Porphyromonas gingivalis infection in the oral cavity is associated with elevated galactose-deficient IgA1 and increased nephritis severity in IgA nephropathy.

BACKGROUND: The relationship between the major periodontal bacteria, Porphyromonas gingivalis, and the pathogenesis of IgA nephropathy (IgAN)-particularly with respect to galactose-deficient IgA1 (Gd-IgA1)-has not been fully elucidated. METHODS: Saliva samples from 30 IgAN patients and 44 patients with chronic kidney disease (CKD) were subjected to analysis of P. gingivalis status via polymerase chain reaction using a set of P. gingivalis-specific primers. The associations between P. gingivalis presence and clinical parameters, including plasma Gd-IgA1, were analyzed in each group. RESULTS: Compared with the CKD group, the IgAN group demonstrated significantly higher plasma Gd-IgA1 levels (p < 0.05). Compared with the P. gingivalis-negative subgroup, the P. gingivalis-positive subgroup exhibited significantly higher plasma Gd-IgA1 levels in both IgAN and CKD patients (p < 0.05). Additionally, among IgAN patients, the P. gingivalis-positive subgroup displayed significantly higher plasma Gd-IgA1 and urine protein levels, compared with the P. gingivalis-negative subgroup (p < 0.05). With respect to renal biopsy findings, the frequencies of segmental glomerulosclerosis and tubular atrophy/interstitial fibrosis were significantly greater in the P. gingivalis-positive subgroup than in the P. gingivalis-negative subgroup, according to the Oxford classification of IgAN (p < 0.05). CONCLUSION: Our findings suggest an association between the presence of P. gingivalis in the oral cavity and the pathogenesis of IgAN, mediated by increased levels of Gd-IgA1.

Title IgA Nephropathy and Oral Bacterial Species Related to Dental Caries and Periodontitis.

A relationship between IgA nephropathy (IgAN) and bacterial infection has been suspected. As IgAN is a chronic disease, bacteria that could cause chronic infection in oral areas might be pathogenetic bacteria candidates. Oral bacterial species related to dental caries and periodontitis should be candidates because these bacteria are well known to be pathogenic in chronic dental disease. Recently, several reports have indicated that collagen-binding protein (cnm)-(+) Streptococcs mutans is relate to the incidence of IgAN and the progression of IgAN. Among periodontal bacteria, Treponema denticola, Porphyromonas gingivalis and Campylobacte rectus were found to be related to the incidence of IgAN. These bacteria can cause IgAN-like histological findings in animal models. While the connection between oral bacterial infection, such as infection with S. mutans and periodontal bacteria, and the incidence of IgAN remains unclear, these bacterial infections might cause aberrantly glycosylated IgA1 in nasopharynx-associated lymphoid tissue, which has been reported to cause IgA deposition in mesangial areas in glomeruli, probably through the alteration of microRNAs related to the expression of glycosylation enzymes. The roles of other factors related to the incidence and progression of IgA, such as genes and cigarette smoking, can also be explained from the perspective of the relationship between these factors and oral bacteria. This review summarizes the relationship between IgAN and oral bacteria, such as cnm-(+) S. mutans and periodontal bacteria.

Inhibitory effects of flavedo, albedo, fruits, and leaves of Citrus unshiu extracts on Streptococcus mutans.

OBJECTVES: Citrus unshiu has been shown to exhibit antimicrobial effects against citrus diseases. In the present study, C. unshiu was divided into flavedo, albedo, fruits, and leaves; the inhibitory effects of these extracts on Streptococcus mutans, a major pathogen of dental caries, were investigated. DESIGN: C. unshiu specimens were separated into flavedo, albedo, fruits, and leaves. First, pH values and polyphenol amounts in Citrus extracts were measured. In addition, Citrus extract was added to the bacterial suspensions of S. mutans MT8148, and inhibitory effects of C. unshiu extracts on MT8148 for antimicrobial activity, bacterial growth, and biofilm formation were analyzed. These assays were also performed using C. sinensis extracts. RESULTS: Among these extracts, albedo exhibited a pH value closest to neutral, while the fruits exhibited the most acidic pH value; the pH values significantly differed between these extracts (P < 0.05). In addition, the amounts of polyphenols were significantly higher in albedo than in other extracts (P < 0.001). All extracts showed inhibitory effects on MT8148 for antimicrobial activity, bacterial growth and biofilm formation. These inhibitory effects were significantly stronger in flavedo, albedo, and fruits, compared with leaves (P < 0.05). Furthermore, extracts of Citrus sinensis also showed inhibitory effects on S. mutans, although these effects were weaker than the effects of C. unshiu. CONCLUSION: These results suggest that extracts from C. unshiu fruits exhibit inhibitory effects on S. mutans, among which albedo may be especially useful for dental caries prevention due to its neutral pH and abundant polyphenols, in addition to its inhibitory effects.

