Many factors have been implicated in the pathogenesis of NAFLD/NASH, including obesity, insulin resistance, oxidative stress and mitochondrial dysfunction [1
]. Recently, the association between low vitamin D level and NAFLD has also been reported [29
]. However, it is still unclear whether any other factors might be involved in the pathogenesis and progression of NASH in its common form. Therefore, identifying the mechanisms responsible for the progression of NASH may be useful for designing therapeutic strategies for these diseases.
In the present study, we showed that the prevalence of P. gingivalis infection was significantly higher in the NAFLD patients than in the healthy subjects. This result suggests that P. gingivalis infection may be involved in the mechanism of onset of NAFLD, because P. gingivalis itself or the endotoxin and cytokines released from the bacteria can easily enter the blood circulation. Multiple regression analysis in NAFLD patients and control subjects to identify the predictive value of P. gingivalis infection for the development of NAFLD using demographic factors such as the age, history of DM and BMI revealed a significantly higher prevalence of P. gingivalis infection in NAFLD patients as compared with that in control subjects, even after adjusting for age, history of DM and BMI. This result suggests that P. gingivalis infection may be an independent risk factor for NAFLD.
A relationship has been reported between infection with periodontal bacteria and the onset of type 2 diabetes mellitus [30
]. Namely, it is considered that the increased serum levels of lipopolysaccharide and TNF-α associated with P. gingivalis
infection induce insulin resistance, leading to the development of type 2 diabetes [30
]. In addition, our colleagues reported relationship between the fimbrial type of the periodontal bacteria causing periodontitis and the risk of development of type 2 diabetes mellitus [32
]. In fact, most NAFLD patients with P. gingivalis
infection show bacteria with invasive types of fimbria, such as II, IV, and Ib. Therefore, it is suggested that the high detection frequency of P. gingivalis
in NAFLD patients may be due to the presence of coexisting DM, based on the correlation between NAFLD and DM. However, in the present study, no significant difference in the frequency of DM was noted between P. gingivalis
-positive and -negative groups among the NAFLD patients (Table ). Therefore, it is suggested that the high detection frequency of P. gingivalis
in NAFLD patients was not due to coexisting DM in our study. In contrast, a statistically significant difference in the frequency of DM was noted between the P. gingivalis
-positive and -negative NASH patients. These results may indicate that both DM and P. gingivalis
infection may be involved in the progression of NAFL to NASH. Namely, both DM and P. gingivalis
infection may cooperatively increase the risk of progression from NAFL to NASH. In fact, the high detection frequency of P. gingivalis
infection in NASH patients was more obvious than that in the NAFL patients.
In comparison between P. gingivalis-positive and negative NASH/NAFLD patients, statistically significant decrease in serum albumin level was observed. These results indicate that decrease in liver function may be accelerated in P. gingivalis-positive patients. In addition, the tendency, but not significant, of increases in hyaluronic acid and IV collagen 7S levels were also observed. As those are indices of the progression of liver fibrosis, it may be hypothesized that liver fibrosis and decrease in function might be accelerated in P. gingivalis-positive patients, although the destroy of liver is not so marked.
Thus, infection with P. gingivalis
may be one of the risk factors for not only the second stage of progression to NASH, but also the first stage of the pathogenesis for NAFL. In fact, the infection of type II P. gingivalis
on NAFLD mouse model dramatically accelerated the NAFLD progression without any other additional treatments such as choline-deficient, l-amino acid-defined diet-fed [33
] or LDL receptor knockout [34
]. The NAFLD progression on P. gingivalis
-infected mice was markedly faster than that on control mice under the HFD condition, but not basal diet condition (see Figure , right panel). These results clearly indicate that both HFD condition and P. gingivalis
infection cooperatively increase the risk of pathogenesis of NAFLD. As the infection of other oral bacteria on NAFLD model did not accelerate the progression to NAFLD, the acceleration of NAFLD progression by P. gingivalis
under HFD condition might be high-virulence P. gingivalis
-specific effect. Further animal experiments will be required.
The mechanism of P. gingivalis
-mediated the pathogenesis of NAFLD/NASH is unclear. The current model of NASH pathogenesis proposes two stages of progression. First, insulin resistance causes lipid accumulation in the hepatocytes; second, cellular insults, such as oxidative stress, lipid toxicity, mitochondrial dysfunction, and/or bacterial endotoxins from the gut cause hepatic inflammation, resulting in the development of NASH [1
]. In fact, administration of lipopolysaccharide (LPS) showed the NASH-like conditions in HFD mice (unpublished data). Because the infection with high-virulence strains of P. gingivalis
may generate a large amount of lipopolysaccharide and TNF-α, it may result in inflammation of not only the local gingiva, but also involve other systemic organs [23
]. Such inflammatory mediators are involved in insulin resistance. In addition, P. gingivalis
can easily invade the blood circulation from the gingiva after several periodontal procedures/processes, including tooth brushing, chewing, subgingival irrigation, and dental extractions [9
]. These reports support our conclusions that infection with P. gingivalis
may be one of the risk factors for the development of NAFLD/NASH.
We also confirmed the efficacy of the periodontal treatments in improving liver function parameters such as serum AST and ALT in NAFLD patients (Figure ). This result indicates that periodontitis caused by P. gingivalis in NAFLD patients may be a risk factor for the aggravation of NAFLD, and that periodontal treatments may be useful supportive measures in the management of patients with NAFLD. Further large scale clinical practice for the periodontal treatments in NAFLD patients will be required in future.