The origin of bacteria found in remote organs converges to the oral cavity [93,94,95,96] (Figure 1). For example, the placental microbiome profiles were most comparable to those of the oral microbiome [1]. The overlap of the unique members of oral microbes with other remote organs is consistent with previous clinical studies in which Fusobacterium nucleatum, a Gram-negative oral anaerobe, was clinically suspected to be a major risk factor in colorectal cancer [97,98,99], oral squamous cell carcinoma (OSCC) [100], and in preterm and term stillbirth [101,102]. Likewise, an infamous oral pathogenic bacterium, Porphyromonas gingivalis, is related to pancreatic cancer [103], colorectal cancer [104,105,106], liver health [107], rheumatoid arthritis [108,109], diabetes [110,111,112], OSCC [113,114], and neurodegenerative diseases [88,89,90,91,92,115,116,117,118]. In the case of atherosclerotic CVD, when the vascular tissues of the coronary and femoral arteries of the patients with CVD were examined, P. gingivalis was found in 42 out of 42 patients [119]. Thus, previously explained by the passive accumulation of fat, the aetiology of CVD is now leaning toward inflammatory responses of the vascular endothelium [120,121]. Notably, live P. gingivalis is known to traffic into endoplasmic reticulum-rich autophagosomes [122] and target host ectonucleotidase-CD73 [123] for its chronic survival, replication, and persistence in the dysbiotic human gingival epithelia [124].

 

Recently, Kitamoto et al. demonstrated the mechanistic underpinnings by which periodontal inflammation due to oral infection contributes to the pathogenesis of extra-oral diseases [12]. In this elaborated study using mice, they showed that periodontitis aggravates gut inflammation by translocating oral Klebsiella/Enterobacter species to the lower digestive tract where it colonizes ectopically to elicit colitis through IL-1β. In parallel, oral Th17 cells induced by oral pathobiont expansion migrate to the gut and promote colitis, constituting both microbial and immunological pathways that link oral and gut health. Furthermore, Dong et al. showed that the alterations of the oral microbiota, especially F. nucleatum colonization in CRC locus, can change the gut bacterial composition within tumours and influence the therapeutic efficacy and prognosis of radiotherapy for primary rectal cancer and CRC liver metastases in mouse models [125]. Kartal et al. applied shotgun metagenomic and 16S rRNA sequencing to faecal and saliva samples from pancreatic ductal adenocarcinoma (PDAC) to identify diagnostic classifiers [96]. While proving that the faecal metagenomic classifiers outperformed the saliva-based classifiers, they also confirmed that the strains of faecal PDAC-associated microbes originate from the oral cavity. Thus, the growing body of examples that show the close relationship of oral pathogens with a variety of systemic diseases enabled the introduction of the term “periodontal medicine”, to describe how periodontal infection and inflammation affect extraoral illness [126,127]. As such, the oral cavity needs to be re-evaluated as a more pivotal organ with the revolution of microbiology in the 21st century [71].

There are many disease model systems proving that oral bacteria induce systemic diseases, such as CVD, type II diabetes mellitus (T2DM), OSCC, and AD (Table 1). For one, the infection of aortic lesions with P. gingivalis activates adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), leading to chronic inflammation via the migration of more immune cells to the lesion sites [128]. The microarray analysis demonstrated that P. gingivalis-treated human aortic endothelial cells (HAECs) upregulated expression levels of ICAM-1, VCAM-1, and interleukin-6 (IL-6). As well as ICAM-1 and VCAM-1 upregulation, pathological enlargement of the atherosclerotic lesion area was well demonstrated in hyperlipidemic (Apoe^−/−) mice orally challenged with P. gingivalis [128,129]. As an effective molecule, lipopolysaccharide from P. gingivalis (PgLPS) was established to promote inflammatory response by increasing mononuclear cell adhesion to human umbilical vein endothelial cells (HUVECs) via ICAM-1 and Toll-like receptor 2 (TLR-2)-dependent mechanism [130]. Subcutaneous infection of obese pigs with P. gingivalis also showed enhanced aortic and coronary arterial atherosclerosis [63]. In addition to P. gingivalis, intravenous infection of hyperlipidemic mice with Aggregatibacter actinomycetemcomitans can promote and accelerate atherosclerotic plaques [131] and time-dependently elevate matrix metalloproteinase-9 (MMP-9) expression [132]. The MMP-9, derived from macrophages, has been highlighted as a risk factor for acute atherosclerosis due to its proteolytic activity in advanced atherosclerotic plaque rupture [133].

