Oral Bacteria and Bowel Diseases – Mini Review

Oral bacteria are considered to be associated with several systemic diseases. Recently, their association with inflammatory bowel disease (Crohn's disease and ulcerative colitis) and colorectal carcinoma has attracted much attention. In this mini-review, the association of oral bacteria with these diseases is briefly summarized. Fusobacterium nucleatum is known as a periodontopathic bacterium, and it is also associated with inflammatory bowel disease and colorectal carcinoma. Campylobacter concisus, which is found at the site of periodontitis, is associated with inflammatory bowel disease. Streptococcus mutans is a famous cariogenic bacterium, but a highlyvirulent strain of this bacterium is also associated with inflammatory bowel disease. In this way, both periodontopathic bacteria and cariogenic bacteria are associated with bowel diseases. Further epidemiological studies are necessary to reveal the cause and effect relationship between oral bacterial and bowel diseases.


Introduction
Oral bacteria are considered to be associated with several systemic diseases such as atherosclerotic disease, adverse pregnancy outcomes, rheumatoid arthritis, and respiratory tract infections [1].
Recently, the association of oral bacteria with inflammatory bowel disease (IBD) and colorectal cancer (CRC) has attracted much attention. IBDs, which include Crohn's disease (CD) and ulcerative colitis (UC), are chronic relapsing idiopathic inflammatory diseases of the gastrointestinal tract [2]. IBD is thought to be associated with both environmental and bacterial factors. Epidemiological studies suggested that environmental factors play an important role in the increased incidence of IBD. On the other hand, colitis did not occur in germ-free animal models of IBD, and intestinal inflammation in patients with CD was resolved after faecal stream diversion [3,4].
In this mini-review, the association of oral bacteria and these diseases will be briefly summarized (Table 1). Campylobactr concisus IBD C. concisus and antibodies to this bacterium were detected in CD 29 High rate of C. concisus isolation from older children and adults 30 Isolation of immunoreactive proteins from C. concisus 32 IBD patients are colonized with specific oral C. concisus, which underwent natural recombination 31 Isolation of zonula occuden toxin (Zot) gene from C. concisus 33 C. concisus Zot is associated with barrier defect of intestine. 34 Autophagy of C. concisus is in part associated with intracellular survival. 35 Increased gastric pH and reduced intestinal bile may be useful for C. concisus colonization. 36 Genetic recombination is common in oral and enteric C. concisus 37 Streptococcus mutans IBD Crohn's disease patients had more caries experience compared to normal population 40 Lactobacillus count and the number of decayed tooth surface were higher in the Crohn's disease 41 Crohn's disease patients had more mutants streptococci counts than non-disease control 42 Collagen binding protein-positive S. mutans is considered to be a risk factor for ulcerative colitis 43 More S. mutans was detected in Crohn's disease patients, not in ulcerative colitis 44 Crohn's disease patients had higher DMFs score and S. mutans counts compared to control 45 Both CD and UC patients had more dental treatment, but it was more pronounced for CD 47

Fusobacterium nucleatum
Fusobacterium nucleatum, which is a Gram-negative fusiform bacterium, is known as one of the most important periodontopathogens [5]. It is commonly detected at the site of periodontitis. In animal experiments, F. nucleatum shows synergistic virulence in mixed infections. When F. nucleatum and Porphyromonas gingivalis, another important periodontopathogen, were simultaneously injected to mice, larger abscesses were formed compared to mice mono-injected with each bacterium [6]. F. nucleatum coaggregates with several kinds of bacteria [7], and it contributes to biofilm formation. F. nucleatum has an outer membrane protein RadD, which is associated with coaggregation [8]. Han et al. identified an adhesion FadA that is unique to oral Fusobacteria [9]. FadA may be associated with colonization in the periodontal environment and is considered to be associated with invasion [10] and systemic dissemination [9].

F. nucleatum and IBD
Verna et al. reported that F. nucleatum septicemia in UC patients is associated with portal vein thrombosis [11]. F. nucleatum is a heterogeneous oral pathogen, and it also resides in the human gut mucosa. In the inflamed biopsy tissue from IBD patients, more invasive F. nucleatum strains are found [12]. Dharmani reported that highly invasive F. nucleatum strains stimulated MUC2 mucin and TNFα production [13]. McGuire et al. compared the genes between actively-invading and passively-invading Fusobacteria [14]: Active invaders had much larger genomes and encoded FadA-related adhesins containing a MORN2 domain.

