REVIEW

Probiotics-Mediated Bioconversion and Periodontitis

Yewon Lee1https://orcid.org/0000-0001-8715-1140, Yohan Yoon1,2https://orcid.org/0000-0002-4561-6218, Kyoung-hee Choi3,*https://orcid.org/0000-0001-7778-2053
Author Information & Copyright
1Department of Food and Nutrition, Sookmyung Women’s University, Seoul 04310, Korea
2Risk Analysis Research Center, Sookmyung Women’s University, Seoul 04310, Korea
3Department of Oral Microbiology, College of Dentistry, Wonkwang University, Iksan 54538, Korea
*Corresponding author : Kyoung-hee Choi, Department of Oral Microbiology, College of Dentistry, Wonkwang University, Iksan 54538, Korea, Tel: +82-63-850-6911, Fax: +82-63-850-7313, E-mail: kheechoi@wonkwang.ac.kr

© Korean Society for Food Science of Animal Resources. This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Received: Sep 01, 2021 ; Revised: Oct 05, 2021 ; Accepted: Oct 08, 2021

Published Online: Nov 01, 2021

Abstract

Novel bioactive metabolites have been developed through a bioconversion of dairy products or other foods using probiotics isolated from dairy products or other fermented foods. These probiotics-mediated bioconversion (PMB) metabolites show antioxidant, anti-inflammatory, antimicrobial, epithelial barrier, and anticancer activities. In addition, the effect of PMB metabolites in periodontitis is recently reported in several studies. Periodontitis is a chronic inflammatory disease caused by infections, and the tooth support tissue is destroyed. Common treatments for periodontitis include scaling and root planning with systemic antibiotics. However, the overuse of antibiotics has led to the emergence of drug-resistant microorganisms and disturbs the beneficial bacteria, including lactobacilli in the oral cavity. For this reason, PMB metabolites, such as fermented milk, have been suggested as substitutes for antibiotics to reduce periodontitis. This paper reviews the recent studies on the correlation between periodontitis and PMB metabolites and classifies the efficacy of major PMB metabolites for periodontitis. The review suggests that PMB is effective for periodontitis, and further studies are needed to confirm the therapeutic effect of PMB metabolites on periodontitis.

Keywords: periodontitis; probiotics; bioconversion; probiotics-mediated bioconversion

Introduction

Periodontitis is a chronic inflammatory disease caused by infections, and the tooth support tissue is destroyed. It is one of the major causes of tooth loss that characterized by the rapid destruction of periodontal attachment (Riep et al., 2009). Common treatments for periodontitis include scaling and root planning with systemic antibiotics. However, the overuse of antibiotics has led to the emergence of drug-resistant microorganisms and disturbs the beneficial bacteria, including lactobacilli in the oral cavity.

Probiotics are defined as live microorganisms that confer health benefits to the host when administered in adequate amounts (Hill et al., 2014). The use of probiotics is not restricted to the gut and intestine but also to the oral cavity and respiratory tract. Probiotics should be selected for their potential nutritional benefits (Gibson et al., 2017). Recently, research on fermented products showing better efficacy by fermenting various additives, including probiotics and prebiotics, has been actively proposed. Prebiotics, plant extracts, or other additives pass through the gastrointestinal (GI) tract undigested. Consequently, these additives act as substrates for advantageous microorganisms and enhance their growth and biological activity (Gibson et al., 2017).

In this review, recent studies on the relationship between probiotic-mediated bioconversion (PMB) and periodontitis have been summarized. The correlation between oral microorganisms and periodontitis was reviewed, the mechanisms used by probiotics to control periodontitis were analyzed, and various studies on PMB have been summarized. In addition, correlations between various metabolites in PMB and periodontitis were considered.

Oral Microbiome Characteristics

The microbiome includes both the microbiota, the microbial community, and the “theater of activity” (structural elements, metabolites/signal molecules, and ambient conditions; Berg et al., 2020). Microbiota refers to bacteria, archaea, fungi, protists, algae, and the microbiome includes the “theater of activity” of theses microbial communities. “Theater of activity” is described as a characteristic microbial community in a reasonably well-defined habitat with unique physiochemical properties. The characteristic consists of microbial structural elements and internal/external structural elements. Microbial structural elements contain proteins/peptides, lipids, polysaccharides, and nucleic acids. Internal/external structural elements contain environmental conditions and microbial metabolites such as signaling molecules, toxins, and organic molecules (Berg et al., 2020). The oral microbiome is the microbiota and “theater of activity” that resides in the oral cavity (Dewhirst et al., 2010; Kolenbrander et al., 2002; Turnbaugh et al., 2007). More than 700 species of oral microbiota have been detected in the human mouth, and one individual’s resident microbiota may consist of 30–100 species. Research on the oral microbiome continues because the oral microbiome has low biological variation, which provides an ideal source for biomarker discovery. The normal temperature of the oral cavity is 37°C, and it is suitable for bacterial growth (Aas et al., 2005; Takahashi et al., 2005). In addition, as saliva maintains a pH of 6.5–7.5 and keeps the mouth hydrated, it is suitable for the growth of most bacteria (Aas et al., 2005; Takahashi et al., 2005). The bacteria in the oral cavity maintain homeostasis by coevolving with both pathogenic and mutualistic bacteria. These bacteria develop communities to form a multispecies organization known as dental plaque (Kolenbrander et al., 2002). The oral cavity includes several distinct microbial habitats, such as periodontal pockets and the surfaces of teeth and cheeks (Danser et al., 2003). Microorganisms in the tongue often move around the oral cavity to colonize other areas, facilitated by saliva (Danser et al., 2003). Representative microbes in the tongue include Aggregatibacter actinomycetemcomitans, Capnocytophaga spp., Porphyromonas gingivalis, Prevotella intermedia, Selenomonas spp., and Veillonella atypica (Danser et al., 2003). Oral microbiome is known to be associated with periodontal diseases and systemic diseases (Zhang et al., 2018). Periodontal diseases often include A. actinomycetemcomitans, P. gingivalis, Tannerella forsythia, and Treponema denticola, in the oral microbiome (Kumar et al., 2003; Socransky et al., 1998). Listgarten (1987) reported that oral microbiome directly or indirectly mediates the inflammatory response to develop periodontal disease. According to Scannapieco (2013) study, high proportion of oral pathogen in the oral microbiome tended to have a high rate of C-reactive protein, which is a marker of cardiovascular disease. Also, periodontal disease patients had a high incidence of type 1 or type 2 diabetes (Borgnakke et al., 2013). The recent studies also suggested an association of poor oral health with cancers, Alzeheimer's disease, dermentia, and Rheumatoid arthritis (Ahn et al., 2012; Kamer et al., 2008; Kaur et al., 2013). Thus, oral microbiome has a key role in not only periodontitis but also other systemic diseases.

Periodontitis

Periodontitis is loss of connective tissue attachment leading to the resorption of alveolar bone and subsequent tooth loss that showed gingival inflammation (Armitage, 1995; Sanz et al., 2018; Tonetti et al, 2013). The disease encompasses hard and soft tissues, inflammatory responses, microbial colonization, and adaptive immune responses. In particular, microbial biofilms are the primary etiological factor in chronic periodontitis (Page, 1986; Sanz et al., 2017). The main pathogenic bacteria associated with periodontitis are A. actinomycetemcomitans, P. gingivalis, Treponema denticola, and Tannerella forsythia. These bacteria have a range of virulent characteristics that allow them to colonize the subgingival sites, escape the defense system of the host, and thereby cause tissue damage. The persistence of the immune response of the host also contributes to disease progression (Gupta, 2011; Houle and Grenier, 2003). There is an increase in plaque mass and a shift toward obligatory anaerobic and proteolytic bacteria, many of which are Gram-negative in periodontal diseases.

