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Probiotic Effects via Modulating Oral Microbial Ecology

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    http://adr.sagepub.com/  Advances in Dental Research  http://adr.sagepub.com/content/21/1/53The online version of this article can be found at: DOI: 10.1177/0895937409335626 2009 21: 53 srcinally published online 31 July 2009 ADR  X. He, R. Lux, H.K. Kuramitsu, M.H. Anderson and W. Shi  Modulating Oral Microbial Ecology via  Achieving Probiotic Effects Published by:  http://www.sagepublications.com On behalf of:  International and American Associations for Dental Research  can be found at: Advances in Dental Research  Additional services and information for http://adr.sagepub.com/cgi/alerts Email Alerts:  http://adr.sagepub.com/subscriptions Subscriptions: http://www.sagepub.com/journalsReprints.nav Reprints:  http://www.sagepub.com/journalsPermissions.nav Permissions:  What is This? - Jul 31, 2009Proof - Aug 7, 2009Version of Record >>  at Niigata University on October 13, 2011 For personal use only. No other uses without permission.adr.sagepub.comDownloaded from  Copyright 2009 by the International Association for Dental Research  53  Achieving Probiotic Effects via   Modulating Oral Microbial Ecology  DOI: 10.1177/0895937409335626  X. He 1 , R. Lux  1 , H.K. Kuramitsu 2 , M.H. Anderson 3 , W. Shi 1 * ,3 1 Section of Oral Biology, School of Dentistry and Department of Microbiology, Immunology and Molecular Genetics, School of Medicine, University of California, Los Angeles, CA 90095, USA; 2 Department of Oral Biology, School of Dental Medicine, State University of New York, Buffalo, USA; and 3 C3 Jian Inc, Inglewood, CA, USA; *corresponding author, wenyuan@ucla.edu Adv Dent Res 21:53-56, August, 2009 KeyWords Probiotics, microbial ecology, dental caries, dental plaque, Strepto-coccus mutans .Presented at the International Conference on Novel Anti-caries and Remineralizing Agents, held in Vina del Mar, Chile, January 10-12, 2008The authors declare no conflict of interest. U nlike many pathogens that are “foreign” invaders, oral patho-gens such as Streptococcus mutans  are part of the “normal” oral microbial flora. While they express certain pathogenic prop-erties, the balance of synergistic and antagonistic interactions determines whether these çommensal pathogens cause damage. Recognition of these microbial ecology-based pathogeneses argues for new strategies for disease treatment and prevention. Probiotics, potentially beneficial live bacteria or yeasts, have  been used to combat dental caries. This includes the application of S. mutans  types that cannot produce acids or other bacteria that interfere with the pathogenic effects of S. mutans . While these approaches show therapeutic effects against S. mutans  experi-mentally, the conversion into commercial products remains a challenge, due to safety and shelf-life issues. New high-tech approaches, such as quorum-sensing interference of pathogenic  bacteria or targeted antimicrobial therapies, offer novel ways to achieve probiotic effects against dental caries. INTRODUCTION For a long time, microbiologists took the reductionist approach to studying complex microbial communities by analyzing indi-vidual bacterial species. The strategy has been used to under-stand the whole by examining smaller components, and has  been the hallmark of much of the industrial and scientific revo-lutions for the past 150 years (  Nelson, 1992). While reduction-ism has greatly advanced microbiology, it was recognized that assembly of smaller pieces cannot explain the whole. Modern microbiologists are learning “system thinking”. From “bio-films” to “metagenomics”, microbiology is experiencing a new trend that emphasizes interactions of different elements within a microbial community. Such approaches are changing our under-standing of microbial physiology and our ability to diagnose/treat microbial infections. This trend is having an impact on oral microbiology as well.Oral microbial communities with the common name “dental  plaque” are some of the most complex microbial floras in the human body, consisting of more than 700 bacterial species (Paster et al  ., 2001, 2006; Aas et al. , 2005). Clinical studies have indi-cated that dental caries is one of the major human diseases caused  by the oral microbial flora (Marsh, 1994). For a very long time, oral microbiologists used reductionism to identify the key patho-gens responsible for dental caries (Miller, 1890; Clarke, 1924; Marsh, 1994). The limitations of reductionism forced scientists to adopt concepts such as inter-species interaction, microbial com-munity, biofilms, poly-microbial disease, etc. These new research directions have revealed new physiological functions, which result from interactions between and among different components, and might not be observed with individual