T2DM is a highly prevalent metabolic disease characterized by prolonged high glucose levels in the blood. Insulin resistance on peripheral tissues has been focused on as the major causing factor of T2DM [144]. Recently, many microbiologists designated gut dysbiosis as a critical factor of insulin resistance development in T2DM accompanied by gut barrier dysfunction [145]. Interestingly, oral infection of mice with P. gingivalis can also induce gut dysbiosis, leading to insulin resistance via a pathway through endotoxin entrance and chronic inflammation [134]. Mice pre-treated with P. gingivalis, F. nucleatum, and Prevotella intermedia showed accelerated insulin resistance after three months of high-fat diet (HFD) feeding [135]. The branched-chain amino acid (BCAA) biosynthesis activity of P. gingivalis is a suggested mechanism of insulin resistance development, as evident that BCAA aminotransferase-deficient (∆bcat) P. gingivalis strain can neither induce insulin resistance nor upregulate serum BCAA in HFD mice model [136].

OSCC is the most malignant cancer of the oral cavity with an increasing rate of incidence, and the risk factors for OSCC include alcohol consumption, smoke, and human papillomavirus [146]. Interestingly, two independent groups suggested that P. gingivalis administration can significantly increase the number and diameter of the lesions in tongue tissues of mice pre-treated with carcinogen 4-nitroquinoline-1 oxide (4NQO). They provided two pathways, dysregulated lipid metabolism and CD11b⁺ myeloid-derived suppressor cells (MDSCs) infiltration, involved with OSCC deterioration by the pathogen [113,114]. Indeed, abnormal lipid regulation by increased expressions of fatty acid-binding protein 4 (FABP4) and FABP5 has been reported to have a crucial role in OSCC development via activation of mitogen-activated protein kinase (MAPK) pathway and MMP-9 [147,148]. By contrast, CD11b⁺ is responsible for MDSCs migration to the tumour microenvironment where the cells have an immunosuppressive role that favours tumour progression [149].

AD is one of the representative neurodegenerative diseases diagnosed with senile plaques and abundant neurofibrillary tangles, which can be deteriorated by oral pathogenic infection. Gingival-infected P. gingivalis was reported to exacerbate the accumulation of Aβ plaques and inflammatory cytokines in brain specimens of amyloid precursor protein (APP) transgenic mice [140]. Interestingly, the anatomic analysis demonstrated that P. gingivalis genomic DNA was detected in brain specimens of 9 out of 12 Apoe^−/− mice orally challenged with P. gingivalis for 24 weeks [139], implicating that P. gingivalis can penetrate the gum and enter the blood-brain barrier (BBB). The result that intravenous injection of P. gingivalis into rats enhanced tau hyperphosphorylation in the hippocampus can reinforce the theory of BBB penetration of P. gingivalis [143]. As similar atherosclerotic CVD, PgLPS has also been designated as P. gingivalis-driven virulence factor affecting AD. It was reported that PgLPS treatment to rat brain neonatal microglial cells promoted the release of inflammatory mediators such as TNF-α and IL-6 [138], and palatal gingival infection of PgLPS into rats induced alveolar bone loss and increased serum Aβ levels [142]. Middle-aged wild-type (WT) mice intraperitoneally challenged with PgLPS for 5 weeks represented learning and memory deficit and microglia-mediated neuroinflammation, although age-matched mice deficient for cathepsin B (Catb^−/−) were insensitive to PgLPS [141]. In addition to PgLPS, gingipain is an AD virulence factor, a unique class of cysteine proteinase that comprises Lys-gingipain (Kgp) and Arg-gingipain (Rgp). The modulatory role of the gingipain on neuroinflammation was well-established using Kgp and Rgp inhibitors (KYT1 and KYT36, respectively) or P. gingivalis KDP129, a gingipain-deficient mutant strain [137]. In this study, KYT1 and KYT36 treatment effectively inhibited P. gingivalis-driven increased expression of IL-6 and TNF-α in immortalized mouse microglial cell line MG6. Injection of P. gingivalis, but not KDP129 strain, into the somatosensory cortex of mice can recruit microglia to the injection site, revealing that gingipain is the effective factor for microglial migration and accumulation around P. gingivalis in the brain [137].