Conventional treatment modalities for periodontal disease include nonsurgical and surgical management, which emphasizes mechanical debridement, often accompanied by antibiotics. The ideal treatment of chronic periodontitis results in a reduction in periodontal pocket depth, with gains in clinical attachment levels (Goodson et al., 2012). Conventionally, nonsurgical periodontal therapy, including oral hygiene instructions and scaling and root planning, is considered the main treatment modality for chronic periodontitis (Claffey et al., 2004). Systemic antibiotic therapy has been used to reinforce mechanical therapy and support host defense by killing the subgingival microbial pathogens that remain after scaling and root planning (van Winkelhoff et al., 1996). In conjunction with scaling and root planning, systemic antibiotics may offer additional benefits. However, antibiotics are not innocuous drugs because they are accompanied with side effects and the potential emergence of antibiotic-resistant bacterial strains (Kapoor et al., 2012). In addition, drug therapy including nonsteroidal anti-inflammatory drugs (anti-cytokine substances, COX-2 inhibitors, and nitric oxide synthetase inhibitors), antiprotease, and anti-bone resorption agents have been used. Despite the widely discussed clinical benefits of nonsurgical periodontal therapies, including antibiotic therapy, and scaling and root planning therapy, they do not always result in improvements, especially for sites with deep probing depths, or when patients suffer from comorbidities (diabetes mellitus, obesity, and cardiovascular disease; D’Aiuto et al., 2018; Teeuw et al., 2014; Tomasi et al., 2007). In addition, there is no commercialized treatment for fundamental periodontitis that can prevent the destruction of gums and alveolar bone. As a result of these limitations, efforts have been made to explore the use of probiotics as an alternative method to modulate the microbial composition of pathogenic biofilms in conjunction with scaling and root planning (Teughels et al., 2008).

Probiotics and Periodontitis

Probiotics are defined as live microorganisms that confer health benefits to the host when administered in adequate amounts (Hill et al., 2014). Probiotics can be used in a variety of internal organs, including the gut, intestine, oral cavity, female urogenital tract, and respiratory tract (Gibson et al., 2017). Recently, probiotics have been used as substitutes for antibiotics to treat various oral diseases, including periodontitis, dental caries, and halitosis.

The main mechanism of probiotics in alleviating periodontitis is to maintain microbial balance in the oral cavity by competing with oral pathogens. Probiotics produce antimicrobial agents, such as lactic acid, acetic acid, diacetyl, and hydrogen peroxide, which inhibit the growth of periodontal pathogens. In addition, probiotics directly interact with dental plaque formation by the intervention of bacterial attachment to each other, thereby competing with other organisms for attachment to the teeth. Probiotics also modulate the host response to oral pathogens. Probiotics not only affect the local immune response but also modulate the systemic immune response in favor of the host. The immunomodulatory mechanisms of probiotics include an inhibition of periodontal pathogens through secretion of metabolites with antimicrobial activity, a stimulation of specific and non-specific immune responses by T lymphocyte activation, and a stimulation of producing cytokines. In this way, probiotics can be effectively used for periodontal disease (Kaźmierczyk-Winciorek et al., 2021). Probiotics are also known to produce antioxidants that neutralize the free electrons required for the mineral action of plaque and prevent the plaque formation. In addition, probiotics reduce the production of oral pathogen-associated pro-inflammatory cytokines. Plaque causes periodontal disease, and probiotics have been proven to inhibit plaque formation. Their mode of action lowers the pH of the saliva so that the bacteria involved in plaque formation cannot form it, and probiotics compete with other organisms for attachment to the teeth. Probiotics can break down the putrescent odor by fixing volatile sulfur compounds and changing them to the gases needed for metabolism.

Ishikawa et al. (2003) observed in vitro inhibition of P. gingivalis, P. intermedia, and Prevotella nigrescens by daily ingestion of Lactobacillus salivarius in tablet form. The inhibitory activity of homofermentative lactobacilli against periodontal pathogens is principally related to the production of acid, not hydrogen peroxide or bacteriocin (Kõll-Klais et al., 2005). Grudianov et al. (2002) analyzed the effect of probiotics on different grades of periodontitis and reported that probiotic treatment group resulted in better microbiota normalization than the control group (Grudianov et al., 2002; Gupta, 2011). Gupta (2011) reported that the prevalence of Lactobacillus gasseri and Lactobacillus fermentum in the oral cavity was greater in healthy participants than chronic periodontitis patients. In addition, lactobacilli inhibited the growth of periodontopathogens, including A. actinomycetemcomitans, P. gingivalis, and P. intermedia suggesting that lactobacilli residing in the oral cavity play a role in the oral ecological balance. Kõll-Klais et al. (2005) observed that L. gasseri strains isolated from periodontally healthy subjects inhibited the growth of A. actinomycetemcomitans more efficiently than that from periodontally diseased subjects. Randomized controlled clinical trials using Bifidobacterium animalis subsp. lactis HN019-containing probiotic lozenges for chronic periodontitis patients reported the test group significantly decreased probing pocket depth and clinical attachment gain higher than control group (Invernici et al., 2018). Also, periodontal pathogens and expression level of proinflammatory cytokines were significantly decreased in the test group. The randomized controlled clinical trials using probiotics (Lactobacillus reuteri DSM17938 and L. reuteri ATCCPTA5289) for an adjunct to periodontitis reported a significant strengthening of pocket closure and a reduction of periodontal tissue inflammation in probiotics intake group compared to placebo group (Grusovin et al., 2020; İnce et al., 2015; Laleman et al., 2020; Pelekos et al., 2020; Schlagenhauf et al., 2020; Tekce et al., 2015; Teughels et al., 2013; Vicario et al., 2013; Vivekananda et al., 2010).

Probiotics-Mediated Bioconversion (PMB)

Definition of probiotics-mediated bioconversion (PMB)

Microbial bioconversion is the process of converting organic compounds into structurally related compounds through enzymatic reactions using microorganisms (Perkins et al., 2016). This strategy has great potential to produce novel bioactive metabolites (Fig. 1). Furthermore, Pervaiz et al. (2013) suggested that microbial bioconversion is a cost-effective and environmentally protective tool for drug design. Probiotics are suitable for the conversion of biomass into value-added products because of their potential nutritional benefits (Aarnikunnas et al., 2003; Berezina et al., 2010; John et al., 2007).

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Fig. 1. Mechanism and function of probiotics-mediated bioconversion.
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Classification of probiotics-mediated bioconversion (PMB)

Dairy products, medicinal plants, or plant compounds contain bioactive compounds, which can be transformed by PMB process, expressing or enhancing biological activity (Table 1). Most PMB metabolites from fermented dairy products include proteins, peptides, oligosaccharides, fats, and organic acids (Ebringer et al., 2008). In particular, lactic acid bacteria (LAB) in fermented dairy products hydrolyze proteins and release specific peptides that have bioactive, immunomodulatory, antifungal, antimicrobial, antioxidant, and anticarcinogenic activities (Fernandez et al., 2017). Probiotics containing many Lactobacillus strains show high hydrolytic activity of milk protein that leads to release bioactive peptides. Bioactive peptides released from fermented milk by Lactobacillus spp. have been reported in various studies to have antioxidant activity and angiotensin I-converting enzyme (ACE) inhibitory activity (Elfahri, 2012; Gobbetti et al., 2004; Gonzalez-Gonzalez et al., 2011; Nejati et al., 2013; Solieri et al., 2015). Digestibility of fat is another bioactive ingredient in fermented milk. Conjugated linoleic acid (CLA) is one of the major ingredients produced by milk fermentation, and the CLA exhibits antidiabetic, antiatherogenic, and immune system modulator effects (Xu et al., 2005). In addition, polyphenol-rich foods have significant antioxidant, anti-inflammatory, and proapoptotic effects, suggesting their use as chemo-preventive agents (Stagos et al., 2012). However, most polyphenols cannot be absorbed in their native forms, and the polyphenols should be modified by microbial conversion (Selma et al., 2009). Rupasinghe et al. (2019) reported that PMB enhanced the bioactivities by producing additional metabolites of cranberry proanthocyanidins. Cranberry proanthocyanidin extract bioconverted by Lactobacillus rhamnosus completely inhibited HepG2 cell proliferation with IC50 values that indicates the amount of bioconversion to inhibit HepG2 cell proliferation by 50%. The major metabolites produced from PMB are 4-hydroxyphenylacetic acid, 3-(4-hydroxyphenyl) propionic acid, catechol, hydrocinnamic acid and pyrogallol (Rupasinhe et al., 2019). Liu et al. (2018a) reported that the major bioactive metabolites for the antioxidative activity of PMB of polyphenol compounds contained epicatechin, catechin, caffeic acid, chlorogenic acid, and hyperoxide. Moreover, L. reuteri and Enterococcus faecalis showed a high bioconversion rate and high anti-radical activity, which might have excellent potential for PMB (Liu et al., 2018a). The pharmacological effects of PMB are also well known. The main bioactive components in ginseng are ginsenosides Rb1, Rb2, and Rc, which are transformed to C-K by the human gut microbiome, which has anticancer effects in tumor cells (Bae et al., 2003). Jung et al. (2019) suggested that bioconversion of red ginseng by Lactobacillus plantarum KCCM11613P generates ginsenoside Rd, which may be converted to compound K to make the inhibitor material in oxidation. Leuconostoc mesenteroides LH1 also produces β-glucosidase to convert Rb1 to Rd, F2, and C-K (Quan et al., 2011). The PMB of Artemisia species also generates novel bioactive metabolites to enhance their functions. Specifically, PMB of Artemisia capillaris exhibited enhanced anti-inflammatory activity (Son et al., 2017), and the extracts of Artemisia argyi folium exhibited immunomodulatory activities, including inhibition of pro-inflammatory cytokines IL-6 and TNF-α production in macrophages (Han et al., 2008). In addition, PMB of Artemisia princeps Pampanini inhibited the degranulation of RBL-2H3 cells, which showed anti-allergic effects (Shin et al., 2006).