Intravenous administration of Streptococcus mutans induces IgA nephropathy-like lesions.

BACKGROUND: IgA nephropathy (IgAN) is one of the most frequently occurring types of chronic glomerulonephritis. Previous analyses have revealed that a major pathogen of dental caries, Streptococcus mutans [which expresses collagen-binding protein (Cnm) on its surface], is involved in the pathogenesis of IgAN. METHODS: Cnm-positive S. mutans isolated from a patient with IgAN was intravenously administered to specific pathogen-free Sprague-Dawley rats to evaluate their kidney conditions. RESULTS: The urinary protein level of the S. mutans group reached a plateau at 30 days, with increased numbers of mesangial cells and an increased mesangial matrix. The numbers of rats with IgA-positive and/or C3-positive glomeruli were significantly greater in the S. mutans group than in the control group at 45 days (P < 0.05). Electron microscopy analyses revealed electron-dense depositions in the mesangial area among rats in the S. mutans group. There were significantly more CD68-positive cells (macrophages) in the glomeruli of the S. mutans group than in the glomeruli of the control group during the late phase (P < 0.05), similar to the findings in patients with IgAN. CONCLUSION: Our results suggested that intravenous administration of Cnm-positive S. mutans caused transient induction of IgAN-like lesions in rats.

Specific strains of Streptococcus mutans, a pathogen of dental caries, in the tonsils, are associated with IgA nephropathy.

Streptococcus mutans is known to be a major causative agent of dental caries, and strains expressing the cell surface collagen-binding Cnm protein contribute to the development of several systemic diseases. A relationship between tonsillar immunity and glomerulonephritis has been recognized in IgA nephropathy (IgAN), and specific pathogens may have effects on tonsillar immunity (mucosal immunity). Here, we present findings showing a relationship between the presence of Cnm-positive S. mutans strains in the tonsils of IgAN patients and IgAN condition/pathogenesis. Analyses of tonsillar specimens obtained from patients with IgAN (n = 61) and chronic tonsillitis (controls; n = 40) showed that the Cnm protein-positive rate was significantly higher in IgAN patients. Among IgAN patients, the tonsillar Cnm-positive group (n = 15) had a significantly higher proportion of patients with high urinary protein (>1.5 g/gCr) and lower serum albumin level than the Cnm-negative group (n = 46). Additionally, Cnm protein and CD68, a common human macrophage marker, were shown to be merged in the tonsils of IgAN patients. These findings suggest that Cnm-positive S. mutans strains in the tonsils may be associated with severe IgAN.

Relationship between Streptococcus mutans expressing Cnm in the oral cavity and non-alcoholic steatohepatitis: a pilot study.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a severe state of non-alcoholic fatty liver disease (NAFLD), which is pathologically characterised by steatosis, hepatocyte ballooning, and lobular inflammation. Host-microbial interaction has gained attention as one of the risk factors for NASH. Recently, cnm-gene positive Streptococcus mutans expressing cell surface collagen-binding protein, Cnm (cnm-positive S. mutans), was shown to aggravate NASH in model mice. Here, we assessed the detection rate of cnm-positive S. mutans in oral samples from patients with NASH among NAFLD. METHODS: This single hospital cohort study included 41 patients with NAFLD. NASH was diagnosed histologically or by clinical score. The prevalence of cnm-positive S. mutans, oral hygiene and blood tests, including liver enzymes, adipocytokines and inflammatory and fibrosis markers, were assessed in biopsy-proven or clinically suspected NASH among NAFLD. RESULTS: Prevalence of cnm-positive S. mutans was significantly higher in patients with NASH than patients without NASH (OR 3.8; 95% CI 1.02 to 15.5). The cnm-positive S. mutans was related to decreased numbers of naturally remaining teeth and increased type IV collagen 7S level (median (IQR) 10.0 (5.0-17.5) vs 20.0 (5.0-25.0), p=0.06; 5.1 (4.0-7.9) vs 4.4 (3.7-5.3), p=0.13, respectively). CONCLUSIONS: Prevalence of cnm-positive S. mutans in the oral cavity could be related to fibrosis of NASH among NAFLD.

A Potential New Risk Factor for Stroke: Streptococcus Mutans With Collagen-Binding Protein.

