**4. The concept of biogenics**

*Prebiotics and Probiotics - Potential Benefits in Nutrition and Health*

**3. Oral application of probiotics and problems**

**2. The potential pathogenicity of dental plaque as oral biofilm**

of the biofilm, and the caries and periodontitis occurrence proliferate.

to accelerate biofilm formation even more. Generally it can be said that with

Oral plaque contains also dental caries and periodontal disease causing organisms [9–12], and when these exert their potential pathogenicity, they are considered

increasing thickness of the biofilm, the bacterial metabolites build up at the bottom

Caries and periodontal diseases are called the two major dental diseases, and both of them occur as oral infectious diseases which are caused by specific bacteria known as cariogenic bacteria (such as *Streptococcus mutans*) and periodontal pathogens (such as *Porphyromonas gingivalis*) growing in plaque. This status is interpreted as dysbiosis of the oral flora. In addition, a small number of fungal genus *Candida* is also present in the indigenous oral resident microflora, and some factors also cause its growth in the plaque, resulting in dysbiosis, which causes a major oral mucosal disease, oral candidiasis. However, there is currently no technique to selectively eliminate only those causative microorganisms from

The method of preventing caries and periodontal disease is basically the mechanical removal of the entire plaque by brushing, etc. However in the case of onset of the disease, antimicrobial drugs are administered for the treatment of the acute phase of periodontal disease, and antifungal administration is the first choice for treatment of oral candidiasis. However, the use of antimicrobial agents has shown problems regarding adverse effects such as drug-resistant bacteria and allergies, indicating the limitation of chemotherapy [13]. Therefore, attention has recently focused on probiotic bacteria such as bifidobacteria and lactobacilli recognizing the usefulness for improving dysbiosis [14]. Although probiotics were originally intended to improve dysbiosis of the intestinal flora [15], their usefulness is also assumed in the dental field. Attempts have been made for direct use in the oral cavity to prevent diseases such as caries and periodontal disease, and several results have been reported [16–18]. Ishikawa *et al*. reported that 4 weeks of oral administration of *Lactobacillus salivarius* TI 2711 (LS1) significantly reduced the major periodontal pathogens of *P. gingivalis*, *Prevotella intermedia*, and

However, in these reports, there are few basic facts on the effects of probiotics on the oral flora and the antibacterial substances produced by them, so progress and establishment of practical applications based on the underlying mechanism has not been accomplished. In addition, genera *Lactobacillus* and *Bifidobacterium*, which are representative probiotic bacteria, exist though in minority in the oral microbiota, but because they metabolize sugar and produce large amounts of organic acid, the general understanding is that they work cooperatively with cariogenic bacteria or

As another fundamental issue, previous studies have highlighted the limitation of colonization and fixation of nonnatural probiotic bacteria in the intestinal tract [20, 21]. This phenomenon of transiency, but not permanency in colonization, is also relevant for probiotic applications in the oral cavity [16, 22, 23]. Even if we are able to address the restriction of colonization of probiotic bacteria in the oral cavity, it comes with the risk of dental caries due to the potential acidic environment gener-

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the flora.

*Prevotella nigrescens* [19].

induce hypersensitivity.

ated by probiotic bacteria.

To overcome the above problems, "biogenics" as a new idea has been introduced. Biogenics is a kind of functional food, using only the ingredients, which have a positive effect on the host with regard to immunostimulating or immunosuppressing mutagenesis, tumorigenesis, peroxidation, hypercholesterolemia, or intestinal putrefaction [24]. Achieving a probiotic effect by the intake of nonviable probiotic bacteria has been proposed in previous reports. For example, the life span of mice increased, when they were fed with pasteurized fermented milk [25, 26]. A significant reduction of the Ehrlich ascites tumor growth in mice was also reported [26]. In addition, it was shown that heat-inactivated *Enterococcus faecalis* [27] or *L. gasseri* [28] showed a beneficial regulatory effect in the gut. Moreover, Nakamura *et al*. [29] found an angiotensin-I-converting enzyme (ACE) inhibitor in a Japanese sterilized milk beverage fermented by *L. helveticus* and *Saccharomyces cerevisiae*. The active substance in this fermented beverage was identified as lactotripeptide metabolically generated in the fermentation pathway. Follow-up studies were able to determine the bioactive metabolites of probiotic bacteria in addition to the antimicrobial substances, such as bacteriocin [30, 31], and other beneficial active substances, such as conjugated linoleic acid (CLA) [30–32], proteins or peptides [33, 34], and polyphenols [35, 36]. Taking all these observations into account, biogenics, which makes use of the bioactive metabolites as foods or medicine, was recently advocated as a new concept [24, 37]. The biogenic effect is independent of the colonization and viability of probiotic bacteria. Hence, biogenics is the direct delivery of an isolated and purified active ingredient of probiotics to the local environment. This strategy may also be useful for oral disease prevention. It may be possible to purify the effective ingredients against oral pathogenic activity of probiotic bacteria for use in the biogenics process. However, this idea requires further study prior to clinical use.