F. nucleatum and colorectal carcinoma
Two reports on F. nucleatum and CRC were reported in 2012 by different authors in the same journal. Kostic reported the association of F. nucleatum with CRC [15], and Castellarin reported the positive association with lymph node metastasis [16]. Kostic et al. examined the effect of F. nucleatum on tumorigenesis by using a mouse model [17].
This bacterium increased tumor multiplicity and selectively recruited tumor-infiltrating myeloid cells. FadA is a unique adhesin of F. nucleatum, and the effect of the protein on carcinogenesis was examined. Rubinstein et al. demonstrated that F. nucleatum adhered to, invaded and induced oncogenic and inflammatory responses through FadA [18]. They also reported that FadA bound to E-cadherin and activated α-catenin signaling. F. nucleatum coaggregates with several microorganisms, which contributes to the progression of periodontitis [18].
In colorectal carcinoma, F. nucleatum is found to co-reside with other gram negative bacteria, such as Campylobacter [19]. Fukugaiti et al. reported that F. nucleatum and Clostridium difficile are detected in CRC patients [20].
F. nucleatum is also known to associate with colorectal adenomas [21]. Flangan et al. reported that F. nucleatum is associated with the progression from adenomas to CRC and suggested that detection of F. nucleatum may be useful as a diagnostic and prognostic determinant in CRC patients [22]. As for prognosis, F. nucleatum is reported to be associated with the worse clinical outcome of CRC [23]. The mechanism of CRC progression by F. nucleatum is not fully understood, but Nosho et al. reported the effect of this bacterium on T cell immunity [24].

Campylobacter concisus
Campylobacter concisus is a Gram-negative, highly fastidious, spiral, and microaerophilic bacterium [25]. C. concisus has been isolated from human gingiva and is linked with periodontal lesions, including gingivitis and periodontitis [26]. Aspartate aminotransferase (AST) is markedly elevated in gingival crevicular fluid from sites with severe gingival inflammation and progressive attachment loss, and C. concisus is often isolated from AST positive sites [27].

Campylobacter concisus and IBD
Campylobacter species, such as C. jejuni, have been recognized as important pathogens of bowel diseases [28]. Zhang et al. demonstrated that a significantly higher presence of C. concisus and significantly higher levels of IgG antibodies specific to C. concisus are present in children with CD than in controls [29], and this bacterium is now recognized as an emerging pathogen of the human gastrointestinal tract. They also detected C. concisus from the saliva of healthy individuals and IBD patients [30]. They suggested that an individual may harbor multiple C. concisus strains in the oral cavity and that some oral C. concisus strains may colonize the lower gastrointestinal tract and be involved in IBD. Ismail et al. reported that patients with IBD were colonized with specific oral C. concisus strains, which underwent natural recombination and obtained invasiveness [31].
The virulence factors of C. concisus were further investigated, and the association of immunoreactive proteins [32] and zonula occludens toxin [33,34] with IBD was reported. Survival of C. concisus in host cells and tissues were also investigated. Autophagy usually contributes to the clearance of intracellular organisms, which is true for C. concisus. However, some strains of C. concisus were found to utilize autophagy for intracellular survival [35]. Ma et al. reported that increased gastric pH and reduced intestinal bile may be beneficial for C. concisus to colonize the intestine [36]. Recently, the genes of C. concisus are being investigated. Mahendran et al. reported the genetic relatedness and population structure of oral and enteric C. concisus species [37]. The relationship between oral and enteric strains of C. concisus will be investigated in the future.

Streptococcus mutans
S. mutans is a Gram-positive oral bacterium. The bacterium metabolizes different kinds of carbohydrates, and creates an acidic environment, which is associated with tooth decay. Streptococci are also known as the cause of infectious endocarditis [38]. Recently, a highly-virulent strain of S. mutans was reported to be associated with hemorrhagic damage in the murine brain [39], and this bacterium attracts much attention in the field of general medicine.

Streptococci and bowel diseases
Sundh et al. examined the microbial features of saliva and reported the association of dental caries and Crohn's disease [40,41]. Among the oral bacteria, S. mutans was found to be most associated with Crohn's disease [42]. Kojima et al investigated the effect of a highly-virulent strain of S. mutans on dextran sodium sulfate-induced mouse colitis [43]. The specific strain of S. mutans, which produced a collagenbinding protein, aggravated colitis. They reported that this highlyvirulent strain of S. mutans was also associated with human IBD. The relationship between dental caries and IBD was further investigated. Brito et al. reported that S. mutans was detected in Crohn's disease but not in ulcerative colitis [44]. It was confirmed that Crohn's disease patients had higher decayed -missing-filled surfaces (DMFs) scores and S. mutans counts compared to the control [45]. Johannsen et al.
reported that both CD and UC patients had received more dental treatment, but this was more pronounced for CD [46].

Conclusion
Oral bacteria are divided into two categories: cariogenic bacteria and periodontopathic bacteria [47]. Most of the periodontopathic bacteria are Gram-negative anaerobic and have many virulence factors associated with soft tissues and bone. It is not surprising that they affect not only the periodontal environment but also the intestine. Some of the periodontopathic bacteria, such as F. nucleatum and C. concisus, are associated with IBD and CRC. On the other hand, S. mutans is considered to be a cariogenic bacterium, and it is interesting that this bacterium also affects soft tissues of the gastric organ. The oral cavity and the intestine are not neighboring organs, but the bacteria of these organs seem to be closely associated. However, there is also the possibility that oral bacteria can only harbor bowel disease sites, and this point should be clarified. Further work by dental and medical doctors may reveal that dental and periodontal treatments decrease the incidence of IBD and CRC.