Table 1. Probiotics mediated bioconversion (PMB) list
Metabolites Bioconverted substrates Probiotics Beneficial effects References
Bioactive peptides Milk Lactobacillus fermentum Antioxidant activity Ebringer et al., 2008
Catechin (flavonoid) Grape seed polyphenols Lactobacillus plantarum Antioxidant activity Tabasco et al., 2011
Daidzein and genistein (flavonoid) Black soymilk Streptococcus thermophiles Antioxidant activity Lee et al., 2015
Chlorogenic acid, caffeic acid, atechin, picatechin, and hyperoside (polyphenol compounds) Lotus seed epicarp Lactobacillus reuteri, Enterococcus faecalis Antioxidant activity Liu et al., 2018a
Gallic acid and protocatechuic acid (phenolic acid) Wine (Pinot Noir) L. plantarum Antioxidant activity Suthanthangjai et al., 2014
Phenolic content Inula britannica extract Lactobacillus acidophilus, S. thermophilus Antioxidant activity Lee et al., 2016
Ginsenoside Ginseng L. plantarum Antioxidant activity Jung et al., 2019
Total polyphenol and flavonoid contents Forsythiae Fructus L. plantarum, L. acidophilus, Lactobacillus casei, Lactobacillus lactis, Leuconostoc mesenteroides Antioxidant, anti-inflammatory activity Yang and Choe, 2011
F5 peptide Milk Lactobacillus helveticus Anti-inflammatory activity Tellez et al., 2010
Isoflavone aglycones Soy milks L. plantarum, Lactobaciilus rhamnosus, L. fermentum, Immunomodulatory effect on Caco-2/T27 cells Di Cagno et al., 2010
Oleuropein Olive extract L. plantarum, Lactobacillus paracasei Anti-microbial activity Omar, 2010
Isoflavone aglycone Biotin-supplemented soymilk L. fermentum Increased permeability of treated cell membranes Ewe et al., 2012
Total phenolic contents and total flavonoids Magnolia flower petal extract Pediococcus acidilactici Antioxidant, anticancer activity Park et al., 2015
Crude, dihydrochalcone, anthocyanin, proanthocyanidin, and catechin Cranberry proanthocyanidins L. rhamnosus Anticancer activity Rupasinghe et al., 2019
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Mechanism of probiotics-mediated bioconversion (PMB) action

The mechanism of PMB action differs depending on the substance and bioconversion, and the bioactive compounds are also diverse. Bioactive peptides are usually produced by LAB proteolysis in fermented milk. For example, fermented milk containing Lactobacillus lactis releases biologically active oligopeptides such as casomorphines, lactorphines, casokinines, and immunopeptides from α-casein, β-casein, and κ-casein (Ebringer et al., 2008). The mechanisms of PMB action using polyphenol-rich foods include deglycosylation, ring fission, dehydroxylation, decarboxylation, or reduction of carbon double bonds (Aura, 2008; Rice-Evans et al., 1997), which convert a few polyphenols into bioactive forms (Thilakarathna et al., 2018). β-Glucosidase catalyzes the hydrolysis of glycosidic bonds to remove glucopyranosyl residues from the nonreducing end of β-glucosides (Ketudat Cairns and Esen, 2010). It is present in bacteria, fungi, and yeast, and exists in some Lactobacillus species (Spano et al., 2005). β-Glucosidase hydrolyzes a wide range of substrates to produce specific aglycones that show bioactive effects (Grandits et al., 2013). These bioactive metabolites, including γ-aminobutyric acid (GABA), hydroxytyrosol, ginsenosides, isoflavones, and phenolic compounds have been known to have antioxidant activity as a major beneficial effect (Lee and Paik, 2017). In addition, the metabolites have anti-inflammatory effects (Yang and Choe, 2011), permeabilizing the membrane of treated cells to act as metabolites (Ewe et al., 2012), and show anticancer activity (Park et al., 2015). For example, Lactobacillus metabolizes polyphenols using glycosidase, and then converting them to secondary metabolites such as catechol, gallic acid, and pyrogallol (Rodríguez et al., 2009; Tabasco et al., 2011). In addition, L. plantarum metabolizes phenolic acids and their derivatives, esters, through the activities of feruloyl esterase, tannase, phenolic acid decarboxylase, and phenolic acid reductase (Curiel et al., 2009; Rodríguez et al., 2008; Wang et al., 2004). Lactobacilli contribute to the release of phenolic acids bound to protocatechuic and p-hydroxybenzoic acids that are insoluble plant cell wall materials. Therefore, probiotics play a major role in increasing the antioxidant activity of polyphenols through the PMB process (Jakesevic et al., 2011; Li et al., 2013).

The mechanism of antimicrobial activity by PMB has also been suggested. PMB using whey showed antimicrobial activity that reduced Escherichia coli and Listeria monocytogenes (Lee et al., 2020). This result suggested that quorum sensing and intercellular connections to form a biofilm structure composed of a bacterial community and extracellular polymeric matrix were inhibited by PMB with whey. According to Zokaityte et al. (2020), the antimicrobial activity of PMB using apple by-products might be due to the synthesis of galactobiose and galactotriose. PMB using apple by-products showed high antimicrobial activity, and high synthesis activity of galactobiose and galactotriose. Also, the PMB showed high production of galactooligosaccharides.

Probiotics-Mediated Bioconversion (PMB) and Periodontitis

Bioactive metabolites for the regulation of periodontal disease

Various studies have reported that PMB regulates periodontal disease. Recent research presented that an administration of fermented milk using Lactobacillus curvatus to periodontitis-induced mice leads to a significant decrease of the expression levels of inflammatory cytokines in the oral gingiva tissue and colon tissue compared to control group (Choi et al., 2021). Also, randomized clinical trial was performed to confirm the effect of PMB with fermented bovine milk in periodontal disease, and papillary-marginal-attached index, gingival index, and probing depth score of the experimental group showed greater tendency than those of placebo group (Oda et al., 2019). Liu et al. (2018b) studied the effect of an ethanol extract of PMB with fermented skim milk on periodontal inflammation in rats. According to this study, the PMB-treated rats showed decreases in the levels of alveolar bone loss and pro-inflammatory cytokines, and oxidative stresses in periodontal tissue. Vieira et al. (2021) reported that PMB with milk kefir reduced alveolar bone loss and pro-inflammatory cytokine expression level on periodontitis-induced rats. Several studies demonstrated that 10-hydroxy-cis-12-octadecenoic acid (HYA) and 10-oxo-trans-11-octadecenoic acid (KetoC), the main bioactive PMB metabolites generated by L. plantarum through saturation metabolism of polyunsaturated fatty acids, were effective in alleviating periodontal disease (Kishino et al., 2013; Sulijaya et al., 2018; Yamada et al., 2018).