organisms. These inter-species-interaction scenarios serve as the foundation for new therapeutic and preventive tools, as discussed in this review. UNDERSTANDING THE ORAL MICROBIAL COMMUNITY  From the initial isolation of S. mutans  by J. Clarke in 1924 to the latest large-scale 16S rRNA/DNA-based oral bacterial studies (Aas et al  ., 2005), the oral microbial community has been shown to be one of the most complex microbial biota in the human body. The oral microbial biofilm, conventionally called “dental plaque”, is a sophisticated microbial community with novel functions that are essential for biofilm architecture and microbial physiology (Marsh, 1994, 2005).From a structural point of view, dental plaque shows a high degree of organization. During dental plaque formation, some oral bacteria are early colonizers that express biochemical com- ponents allowing them to adhere effectively to specific tissues (teeth or periodontal tissue). The later colonizers often contain components that enable them to adhere to the early colonizers,  bringing competitive advantages. Within an established dental  plaque, specific bacterial species are often found located adja-cent to each other or mixed together to form unique structures that may confer adherence or growth advantages.  at Niigata University on October 13, 2011 For personal use only. No other uses without permission.adr.sagepub.comDownloaded from  Copyright 2009 by the International Association for Dental Research  54 He et al.   Adv Dent Res  21: 2009 From a microbial physiology aspect, oral microbial commu-nities are classic examples of biofilms. As initially proposed by Costerton, the behavior displayed by oral microbial organisms grown in liquid culture is very different from that of the same organisms grown on a solid surface or within a community such as dental plaque (Costerton et al  ., 1995). This is of significant medical interest, since it has been well-documented that there is an increased resilience of oral bacteria within dental plaque to antimicrobial agents, relative to their planktonic susceptibility. Confirmation of these differences has been provided by investi-gations revealing that oral bacteria grown within biofilm showed a pattern of gene expression and protein synthesis that is distinct from that of comparable planktonic cells (Burne et al. , 1997; Black et al.,  2003).Because of the multi-species nature of dental plaque, the oral microbial community is one of the best biofilm models for studying inter-species interactions. Based on our current knowl-edge, it is reasonable to assume that the interactions between the oral microbial residents may influence the properties of the whole community. For example, while the oral “pathogens” such as S. mutans  express certain pathogenic properties (such as acid production), a dynamic balance of synergistic and antagonistic interactions with its neighboring bacteria is crucial in determining whether these pathogenic factors cause damage (Kleinberg, 2002; Marsh, 2005). In other words, within com- plex biofilms, it is not merely the presence of a single organism,  but the interactions between and among the biofilm residents that are crucial and determine the properties of a biofilm. As an example, in the presence of nearby base-producing bacteria, S. mutans  in dental plaque may not be pathogenic. Thus, for den-tal caries, it is now recognized that this disease results not solely because of the presence of S. mutans  or any single organ-ism in dental plaque. Rather, it is the interaction of multiple acid-producing organisms such as S. mutans  with other biofilm residents (Kleinberg, 2002; Marsh, 2005). Such a microbial ecology-based theory serves as a new paradigm to understand the relationship between dental plaque and the host in health or disease, offering new strategies for disease treatment and  prevention. NEW APPROACHES FOR CONTROLLING DENTAL CARIES via    MODULATING THE ORAL MICROBIAL ECOLOGY  Current dental therapy is primarily focused on the removal of dental plaque. Since dental plaque is made of large numbers of commensal bacteria, together with a limited number of oral  pathogens, such an approach may not be effective, since the “remove all or kill all” approach creates open, non-competitive surfaces for pathogens to repopulate the oral cavity. With our new understanding of the oral microbial community interac-tions, there is now interest in approaches that selectively inhibit oral pathogens or modulate the microbial composition of dental  plaque to control community-based microbial pathogenesis. In the past several years, oral microbiology has become a lead-ing area for developing technologies which might also be useful for managing other community-based microbial pathogenesis. Among them, the probiotic approach has been a popular method for modulating microbial communities. Probiotic approaches The term ‘probiotics’ refers to “live micro-organisms, which, when administered in adequate amounts, confer a health benefit on the host” (Guarner et al  ., 2005). The concept of ‘probiotics’ evolved from Elie Metchnikoff’s ideas that the bacteria in fer-mented products could compete with microbes that are injurious to the host and thus are beneficial for health (Metchnikoff, 1907). In the past decade, there have been numerous exciting discoveries that revealed many beneficial effects resulting from the administration of probiotics, ranging from direct inhibition of pathogenic microbes to improving host immune functions (Harish and Varghese, 2006).Recently, more evidence suggests that probiotic therapy might be applied to the maintenance of oral health (Caglar et al.,  2005a; Meurman, 2005; Meurman and Stamatova  ,  2007). Classic probiotic strains, such as those that belong to the genera  Lactobacillus  and  Bifidobacterium , have been tested for their ability to confer probiotic effect in the oral cavity. Using ran-domized controlled trials, Meurman and colleagues demon-strated that long-term consumption of milk containing the  probiotic  Lactobacillus rhamuosus  GG strain reduced initial caries in kindergarten children (Nase et al  ., 2001). Caglar et al.  also showed that administration of the probiotic bacterium  Lactobacillus reuteri  ATCC 55739 or  Bifidobacterium  DN-173 010 induced significant reduction of cariogenic S. mutans  in saliva (Caglar et al  ., 2005b, 2006).In addition to the classic probiotic strains, other oral residents or genetically modified strains have also been tested for their abil-ity to inhibit cariogenic microbes. Hillman and colleagues intro-duced a non-acid-producing S. mutans  strain that produces a  bacteriocin active against other S. mutans  strains into the oral cav-ity to replace the naturally occurring cariogenic strains (Hillman, 2002). Both in vitro  and animal model assessments suggest its  potential in reducing S. mutans  colonization. This approach is currently awaiting evaluation for its efficacy in humans.Another potential probiotic approach for reducing dental caries involves the use of oral streptococci that are able to metabolize arginine or urea to ammonia (Marquis et al  ., 1993). Since such organisms naturally occur in dental plaque, and therefore may not offer safety concerns, they could be used in probiotic approaches for controlling dental caries.Co-infection of rats with oral streptococci S. salivarius TOVE-R and S. mutans  reduced dental caries incidence relative to the latter organisms alone. This is likely due to the ability of TOVE-R to pre-empt the initial colonization of tooth surfaces and displace the cariogenic S. mutans that have already colo-nized the tooth surfaces (Tanzer et al. , 1985).Various oral streptococci have mutual antagonistic effects. Implantation of specific oral streptococci or the encouragement of their growth in dental plaque may thus be considered a probi-otic approach by encouraging an ecological shift. Recently, S. oligofermentans, a bacterium that could be isolated only from caries-free humans, was found to metabolize lactic acid into hydrogen peroxide, thus inhibiting the growth of S. mutans at Niigata University on October 13, 2011 For personal use only. No other uses without permission.adr.sagepub.comDownloaded from  Copyright 2009 by the International Association for Dental Research  Adv Dent Res  21: 2009 Achieving Probiotic Effects 55 (Tong et al.,  2007). This property makes it a good candidate for  probiotic application. Other new approaches to achieve probiotic effects While the therapeutic effects of various probiotics have been dem-onstrated, it has, to date, been very difficult to develop probiotic- based commercial products, since the complexity of live organisms makes it virtually impossible for traditional toxicity studies to be conducted. While arguments have been used that most organisms selected for probiotic applications exist naturally in the oral cavity, and are likely safe, these arguments lack a solid rationale, since S. mutans  itself naturally exists in the oral cavity. Another major challenge for probiotic-based products is the instability of such products. Live organisms often have short shelf-times and require complex storage conditions.The beneficial effects of probiotic therapy are mainly achieved through the modulation of existing microbial flora associated with the host, thus attaining a balanced and healthy microbes-host relationship. Recognizing the disadvantages of traditional probiotic approaches, microbiologists are devel-oping novel techniques and products that do not involve live organisms, yet generate targeted effects against pathogenic factors or organisms, thus achieving similar probiotic effects. Inhibiting adherence with antagonists Since S. mutans ’ virulence   is strongly associated with its adher-ence, reducing