of caries, but specific to the process of transplantation therapy instead of the progress of liver condition.(19) Sjögren's syndrome is an immune-mediated disease common in people with chronic hepatobiliary diseases,(47, 48) in which saliva reduction followed by a decrease in salivary proteins and acid buffering capacity could lower the oral prevention of bacteria and carbohydrates. Actually, active caries patients were more related to xerostomia, lower salivary flow rate and worse oral and general health conditions.(49) However, research in 2022 found that primary Sjögren's Syndrome patients had even less frequent liver steatosis and fibrosis.(50) Unhealthy lifestyles like high-sugar and high-fat diets and circadian rhythm disruption can lead to metabolism disorders, obesity, NAFLD, and dental caries at the same time. The aforementioned could probably explain that despite positive observational findings being in line with previous studies, our MR analysis didn’t significantly support the causal association.
The study's advantages are the following: (1) We combined observational data from NHANES with bidirectional MR analyses in an attempt to find the causal or mutual relationship among the diseases. Due to the genetic information as instrumental variables, the sample size is quite appreciable. (2) We extracted data from NHANES 2017–2020, which is more adjacent than previous studies. Notably, LSM, the imaging standard to define liver conditions only second to the gold examination of liver biopsy, is newly collected and applied in our study, providing a more objective and quantitative perspective for the assessment of liver damage in a large population than common ultrasound results. (3) We brought SF and AF into an investigation with dental caries for the first time, presenting a consecutive view of liver conditions and triggering further reflection on pathological development.
However, there are several limitations: (1) According to the protocol in NHANES 2017–2020, the assessment of dental caries only includes coronal caries, so data for the more comprehensive dental caries, such as root caries, is so far unavailable for analysis. (2) The MR study may have the problem of information bias due to different examinations for individuals with/without NAFLD and fibrosis. (3) NHANES data reflects the situation of Americans, while the GWAS and FinnGen data for MR were collected in Europeans, so the discordance of the population in observational and genetic data may lead to biased results and limited our findings extrapolated to other populations. Further studies applying data in the same population could be expected.