Role of probiotics-mediated bioconversion (PMB) in periodontitis
Antioxidative activity

Reactive oxygen species (ROS) induced by pathogenic bacteria play an important physiological role in intracellular signaling pathways and promote the production of pro-inflammatory cytokines in gingival epithelial cells (Wang et al., 2017). ROS production results in E-cadherin damage in the junctional epithelium of the periodontium (Lee et al., 2016a). Thus, periodontitis can be defined as a disease associated with oxidative stress (Varela-López et al., 2015). Enzymatic antioxidants include superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), and these antioxidants convert superoxide radical and hydrogen peroxide into harmless product water (Hyun et al., 2002; Weydert and Cullen, 2010). According to Novakovic et al. (2014), CAT, GPx, and SOD levels were significantly higher in healthy periodontal patients than in patients with chronic periodontitis. Fermented goat milk increased the antioxidant activity and reduced GPx1 expression, thus limiting biomolecular oxidative damage compared to unfermented milk (Moreno-Fernandez et al., 2017). Ebringer et al. (2008) suggested that the main antioxidant factors of fermented milk were peptides released from α-casein, α-lactalbumin, and β-lactoglobulin (Ebringer et al., 2008). KetoC, a PMB metabolite, stimulates antioxidant-related gene expression, and its treatment increased heme oxygenase-1 expression in gingival epithelial cells (Yokoji-Takeuchi et al., 2020). In addition, the metabolite activates Nrf2-ARE signaling by binding to the G protein-coupled receptor (GPR) efficiently (Yokoji-Takeuchi et al., 2020). Flavonoid compounds, such as catechin, daidzein, and genistein, which are major bioactive metabolites produced in the PMB process, increased the 1,1-diphenyl-2-picryl hydrazyl (DPPH) free radical scavenging activities (Lee et al., 2015). Phenolic compounds are major products of fermentation, also increase anti-radical activity (Lee et al., 2016b; Liu et al., 2018a; Suthanthangjai et al., 2014). Ginsenoside, an active compound in ginseng, is converted to smaller compound such as compound K during fermentation with probiotics, and this compound has enhanced inhibitory activity of β-carotene and linoleic acid oxidation (Jung et al., 2019). In addition, PMB using ginseng has bioactive metabolites such as flavonoids produced during the fermentation process of probiotics and ginseng, displaying higher SOD-like activity than general ginseng (Doh et al., 2010). Hence, flavonoid compounds derived from PMB, which have antioxidant and anti-radical activities, are thought to be effective against periodontitis.

Anti-inflammatory activity

Anti-inflammatory activity has become a treatment strategy for periodontitis (Sulijaya et al., 2019). Fermented milk with Lactobacillus helveticus LH-2 and its fraction peptide F5 increased TNF-α, IL-1β, and IL-6 through stimulation of macrophages with production of nitric oxide and phagocytic activity, which showed that the F5 peptide fraction could modulate macrophage functions (Tellez et al., 2010). KetoC exhibits anti-inflammatory efficacy through mitogen-activated protein kinase and NF-κB signaling in RAW 264.7 macrophages induced by bacterial lipopolysaccharide (Yang et al., 2017). In addition, KetoC binding to its receptor GPR 120 suppressed TNF-α, IL-1β, and IL-6 in macrophages stimulated with P. gingivalis LPS to partially inhibit NF-κB and p65, which could be an anti-inflammatory bioactive metabolite in periodontal disease (Sulijaya et al., 2018). HYA inhibits the loss of alveolar bone by reducing the mRNA levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in gingival tissue in vivo (Yamada et al., 2018). HYA also decreased the expression of tumor necrosis factor receptor 2 (TNFR2) in colitis mice, thereby decreasing the production of pro-inflammatory cytokines (Miyamoto et al., 2015). The total polyphenol and flavonoid contents and bioactive metabolites of PMB of Forsythiae Fructus extracts inhibited nitric oxide synthesis (Yang and Choe, 2011). PMB of soymilk synthesized isoflavone aglycones (daidzein, genistein, and glycitein) and equol, and PMB inhibited the inflammatory status of Caco-2/TC7 cells (Di Cagno et al., 2010). It is believed that the anti-inflammatory effects of PMB, such as HYA, polyphenol, and flavonoid contents, daidzein, genistein, and glycitein, may also act on periodontitis.

Antimicrobial activity

Glycosylated caseinomacropeptide, produced by hydrolyzing the κ-casein phenylalanine-105 and methionine-106 peptide bonds by the action of chymosin in the process of milk fermentation, inhibited the entry of toxins, pathogenic adhesion to the cell wall, and infections by oral pathogens such as P. gingivalis, S. mutans, and Streptococcus sobrinus (Córdova-Dávalos et al., 2019; Malkoski et al., 2001). KetoC inhibited the growth of P. gingivalisin vitro and reduced alveolar bone destruction in a periodontitis mouse model (Sulijaya et al., 2019). Furthermore, fluorescence microscopy after LIVE/DEAD bacterial staining of KetoC-treated P. gingivalis cells showed that KetoC decreased the viability of the bacteria (Sulijaya et al., 2019). In addition, a comparative analysis of the inhibitory effects of KetoC and KetoB against P. gingivalis showed that only KetoC lowered the viability and proliferation rate of P. gingivalis (Sulijaya et al., 2019). According to Lee et al. (2020) study, PMB of whey showed anti-biofilm effect against pathogenic bacteria. The PMB of olive produces oleuropein, a type of phenolic compound, which exhibits antimicrobial activity (Omar, 2010). In other words, olive extract-derived oleuropein generated by probiotic-mediated fermentation hindered the growth of Bacillus cereus, Campylobacter jejuni, Escherichia coli, Helicobacter pylori, Klebsiella pneumoniae, Salmonella Enteritidis, and Staphylococcus aureus (Omar, 2010). Also, PMB of soy increased aglycone production by β-glucosidase activity of probiotics and inhibited the growth of oral pathogens (Enterococcus faecalis, Streptococcus pyogenes, and S. aureus; How et al., 2020).

Epithelial barrier function

Destruction of the gingival epithelial barrier by proteases and infiltration into the basal tissue causes periodontal tissue disruption in periodontitis (Brooke et al., 2012; DiRienzo, 2014). Various bacteria may interact with the epithelial cells, generating gingival barrier function (Takahashi et al., 2019). Probiotics in PMB induce antimicrobial peptides against barrier-disrupting microbial pathogens (Diamond et al., 2009; Ostaff et al., 2013; Sulijaya et al., 2016). LfcinB, known as a major antibacterial peptide in fermented milk, showed efficacy in the intestinal epithelial barrier function and was also suggested to be effective in improving intestinal tight junctions (Haiwen et al., 2019; Sibel Akalın, 2014). Bacteriocins derived from PMB such as salivaricin, reuterin, plantaricin, and nisin are also main antimicrobial peptides that relevant to oral cavity (Baca-Castanon et al., 2015; Heeney et al., 2019; Masdea et al., 2012). In addition, PMB metabolites, such as HYA and KetoC, stimulate tight junction-related gene expression to regulate the epithelial barrier. An in vivo study using a mouse experimental periodontitis model showed that HYA treatment of periodontitis-induced mice reduced inflammation and damage in mouse gingival tissues by inhibiting the breakdown of E-cadherin/-catenin in P. gingivalis, thereby strengthening the epithelial barrier junction (Yamada et al., 2018).

Conclusion

The aim of this review was to summarize the use of PMB and the major metabolites in the oral cavity. The microbial environment in the oral cavity is highly correlated with periodontitis, and various treatment methods have been proposed to control the disease. Studies on various mechanisms to control periodontitis by PMB and probiotics have been reported. Although there have not been many studies on PMB that control the oral cavity of periodontitis, there have been many studies on their antioxidant, anti-inflammatory, and antimicrobial effects in relation to periodontitis. The main components of these activities include KetoC and HYA biotransformed from phenols or flavonoid compounds, as a result of probiotic-mediated fermentation of dairy products, plants, or fruits. This suggests that PMB is effective against periodontitis, and studies are needed to confirm the treatment effect on periodontitis using bioactive compounds of PMB, especially to confirm the efficacy of KetoC and HYA on periodontitis.

Conflicts of Interest

The authors declare no potential conflicts of interest.

Acknowledgements

This study was supported by Wonkwang University in 2021.

Author Contributions

Conceptualization: Yoon YH, Choi KH. Writing - original draft: Lee Y. Writing - review and editing: Lee Y, Yoon YH, Choi KH.

Ethics Approval

This article does not require IRB/IACUC approval because there is no human or animal participants.

References

1.