the adherence of S. mutans  to the tooth’s surface should create a microbial community with less S. mutans . For example, a cell-surface protein of S. mutans,  termed SpaP or Ag I/II, has been identified as an adhesin which interacts with the tooth pellicle (Jenkinson and Demuth, 1997). A synthetic dode-capeptide analogue of the active binding site of SpaP has been shown to inhibit attachment of S. mutans  to teeth both in vivo  and in vitro  (Kelly et al. , 1999). Such analogs are potential therapeutic agents that could be incorporated into toothpastes or mouthrinses. Passive immunization Another general approach for controlling bacterial pathogens has been the development of specific vaccination strategies. In the case of dental caries, this possibility has been investigated for the past four decades (Russell et al.,  2004). Despite promis-ing results in experimental animal models, it appears unlikely that active immunization approaches will be pursued further in most developed countries, because of economic and ethical concerns. As an alternative to active immunization, passive immunization strategies have been proposed (Koga et al. , 2002). However, it remains unclear whether these approaches will lead to a general strategy for immunizing susceptible children against dental caries in the future. Interference with signaling mechanisms Several pathogenic properties of S. mutans  are regulated by a quorum-sensing mechanism involving Competence Stimulating Peptide (CSP) as the signaling molecule. The addition of a high concentration of CSP can interfere with signaling events of S. mutans  and induce the death of the bacterium, thus exhibiting a potential beneficial effect against dental caries (Cvitkovitch et al. , 2003; Qi et al  ., 2005). Targeted antimicrobial therapy via   a novel STAMP technology  Eckert et al  . (2006) reasoned that, with the exception of a limited number of pathogens, the majority of indigenous oral micro- organisms are benign or beneficial. Currently available antimi-crobials exhibit broad-spectrum killing properties. Indiscriminate killing of all microbes by these conventional antimicrobials dis-rupts the ecological balance of the indigenous microbiota, with unknown clinical consequences. These investigators formulated a new class of antimicrobials called ‘Specifically Targeted Anti-microbial Peptides’ (STAMPs). A STAMP is a fusion peptide with two moieties: a killing moiety, made of a non-specific anti-microbial peptide; and a targeting moiety, containing a species-specific binding peptide. The targeting moiety provides specific  binding to a selected pathogen and facilitates the targeted deliv-ery of an attached antimicrobial peptide. In one of their recently  published papers (Eckert et al. , 2006), these investigators explored a pheromone    produced by S. mutans , namely, CSP, as a STAMP-targeting domain to mediate S. mutans -specific   delivery of a killing domain. They discovered that such   STAMPs were  potent   against S. mutans  grown in liquid or biofilm states. Further studies showed   that an 8-amino-acid region within the CSP sequence was sufficient   for targeted delivery of the killing domain to   S. mutans . The STAMPs were capable of eliminating   S. mutans  from multispecies biofilms without affecting closely   related non-cariogenic oral streptococci, indicating the potential   of these molecules to be developed into “probiotic” antimicrobi-als   that may selectively eliminate pathogens while preserving   the  protective benefits of the normal flora. This proof-of-principle demonstration with S. mutans suggests that it may be possible to develop other STAMPs which are specifically targeted to other  biofilm pathogens. CONCLUSIONS Most of the bacteria which are of dental and medical concern reside in multi-species biofilm structures, and these microbial communities exhibit properties that are dependent on how the resident organisms interact. Our ability to identify the resident organisms in biofilms and decipher the interactions between and among key components has rapidly increased during the past decade. Continued expansion of such information in the future may facilitate an exogenous modulation of the interactions between  biofilm constituents, and thereby result in novel approaches for controlling biofilm activities.  ACKNOWLEDGMENTS The authors acknowledge researchers in our laboratories who have contributed to some of the work cited in this review. Studies cited from our laboratories were supported by NIH grants GM54666 (WS), and MD01831 (MA/WS), DE03258 (HK), DE09821 (HK), and by a University of California discovery grant.  at Niigata University on October 13, 2011 For personal use only. No other uses without permission.adr.sagepub.comDownloaded from  Copyright 2009 by the International Association for Dental Research
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