BACKGROUND: Among human oral bacteria, particular kinds of Streptococcus mutans (SM) known as dental caries pathogens contain a collagen-binding protein, Cnm, and show platelet aggregation inhibition and matrix metalloproteinase-9 activation. We have previously reported that these strains may be a risk factor for intracerebral hemorrhage. As a major sample-providing hospital, we report the clinical details, including intracranial aneurysms and ischemic stroke. METHODS: After the study received approval from the Ethical Committee, 429 samples of whole saliva were obtained from patients who were admitted to or visited our hospital between February 16, 2010, and February 28, 2011. The study cohort comprised 48 patients with cardioembolic stroke (CES), 151 with non-CES infarct, 54 with intracerebral hemorrhage (ICH), 43 with ruptured intracranial aneurysm (RIA), and 97 with unruptured intracranial aneurysm (UIA). Cultured SM was identified as Cnm-positive when the corresponding gene was positive. The results were compared with those from 79 healthy volunteers. Relationships between Cnm-positive SM and known risk factors, including hypertension, diabetes, hyperlipidemia, smoking, and alcohol consumption, were analyzed. RESULTS: A statistically significant high Cnm-positive rate was observed in patients with CES, non-CES infarct, ICH, and RIA (P = 0.002, 0.039, 0.013, and 0.009, respectively). There were no relationships between Cnm-positive SM and known risk factors. CONCLUSIONS: Specific types of oral SM can be a risk factor for cardioembolic infarct, intracerebral hemorrhage, and intracranial aneurysm rupture. Further study is needed.

Distribution and molecular characterization of Porphyromonas gulae carrying a new fimA genotype.

Porphyromonas gulae is a gram-negative black-pigmented anaerobe which is known to be a pathogen for periodontitis in dogs. Approximately 41kDa filamentous appendages on the cell surface (FimA) encoded by the fimA gene are regarded as important factors associated with periodontitis. The fimA genotype was classified into two major types and strains in type B were shown to be more virulent than those in type A. In the present study, we characterized a strain with a novel fimA genotype and designated it as type C. The putative amino acid sequence was shown to be similar to the genotype IV fimA of Porphyromonas gingivalis, a major pathogen of human periodontitis. Analyses using an oral squamous cell carcinoma cell line derived from tongue primary lesions revealed that the type C strain inhibited proliferation and scratch closure more than genotype A and B strains. In addition, experiments using a mouse abscess model demonstrated that the type C strain could induce much higher systemic inflammation when compared with strains of the other genotypes. Furthermore, molecular analyses of oral swab specimens collected from dogs demonstrated that the detection frequencies of P. gulae and the genotype C in the periodontitis group were significantly higher than those in the periodontally healthy group. These results suggest that FimA of P. gulae is diverse with the virulence of genotype C strains the highest and that molecular identification of genotype C P. gulae could be a possible useful marker for identifying dogs at high risk of developing periodontitis.

Involvement of a periodontal pathogen, Porphyromonas gingivalis on the pathogenesis of non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome that is closely associated with multiple factors such as obesity, hyperlipidemia and type 2 diabetes mellitus. However, other risk factors for the development of NAFLD are unclear. With the association between periodontal disease and the development of systemic diseases receiving increasing attention recently, we conducted this study to investigate the relationship between NAFLD and infection with Porphyromonas gingivalis (P. gingivalis), a major causative agent of periodontitis. METHODS: The detection frequencies of periodontal bacteria in oral samples collected from 150 biopsy-proven NAFLD patients (102 with non-alcoholic steatohepatitis (NASH) and 48 with non-alcoholic fatty liver (NAFL) patients) and 60 non-NAFLD control subjects were determined. Detection of P. gingivalis and other periodontopathic bacteria were detected by PCR assay. In addition, effect of P. gingivalis-infection on mouse NAFLD model was investigated. To clarify the exact contribution of P. gingivalis-induced periodontitis, non-surgical periodontal treatments were also undertaken for 3 months in 10 NAFLD patients with periodontitis. RESULTS: The detection frequency of P. gingivalis in NAFLD patients was significantly higher than that in the non-NAFLD control subjects (46.7% vs. 21.7%, odds ratio: 3.16). In addition, the detection frequency of P. gingivalis in NASH patients was markedly higher than that in the non-NAFLD subjects (52.0%, odds ratio: 3.91). Most of the P. gingivalis fimbria detected in the NAFLD patients was of invasive genotypes, especially type II (50.0%). Infection of type II P. gingivalis on NAFLD model of mice accelerated the NAFLD progression. The non-surgical periodontal treatments on NAFLD patients carried out for 3 months ameliorated the liver function parameters, such as the serum levels of AST and ALT. CONCLUSIONS: Infection with high-virulence P. gingivalis might be an additional risk factor for the development/progression of NAFLD/NASH.