Aarnikunnas J, Von Weymarn N, Rönnholm K, Leisola M, Palva A. 2003; Metabolic engineering of Lactobacillus fermentum for production of mannitol and pure L-lactic acid or pyruvate. Biotechnol Bioeng. 82:653-663

2.

Aas JA, Paster BJ, Stokes LN, Olsen I, Dewhirst FE. 2005; Defining the normal bacterial flora of the oral cavity. J Clin Microbiol. 43:5721-5732

3.

Ahn J, Chen CY, Hayes RB. 2012; Oral microbiome and oral and gastrointestinal cancer risk. Cancer Causes Control. 23:399-404

4.

Armitage GC. 1995; Clinical evaluation of periodontal diseases. Periodontol 2000. 7:39-53

5.

Aura AM. 2008; Microbial metabolism of dietary phenolic compounds in the colon. Phytochem Rev. 7:407-429

6.

Baca-Castañón ML, De la Garza-Ramos MA, Alcázar-Pizaña AG, Grondin Y, Coronado-Mendoza A, Sánchez-Najera RI, Cárdenas-Estrada E, Medina-De la Garza CE, Escamilla-García E. 2015; Antimicrobial effect of Lactobacillus reuteri on cariogenic bacteria Streptococcus gordonii, Streptococcus mutans, and periodontal diseases Actinomyces naeslundii and Tannerella forsythia. Probiotics Antimicrob. 7:1-8

7.

Bae EA, Kim NY, Han MJ, Choo MK, Kim DH. 2003; Transformation of ginsenosides to compound K (IH-901) by lactic acid bacteria of human intestine. J Microbiol Biotechnol. 13:9-14.

8.

Berezina OV, Zakharova NV, Brandt A, Yarotsky SV, Schwarz WH, Zverlov VV. 2010; Reconstructing the clostridial n-butanol metabolic pathway in Lactobacillus brevis. Appl Microbiol Biotechnol. 87:635-646

9.

Berg G, Rybakova D, Fischer D, Cernava T, Vergès MCC, Charles T, Chen X, Cocolin L, Eversole K, Corral GH, Kazou M, Kinkel L, Lange L, Lima N, Loy A, Macklin JA, Maguin E, Mauchline T, McClure R, Mitter B, Ryan M, Sarand I, Smidt H, Schelkle B, Roume H, Kiran GS, Selvin J, de Souza RSC, van Overbeek L, Singh BK, Wagner M, Walsh A, Sessitsch A, Schloter M. 2020; Microbiome definition re-visited: Old concepts and new challenges. Microbiome. 8:103

10.

Borgnakke WS, Ylöstalo PV, Taylor GW, Genco RJ. 2013; Effect of periodontal disease on diabetes: Systematic review of epidemiologic observational evidence. J Periodontol. 84:S135-S152

11.

Brooke MA, Nitoiu D, Kelsell DP. 2012; Cell-cell connectivity: Desmosomes and disease. J Pathol. 226:158-171

12.

Choi Y, Park E, Kim S, Ha J, Oh H, Kim Y, Lee Y, Seo Y, Kang J, Lee S, Lee H, Yoon Y, Choi KH. 2021; Fermented milk with Lactobacillus curvatus SMFM2016-NK alleviates periodontal and gut inflammation, and alters oral and gut microbiota. J Dairy Sci. 104:5197-5207

13.

Claffey N, Polyzois I, Ziaka P. 2004; An overview of nonsurgical and surgical therapy. Periodontol 2000. 36:35-44

14.

Córdova-Dávalos LE, Jiménez M, Salinas E. 2019; Glycomacropeptide bioactivity and health: A review highlighting action mechanisms and signaling pathways. Nutrients. 11:598

15.

Curiel JA, Rodríguez H, Acebrón I, Mancheño JM, De Las Rivas B, Muñoz R. 2009; Production and physicochemical properties of recombinant Lactobacillus plantarum tannase. J Agric Food Chem. 57:6224-6230

16.

D’Aiuto F, Gkranias N, Bhowruth D, Khan T, Orlandi M, Suvan J, Masi S, Tsakos G, Hurel S, Hingorani AD, Donos N, Deanfield JE. For the TASTE Group. 2018. Systemic effects of periodontitis treatment in patients with type 2 diabetes: A 12 month, single-centre, investigator-masked, randomised trial. Lancet Diabetes Endocrinol. 6:954-965

17.

Danser MM, Gómez SM, Van der Weijden GA. 2003; Tongue coating and tongue brushing: A literature review. Int J Dent Hyg. 1:151-158

18.

Dewhirst FE, Chen T, Izard J, Paster BJ, Tanner ACR, Yu WH, Lakshmanan A, Wade WG. 2010; The human oral microbiome. J Bacteriol. 192:5002-5017

19.

Di Cagno R, Mazzacane F, Rizzello CG, Vincentini O, Silano M, Giuliani G, De Angelis M, Gobbetti M. 2010; Synthesis of isoflavone aglycones and equol in soy milks fermented by food-related lactic acid bacteria and their effect on human intestinal Caco-2 cells. J Agric Food Chem. 58:10338-10346

20.

Diamond G, Beckloff N, Weinberg A, Kisich KO. 2009; The roles of antimicrobial peptides in innate host defense. Curr Pharm Des. 15:2377-2392

21.

Di Rienzo JM. 2014; Breaking the gingival epithelial barrier: Role of the Aggregatibacter actinomycetemcomitans cytolethal distending toxin in oral infectious disease. Cells. 3:476-499

22.

Doh ES, Chang JP, Lee KH, Seong NS. 2010; Ginsenoside change and antioxidation activity of fermented ginseng. Korean J Med Crop Sci. 18:255-265.

23.

Ebringer L, Ferenčík M, Krajčovič J. 2008; Beneficial health effects of milk and fermented dairy products: Review. Folia Microbiol. 53:378-394

24.

Elfahri K. 2012 Release of bioactive peptides from milk proteins by Lactobacillus species. M.S. thesis,Victoria Univ. Melbourne, Australia: .

25.

Ewe JA, Wan-Abdullah WN, Alias AK, Liong MT. 2012; Effects of ultrasound on growth, bioconversion of isoflavones and probiotic properties of parent and subsequent passages of Lactobacillus fermentum BT 8633 in biotin-supplemented soymilk. Ultrason Sonochem. 19:890-900

26.

Fernandez MA, Picard-Deland É, Le Barz M, Daniel N, Marette A. 2017; Yogurt and health. In Fermented foods in health and disease prevention. 1st ed In: Frias J, Martinez-Villaluenga C, Peñas E, editors.(ed)Elsevier Science & Technology Books. Québec, QU, Canada: pp p. 305-338

27.

Gibson GR, Hutkins R, Sanders ME, Prescott SL, Reimer RA, Salminen SJ, Scott K, Stanton C, Swanson KS, Cani PD, Verbeke K, Reid G. 2017; Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nat Rev Gastroenterol Hepatol. 14:491-502

28.

Gobbetti M, Minervini F, Rizzello CG. 2004; Angiotensin I-converting-enzyme-inhibitory and antimicrobial bioactive peptides. Int J Dairy Technol. 57:173-188

29.

Gonzalez-Gonzalez CR, Tuohy KM, Jauregi P. 2011; Production of angiotensin-I-converting enzyme (ACE) inhibitory activity in milk fermented with probiotic strains: Effects of calcium, pH and peptides on the ACE-inhibitory activity. Int Dairy J. 21:615-622

30.

Goodson JM, Haffajee AD, Socransky SS, Kent R, Teles R, Hasturk H, Bogren A, Van Dyke T, Wennstrom J, Lindhe J. 2012; Control of periodontal infections: A randomized controlled trial I. The primary outcome attachment gain and pocket depth reduction at treated sites. J Clin Periodontol. 39:526-536

31.

Grandits M, Michlmayr H, Sygmund C, Oostenbrink C. 2013; Calculation of substrate binding affinities for a bacterial GH78 rhamnosidase through molecular dynamics simulations. J Mol Catal B Enzym. 92:34-43

32.

Grudianov AI, Dmitrieva NA, Fomenko EV. 2002; Use of probiotics bifidumbacterin and acilact in tablets in therapy of periodontal inflammations. Stomatologiia. 81:39-43.

33.

