Periodontitis is a chronic dental disease with a high risk of recurrence, in which the periodontal tissue is destroyed by bacteria accumulating in the teeth (1). Several risk factors such as poor oral health, hormonal changes, bacterial infection have been reported to be associated with the initiation and progression of periodontal disease (2). Periodontitis is mostly caused by gram-negative bacteria such as
Diabetes is accompanied by complications such as hypertension, cardiovascular disease, skin lesions, and obesity (7, 8). A multidirectional relationship between diabetes and periodontitis has been reported, with diabetes increasing the risk of periodontitis and periodontal inflammation negatively affecting control of blood glucose levels (9-11). Non-alcoholic fatty liver disease (NAFLD) is frequently observed in patients with T2D and is known to be associated with increased insulin resistance triggered by fatty acid accumulation, inflammation and reactive oxygen species production (12-14). Moreover, it has been reported in many studies that periodontitis contributes to the progression of NAFLD (15, 16).
It has been shown that hepatic CD36, which acts as a transcriptional regulator of PPARγ, is significantly upregulated in obese rats with periodontitis (17). Depletion of CD36 from hepatocytes attenuates fatty liver disease and ameliorates insulin sensitivity in obese mice (18). As another important fatty acid regulator, the fatty acid-binding protein 4 (FABP4) can induce systemic disease progression (19). FABP4 expression is increased in macrophages upon infection with
The link between periodontitis and T2D or fatty liver disease is associated with the production and expression of inflammatory factors including proinflammatory cytokines, chemokines, and metabolic regulators (22). The higher levels of tumor necrosis factor α (TNFα), interleukin (IL)-1β, and CRP induce insulin resistance by impairing insulin action (23, 24). A marked elevation of components of the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome at both the gene and protein levels have been reported in patients with periodontitis and T2D (25). Moreover, several inflammatory responses mediated by proinflammatory cytokines or inflammasome activation have been suggested to play an important role in the induction of hepatic inflammation in NASH (26, 27).
Since obesity is a major cause for chronic diseases including T2D and NAFLD (28), we used HFD-induced obese mice model. To investigate the correlation of periodontitis and T2D or fatty liver disease, HFD-fed mice were inoculated with
To investigate the correlation between periodontitis and liver malfunction, periodontitis was induced by
We next measured blood glucose using intraperitoneal glucose tolerance test (IPGTT) to investigate the bidirectional relationship between periodontitis and glucose homeostasis. After 6 hours of fasting, the blood glucose levels were measured. Fasting blood glucose was higher in all HFD-fed groups than in the NC group but was not altered by
Given that fatty liver disease can be exacerbated in association with periodontitis, we then analyzed lipid accumulation, inflammation and hepatocyte degeneration in liver tissues. Upon histological examination by hematoxylin and eosin (H&E) staining (Fig. 3A), the evaluation of steatosis, inflammation, and hepatocyte ballooning were conducted to calculate NASH score (Fig. 3B-E). Our results showed that livers of NC-p.g. group mice had minimal steatosis, and no signs of lobular inflammation and hepatocyte ballooning (NASH score 0-1). The total score of HFD-fed mice (NASH score 4-7) was significantly elevated compared to that in the NC group (Fig. 3B). The HFD-p.g. group (NASH score 5-9) exhibited significantly increased total score compared with HFD control group (NASH score 4-7). Overall, increased steatosis, lobular inflammation, and hepatocyte ballooning were displayed in the HFD groups (Fig. 3C-E). In the HFD groups infected with
We next assessed the expression level of several risk factors that play a crucial role in the progression of fatty liver disease. The mRNA expression levels of genes related to inflammation and lipid or glucose metabolism in liver were determined (Fig. 4A). We analyzed the expression of several metabolic regulators including Foxo1, PparγC1α, Cd36, and Fabp4 in the liver. Decreased Foxo1 expression was observed in the HFD and HFD-p.g. groups. Importantly, the expression level of PparγC1α, a key regu-lator of adipocyte differentiation and lipid metabolism, was significantly upregulated upon
Periodontitis is an inflammatory disease that leads to alveolar bone loss and further exerts various adverse impacts on systemic health. It is widely accepted that immune responses to peri-odontogenic pathogen play key roles in the progression of metabolic diseases (29). In the present study, we reported that
A previous study has experimentally demonstrated that
The upregulation of components of various inflammasomes in patients with periodontitis was reported by Bostanci
Despite the slight symptoms in alveolar bone loss and related inflammation, we here observed that the administration of
The limitation of our study is that the animal model we used here is not a perfect model for the study on the correlation between periodontitis and liver metabolism and that symptoms for both diseases are too mild. Therefore, further investigations using severe periodontitis model are required since damages in periodontal tissue and subsequent exacerbating effects of periodontitis on systemic disease are all cumulative. To this end, increased dosage of bacterial infection, shorter interval of bacterial inoculation, or combined treatment with molar ligation might be adopted for future study. In conclusion, our data revealed that the administration of
The detailed methods are described in the “Supplementary Materials and Methods”.
8-week-old C57Bl/6 wild-type (WT) mice were housed in specific pathogen-free controlled conditions on 12 h day light/dark cycle. Mice were randomly divided into five groups: negative control group (NC), negative control with
To assess hepatic morphology and scoring, liver samples are fixed in 10% neutral buffered formalin and stained with hematoxylin and eosin. Histological scoring was performed by three-stage ranges system as follows: Degree of steatosis (0-3), lobular inflammation (0-3), hepatocyte ballooning (0-2) (40).
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. NRF-2018R1A5A2023879). We would like to thank Editage (www.editage.co.kr) for English language editing.
The authors have no conflicting interests.