Grusovin MG, Bossini S, Calza S, Cappa V, Garzetti G, Scotti E, Gherlone EF, Mensi M. 2020; Clinical efficacy of Lactobacillus reuteri-containing lozenges in the supportive therapy of generalized periodontitis stage III and IV, grade C: 1-year results of a double-blind randomized placebo-controlled pilot study. Clin Oral Invest. 24:2015-2024

34.

Gupta G. 2011; Probiotics and periodontal health. J Med Life. 4:387-394

35.

Haiwen Z, Rui H, Bingxi Z, Qingfeng G, Jifeng Z, Xuemei W, Beibei W. 2019; Oral administration of bovine lactoferrin-derived lactoferricin (Lfcin) B could attenuate enterohemorrhagic Escherichia coli O157:H7 induced intestinal disease through improving intestinal barrier function and microbiota. J Agric Food Chem. 67:3932-3945

36.

Han HS, Park WS, Lee YJ. 2008; Studies on the immunomodulating acitivity of fermented Artemisiae argyifolium extract. Korean J Herbol. 23:103-112.

37.

Heeney DD, Zhai Z, Bendiks Z, Barouei J, Martinic A, Slupsky C, Marco ML. 2019; Lactobacillus plantarum bacteriocin is associated with intestinal and systemic improvements in diet-induced obese mice and maintains epithelial barrier integrity in vitro. Gut Microbes. 10:382-397

38.

Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, Morelli L, Berni Canani R, Flint HJ, Salminen S, Calder PC, Sanders ME. 2014; Expert consensus document: The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol. 11:506-514

39.

Houle MA, Grenier D. 2003; Periodontal diseases: Current knowledge: Current concepts in periodontal diseases. Med Mal Infect. 33:331-340.

40.

How YH, Ewe JA, Song KP, Kuan CH, Kuan CS, Yeo SK. 2020; Soy fermentation by indigenous oral probiotic Streptococcus spp. and its antimicrobial activity against oral pathogens. Int Food Res J. 27:357-365.

41.

Hyun DH, Lee M, Hattori N, Kubo SI, Mizuno Y, Halliwell B, Jenner P. 2002; Effect of wild-type or mutant Parkin on oxidative damage, nitric oxide, antioxidant defenses, and the proteasome. J Biol Chem. 277:28572-28577

42.

İnce G, Gürsoy H, İpçi SD, Cakar G, Emekli-Alturfan E, Yılmaz S. 2015; Clinical and biochemical evaluation of lozenges containing Lactobacillus reuteri as an adjunct to non-surgical periodontal therapy in chronic periodontitis. J Periodontol. 86:746-754

43.

Invernici MM, Salvador SL, Silva PHF, Soares MSM, Casarin R, Palioto DB, Souza SLS, Taba M, Novaes AB, Furlaneto FAC, Messora MR. 2018; Effects of Bifidobacterium probiotic on the treatment of chronic periodontitis: A randomized clinical trial. J Clin Periodontol. 45:1198-1210

44.

Ishikawa H, Aiba Y, Nakanishi M, Oh-hashi Y, Koga Y. 2003; Suppression of periodontal pathogenic bacteria in the saliva of humans by the administration of Lactobacillus salivarius TI 2711. J Jpn Soc Periodontol. 45:105-112

45.

Jakesevic M, Aaby K, Borge GIA, Jeppsson B, Ahrné S, Molin G. 2011; Antioxidative protection of dietary bilberry, chokeberry and Lactobacillus plantarum HEAL19 in mice subjected to intestinal oxidative stress by ischemia-reperfusion. BMC Complement Altern Med. 11:8

46.

John RP, Nampoothiri KM, Pandey A. 2007; Fermentative production of lactic acid from biomass: An overview on process developments and future perspectives. Appl Microbiol Biotechnol. 74:524-534

47.

Jung J, Jang HJ, Eom SJ, Choi NS, Lee NK, Paik HD. 2019; Fermentation of red ginseng extract by the probiotic Lactobacillus plantarum KCCM 11613P: Ginsenoside conversion and antioxidant effects. J Ginseng Res. 43:20-26

48.

Kamer AR, Dasanayake AP, Craig RG, Glodzik-Sobanska L, de Bry M, Leon MJ. 2008; Alzheimer’s disease and peripheral infections: The possible contribution from periodontal infections, model and hypothesis. J Alzheimers Dis. 13:437-449

49.

Kapoor A, Malhotra R, Grover V, Grover D. 2012; Systemic antibiotic therapy in periodontics. Dent Res J. 9:505-515

50.

Kaur S, White S, Bartold PM. 2013; Periodontal disease and rheumatoid arthritis: A systematic review. J Dent Res. 92:399-408

51.

Kaźmierczyk-Winciorek M, Nędzi-Góra M, Słotwińska SM. 2021; The immunomodulating role of probiotics in the prevention and treatment of oral diseases. Cent Eur J Immunol. 46:99-104

52.

Ketudat Cairns JR, Esen A. 2010; β-Glucosidases. Cell Mol Life Sci. 67:3389-3405

53.

Kishino S, Takeuchi M, Park SB, Hirata A, Kitamura N, Kunisawa J, Kiyono H, Iwamoto R, Isobe Y, Arita M, Arai H, Ueda K, Shima J, Takahashi S, Yokozeki K, Shimizu S, Ogawa J. 2013; Polyunsaturated fatty acid saturation by gut lactic acid bacteria affecting host lipid composition. Proc Natl Acad Sci USA. 110:17808-17813

54.

Kolenbrander PE, Andersen RN, Blehert DS, Egland PG, Foster JS, Palmer RJ. 2002; Communication among oral bacteria. Microbiol Mol Biol Rev. 66:486-505

55.

Kõll-Klais P, Mändar R, Leibur E, Marcotte H, Hammarström L, Mikelsaar M. 2005; Oral lactobacilli in chronic periodontitis and periodontal health: Species composition and antimicrobial activity. Oral Microbiol Immunol. 20:354-361

56.

Kumar PS, Griffen AL, Barton JA, Paster BJ, Moeschberger ML, Leys EJ. 2003; New bacterial species associated with chronic periodontitis. J Dent Res. 82:338-344

57.

Laleman I, Pauwels M, Quirynen M, Teughels W. 2020; A dual-strain Lactobacilli reuteri probiotic improves the treatment of residual pockets: A randomized controlled clinical trial. J Clin Periodontol. 47:43-53

58.

Lee G, Kim HJ, Kim HM. 2016a; RhoA-JNK regulates the E-cadherin junctions of human gingival epithelial cells. J Dent Res. 95:284-291

59.

Lee J, Kim M, Kim D, Yu C, Kim BS, Lee JS, Kang SS. 2020; Anti-biofilm effect of bioconversion of whey by lactic acid bacteria against foodborne pathogenic bacteria. Curr Top Lactic Acid Bacteria Probiotics. 6:25-31

60.

Lee M, Hong GE, Zhang H, Yang CY, Han KH, Mandal PK, Lee CH. 2015; Production of the isoflavone aglycone and antioxidant activities in black soymilk using fermentation with Streptococcus thermophilus S10. Food Sci Biotechnol. 24:537-544

61.

Lee NK, Jeewanthi RKC, Park EH, Paik HD. 2016b; Short communication: Physicochemical and antioxidant properties of Cheddar-type cheese fortified with Inula britannica extract. J Dairy Sci. 99:83-88

62.

Lee NK, Paik HD. 2017; Bioconversion using lactic acid bacteria: Ginsenosides, GABA, and phenolic compounds. J Microbiol Biotechnol. 27:869-877

63.

Li S, Chen L, Yang T, Wu Q, Lv Z, Xie B, Sun Z. 2013; Increasing antioxidant activity of procyanidin extracts from the pericarp of Litchi chinensis processing waste by two probiotic bacteria bioconversions. J Agric Food Chem. 61:2506-2512

64.

Listgarten MA. 1987; Nature of periodontal diseases: Pathogenic mechanisms. J Periodontal Res. 22:172-178

65.

Liu TH, Tsai TY, Pan TM. 2018b; Effects of an ethanol extract from Lactobacillus paracasei subsp. paracasei NTU 101 fermented skimmed milk on lipopolysaccharide-induced periodontal inflammation in rats. Food Funct. 9:4916-4925

66.

Liu Y, Hui X, Ibrahim SA, Huang W. 2018a; Increasing antiradical activity of polyphenols from lotus seed epicarp by probiotic bacteria bioconversion. Molecules. 23:2667

67.

Malkoski M, Dashper SG, O’Brien-Simpson NM, Talbo GH, Macris M, Cross KJ, Reynolds EC. 2001; Kappacin, a novel antibacterial peptide from bovine milk. Antimicrob Agents Chemother. 45:2309-2315

68.

Masdea L, Kulik EM, Hauser-Gerspach I, Ramseier AM, Filippi A, Waltimo T. 2012; Antimicrobial activity of Streptococcus salivarius K12 on bacteria involved in oral malodour. Arch Oral Biol. 57:1041-1047

69.

Miyamoto J, Mizukure T, Park SB, Kishino S, Kimura I, Hirano K, Bergamo P, Rossi M, Suzuki T, Arita M, Ogawa J, Tanabe S. 2015; A gut microbial metabolite of linoleic acid, 10-hydroxy-cis-12-octadecenoic acid, ameliorates intestinal epithelial barrier impairment partially via GPR40-MEK-ERK pathway. J Biol Chem. 290:2902-2918

70.

Moreno-Fernandez J, Diaz-Castro J, Alférez MJM, Boesch C, Nestares T, López-Aliaga I. 2017; Fermented goat milk improves antioxidant status and protects from oxidative damage to biomolecules during anemia recovery. J Sci Food Agric. 97:1433-1442

71.

Nejati F, Rizzello CG, Di Cagno R, Sheikh-Zeinoddin M, Diviccaro A, Minervini F, Gobbetti M. 2013; Manufacture of a functional fermented milk enriched of angiotensin-I converting enzyme (ACE)-inhibitory peptides and γ-amino butyric acid (GABA). LWT-Food Sci Technol. 51:183-189

72.

Novakovic N, Todorovic T, Rakic M, Milinkovic I, Dozic I, Jankovic S, Aleksic Z, Cakic S. 2014; Salivary antioxidants as periodontal biomarkers in evaluation of tissue status and treatment outcome. J Periodont Res. 49:129-136

73.

Oda Y, Furutani C, Mizota Y, Wakita A, Mimura S, Kihara T, Ohara M, Okada A, Okada M, Nikawa H. 2019; Effect of bovine milk fermented with Lactobacillus rhamnosus L8020 on periodontal disease in individuals with intellectual disability: A randomized clinical trial. J Appl Oral Sci. 27e20180564

74.

Omar SH. 2010; Oleuropein in olive and its pharmacological effects. Sci Pharm. 78:133-154

75.

Ostaff MJ, Stange EF, Wehkamp J. 2013; Antimicrobial peptides and gut microbiota in homeostasis and pathology. EMBO Mol Med. 5:1465-1483

76.

Page RC. 1986; Gingivitis. J Clin Periodontol. 13:345-355

77.

Park H, Kim HS, Eom SJ, Kim KT, Paik HD. 2015; Antioxidative and anticanceric activities of Magnolia (Magnolia denudata) flower petal extract fermented by Pediococcus acidilactici KCCM 11614. Molecules. 20:12154-12165

78.

Pelekos G, Acharya A, Eiji N, Hong G, Leung WK, McGrath C. 2020; Effects of adjunctive probiotic L. reuteri lozenges on S/RSD outcomes at molar sites with deep pockets. J Clin Periodontol. 47:1098-1107

79.

Perkins C, Siddiqui S, Puri M, Demain AL. 2016; Biotechnological applications of microbial bioconversions. Crit Rev Biotechnol. 36:1050-1065

80.

Pervaiz I, Ahmad S, Madni MA, Ahmad H, Khaliq FH. 2013; Microbial biotransformation: A tool for drug designing. Appl Biochem Microbiol. 49:435-449

81.

Quan LH, Piao JY, Min JW, Yang DU, Lee HN, Yang DC. 2011; Bioconversion of ginsenoside rb1 into compound k by Leuconostoc citreum LH1 isolated from kimchi. Braz J Microbiol. 42:1227-1237

82.

Rice-Evans C, Miller N, Paganga G. 1997; Antioxidant properties of phenolic compounds. Trends Plant Sci. 2:152-159

83.

Riep B, Edesi-Neuss L, Claessen F, Skarabis H, Ehmke B, Flemmig TF, Bernimoulin JP, Göbel UB, Moter A. 2009; Are putative periodontal pathogens reliable diagnostic markers?. J Clin Microbiol. 47:1705-1711

84.

Rodríguez H, Curiel JA, Landete JM, de las Rivas B, de Felipe FL, Gómez-Cordovés C, Mancheño JM, Muñoz R. 2009; Food phenolics and lactic acid bacteria. Int J Food Microbiol. 132:79-90

85.

Rodríguez H, Landete JM, de las Rivas B, Muñoz R. 2008; Metabolism of food phenolic acids by Lactobacillus plantarum CECT 748T. Food Chem. 107:1393-1398

86.

Rupasinghe HPV, Parmar I, Neir SV. 2019; Biotransformation of cranberry proanthocyanidins to probiotic metabolites by Lactobacillus rhamnosus enhances their anticancer activity in HepG2 cells in vitro. Oxid Med Cell Longev. 2019:4750795

87.

Sanz M, Beighton D, Curtis MA, Cury JA, Dige I, Dommisch H, Ellwood R, Giacaman RA, Herrera D, Herzberg MC, Könönen E, Marsh PD, Meyle J, Mira A, Molina A, Mombelli A, Quirynen M, Reynolds MC, Shapira L, Zaura E. 2017; Role of microbial biofilms in the maintenance of oral health and in the development of dental caries and periodontal diseases. Consensus report of group 1 of the joint EFP/ORCA workshop on the boundaries between caries and periodontal disease. J Clin Periodontol. 44:S5-S11

88.

Sanz M, Ceriello A, Buysschaert M, Chapple I, Demmer RT, Graziani F, Herrera D, Jepsen S, Lione L, Madianos P, Mathur M, Montanya E, Shapira L, Tonetti M, Vegh D. 2018; Scientific evidence on the links between periodontal diseases and diabetes: Consensus report and guidelines of the joint workshop on periodontal diseases and diabetes by the International Diabetes Federation and the European Federation of Periodontology. J Clin Periodontol. 45:138-149

89.

Scannapieco FA. 2013; The oral microbiome: Its role in health and in oral and systemic infections. Clin Microbiol Newsl. 35:163-169

90.

Schlagenhauf U, Rehder J, Gelbrich G, Jockel-Schneider Y. 2020; Consumption of Lactobacillus reuteri-containing lozenges improves periodontal health in navy sailors at sea: A randomized controlled trial. J Periodontol. 91:1328-1338

91.

Selma MV, Espín JC, Tomás-Barberán FA. 2009; Interaction between phenolics and gut microbiota: Role in human health. J Agric Food Chem. 57:6485-6501

92.

Shin YW, Bae EA, Lee BM, Min SW, Baek NI, Ryu SN, Chung HG, Kim DH. 2006; Effect of fermented lactic acid bacteria on antiallergic effect of Artemisia princeps pampanini. J Microbiol Biotechnol. 16:1464-1467.

93.

Sibel Akalın A. 2014; Dairy-derived antimicrobial peptides: Action mechanisms, pharmaceutical uses and production proposals. Trends Food Sci Technol. 36:79-95

94.

Socransky SS, Haffajee AD, Cugini MA, Smith C, Kent RL. 1998; Microbial complexes in subgingival plaque. J Clin Periodontol. 25:134-144

95.

Solieri L, Rutella GS, Tagliazucchi D. 2015; Impact of non-starter lactobacilli on release of peptides with angiotensin-converting enzyme inhibitory and antioxidant activities during bovine milk fermentation. Food Microbiol. 51:108-116

96.

Son HU, Lee S, Heo JC, Lee SH. 2017; The solid-state fermentation of Artemisia capillaris leaves with Ganoderma lucidum enhances the anti-inflammatory effects in a model of atopic dermatitis. Int J Mol Med. 39:1233-1241

97.

Spano G, Rinaldi A, Ugliano M, Moio L, Beneduce L, Massa S. 2005; A β-glucosidase producing gene isolated from wine Lactobacillus plantarum is regulated by abiotic stresses. J Appl Microbiol. 98:855-861

98.

Stagos D, Amoutzias GD, Matakos A, Spyrou A, Tsatsakis AM, Kouretas D. 2012; Chemoprevention of liver cancer by plant polyphenols. Food Chem Toxicol. 50:2155-2170

99.

Sulijaya B, Masulili SLC, Lessang R, Soeroso Y, Auerkari EI. 2016; The human beta-defensin-1 level from smokers with chronic periodontitis. Asian J Pharm Clin Res. 9:174-176.

100.

Sulijaya B, Takahashi N, Yamada M, Yokoji M, Sato K, Aoki-Nonaka Y, Nakajima T, Kishino S, Ogawa J, Yamazaki K. 2018; The anti-inflammatory effect of 10-oxo-trans-11-octadecenoic acid (KetoC) on RAW 264.7 cells stimulated with Porphyromonas gingivalis lipopolysaccharide. J Periodontal Res. 53:777-784

101.

Sulijaya B, Yamada-Hara M, Yokoji-Takeuchi M, Matsuda-Matsukawa Y, Yamazaki K, Matsugishi A, Tsuzuno T, Sato K, Aoki-Nonaka Y, Takahashi N, Kishino S, Ogawa J, Tabeta K, Yamazaki K. 2019; Antimicrobial function of the polyunsaturated fatty acid KetoC in an experimental model of periodontitis. J Periodontol. 90:1470-1480

102.

Suthanthangjai W, Kilmartin PA, Phillips ARJ, Davies K, Ansell J. 2014; Bioconversion of Pinot noir anthocyanins into bioactive phenolic compounds by lactic acid bacteria. Nutr Aging. 2:145-149

103.

Tabasco R, Sánchez-Patán F, Monagas M, Bartolomé B, Moreno-Arribas MV, Peláez C, Requena T. 2011; Effect of grape polyphenols on lactic acid bacteria and bifidobacteria growth: Resistance and metabolism. Food Microbiol. 28:1345-1352

104.

Takahashi N. 2005; Microbial ecosystem in the oral cavity: Metabolic diversity in an ecological niche and its relationship with oral diseases. Int Congr Ser. 1284:103-112

105.

Takahashi N, Sulijaya B, Yamada-Hara M, Tsuzuno T, Tabeta K, Yamazaki K. 2019; Gingival epithelial barrier: Regulation by beneficial and harmful microbes. Tissue Barriers. 7e1651158

106.

Teeuw WJ, Slot DE, Susanto H, Gerdes VEA, Abbas F, D’Aiuto F, Kastelein JJP, Loos BG. 2014; Treatment of periodontitis improves the atherosclerotic profile: A systematic review and meta-analysis. J Clin Periodontol. 41:70-79

107.

Tekce M, Ince G, Gursoy H, Dirikan Ipci S, Cakar G, Kadir T, Yılmaz S. 2015; Clinical and microbiological effects of probiotic lozenges in the treatment of chronic periodontitis: A 1-year follow-up study. J Clin Periodontol. 42:363-372

108.

Tellez A, Corredig M, Brovko LY, Griffiths MW. 2010; Characterization of immune-active peptides obtained from milk fermented by Lactobacillus helveticus. J Dairy Res. 77:129-136

109.

Teughels W, Durukan A, Ozcelik O, Pauwels M, Quirynen M, Haytac MC. 2013; Clinical and microbiological effects of Lactobacillus reuteri probiotics in the treatment of chronic periodontitis: A randomized placebo-controlled study. J Clin Periodontol. 40:1025-1035

110.

Teughels W, Van Essche M, Sliepen I, Quirynen M. 2008; Probiotics and oral healthcare. Periodontol 2000. 48:111-147

111.

Thilakarathna WW, Langille MG, Rupasinghe HPV. 2018; Polyphenol-based prebiotics and synbiotics: Potential for cancer chemoprevention. Curr Opin Food Sci. 20:51-57

112.

Tomasi C, Leyland AH, Wennström JL. 2007; Factors influencing the outcome of non-surgical periodontal treatment: A multilevel approach. J Clin Periodontol. 34:682-690

113.

Tonetti MS, Van Dyke TE. Working group 1 of the Joint EFP/AAP workshop. 2013. Periodontitis and atherosclerotic cardiovascular disease: Consensus report of the joint EFP/AAP workshop on periodontitis and systemic diseases. J Clin Periodontol. 40:S24-S29

114.

Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. 2007; The human microbiome project. Nature. 449:804-810

115.

van Winkelhoff AJ, Rams TE, Slots J. 1996; Systemic antibiotic therapy in periodontics. Periodontol 2000. 10:45-78

116.

Varela-López A, Battino M, Bullón P, Quiles JL. 2015; Dietary antioxidants for chronic periodontitis prevention and its treatment. A review on current evidences from animal and human studies. ARS Pharm. 56:131-140

117.

Vicario M, Santos A, Violant D, Nart J, Giner L. 2013; Clinical changes in periodontal subjects with the probiotic Lactobacillus reuteri Prodentis: A preliminary randomized clinical trial. Acta Odontol Scand. 71:813-819

118.

Vieira LV, de Sousa LM, Maia TAC, Gusmão JNFM, Goes P, Pereira KMA, Miyajima F, Gondim DV. 2021; Milk kefir therapy reduces inflammation and alveolar bone loss on periodontitis in rats. Biomed Pharmacother. 139:111677

119.

Vivekananda MR, Vandana KL, Bhat KG. 2010; Effect of the probiotic Lactobacilli reuteri (Prodentis) in the management of periodontal disease: A preliminary randomized clinical trial. J Oral Microbiol. 2:5344

120.

Wang X, Geng X, Egashira Y, Sanada H. 2004; Purification and characterization of a feruloyl esterase from the intestinal bacterium Lactobacillus acidophilus. Appl Environ Microbiol. 70:2367-2372

121.

Wang Y, Andrukhov O, Rausch-Fan X. 2017; Oxidative stress and antioxidant system in periodontitis. Front Physiol. 8:910

122.

Weydert CJ, Cullen JJ. 2010; Measurement of superoxide dismutase, catalase and glutathione peroxidase in cultured cells and tissue. Nat Protoc. 5:51-66

123.

Xu S, Boylston TD, Glatz BA. 2005; Conjugated linoleic acid content and organoleptic attributes of fermented milk products produced with probiotic bacteria. J Agric Food Chem. 53:9064-9072

124.

Yamada M, Takahashi N, Matsuda Y, Sato K, Yokoji M, Sulijaya B, Maekawa T, Ushiki T, Mikami Y, Hayatsu M, Mizutani Y, Kishino S, Ogawa J, Arita M, Tabeta K, Maeda T, Yamazaki K. 2018; A bacterial metabolite ameliorates periodontal pathogen-induced gingival epithelial barrier disruption via GPR40 signaling. Sci Rep. 8:9008

125.

Yang HE, Li Y, Nishimura A, Jheng HF, Yuliana A, Kitano-Ohue R, Nomura W, Takahashi N, Kim CS, Yu R, Kitamura N, Park SB, Kishino S, Ogawa J, Kawada T, Goto T. 2017; Synthesized enone fatty acids resembling metabolites from gut microbiota suppress macrophage-mediated inflammation in adipocytes. Mol Nutr Food Res. 61:1700064

126.

Yang SJ, Choe TB. 2011; Antioxidant activity and whitening effect of Forsythiae fructus extracts. Korean J Med Crop Sci. 19:472-477

127.

Yokoji-Takeuchi M, Takahashi N, Yamada-Hara M, Sulijaya B, Tsuzuno T, Aoki-Nonaka Y, Tabeta K, Kishino S, Ogawa J, Yamazaki K. 2020; A bacterial metabolite induces Nrf2-mediated anti-oxidative responses in gingival epithelial cells by activating the MAPK signaling pathway. Arch Oral Biol. 110:104602

128.

Zhang Y, Wang X, Li H, Ni C, Du Z, Yan F. 2018; Human oral microbiota and its modulation for oral health. Biomed Pharmacother. 99:883-893

129.

Zokaityte E, Cernauskas D, Klupsaite D, Lele V, Starkute V, Zavistanaviciute P, Ruzauskas M, Gruzauskas R, Juodeikiene G, Rocha JM, Bliznikas S, Viskelis P, Ruibys R, Bartkiene E. 2020; Bioconversion of milk permeate with selected lactic acid bacteria strains and apple by-products into beverages with antimicrobial properties and enriched with galactooligosaccharides. Microorganisms. 8:1182