Colonisation resistance arises from the integrastion and synergy of a microbial flora, which thereby excludes extraneous potential colonisers. The factors influencing colonisation resistance in the oral cavity are considered and specific examples of actual or potential clinical applications are discussed. these are based on pre-emptive colonisation or competitive displacement

Donoghue, HD

UCL Discovery

MICROBIAL ECOLOGY IN HEALTH AND DISEASE VOL. 3 i-iv (1 990) Can the Colonisation Resistance of the Oral Microflora be Enhanced? HELEN D. DONOGHUE University College and Middlesex School of Dentistry, Mortimer Market, London WClE 6JD, UK Colonisation resistance arises from the integration and synergy of a microbial flora, which thereby excludes extraneous potential colonisers. The factors influencing colonisation resistance in the oral cavity are considered and specific examples of actual or potential clinical applications are discussed. These are based on pre-emptive colonisation or competitive displacement. INTRODUCTION The oral cavity offers a large number of shedding and non-shedding surfaces for colonisation. Initial colonisers tend to be aerobes or facultative anaer- obes, relatively quick-growing, and able to adhere or be retained at a particular surface. Although many specific interactions are known between micro- organisms and oral surfaces, there is an element of chance involved in which organisms initially col- onise any particular site and thus fill the related niches in the ecosystem. These initial random events thereby determine the sequence of subsequent eco- logical succession.2 The oral cavity, in addition to its spatial heterogeneity, is subjected to temporal  fluctuation^,^' e.g. in the rate of salivary flow, and in the host diet which varies in composition and fre- quency of intake. These characteristics of the oral cavity result in a large number of ecological niches, which may be physical, metabolic and temporal. Therefore, an extremely rich and complex commen- sal flora develops, primarily in surface-associated microbial films. Once the oral flora has become established, inter-relationships build up and the flora becomes synergistically integrated." Thus, homeostasis tends to restore the initial community when alien microorganisms are introduced. This is observed as the phenomenon known as colonisation resistance . FACTORS AFFECTING COLONISATION RESISTANCE Microbial factors Surface efects Potential colonising microorga- nisms have to attach to a surface because the short residence time of saliva is insufficient to support a microbial population. However, although many studies have shown that synergistic interactions can 089 14)60X/90/02000i4 $05.00 0 1990 by John Wiley & Sons, Ltd. occur enabling organisms to co-aggregate, or to col- onise in combination with other species, it appears that even non-adherent bacteria, such as lacto- bacilli, can colonise if there are sufficient stagnation sites. Attachment inhibition has been proposed as one of the explanations for the observation that human oral streptococci suppressed colonisation of Candida albicans in mice. However, metabolic exclusion appears to be far more important than surface interactions in colonisation resistance, shown by the overgrowth of extraneous organisms in the absence of any commensal flora. Stability and complexity of the flora Because it takes time for the commensal flora to accumulate, and for microbial metabolic interactions to develop and become integrated, it is unsurprising that colon- isation resistance increases with the age of the community. Neonates are especially vulnerable and the phenomenon of overgrowth in sites such as the pharynx has been ~ e l l - r e p o r t e d . ~ ~  In caries research, the ability of dental plaque to resist colonisation by Streptococcus mutans has been studied. Specific pathogen-free rats were used to show that the longer the resident microflora was allowed to equilibrate before S. mutans challenge, the lower was the chance of its e~tablishment.'~ This observation has also been made in the model mouth, where the ability of a three-species mixture of Actinomyces viscosus, 'S .  mitior' and Veillonella dispar' to exclude S. mutans developed within 24 h of incubation.20 Microbial antagonists Oral streptococci have been recognised for many years for their potential role in excluding pathogens from the pharynx by hydrogen peroxide production.22 Microbially- produced hydrogen peroxide has also been shown to inhibit S. mutans in mixed culture in the model 11 mouth.6 Hydrogen peroxide-producing strepto- cocci appear to play an important role in inhibiting the growth of periodontopathic bacteria in sub- gingival plaque, shown by human epidemiological studies," as well as by in vitro and animal exper- i m e n t ~ . ' ~  Other metabolic end-products such as acids can act as inhibitors, either by a direct effect5 or by changing the environmental pH. Many oral commensals produce bacteriocins or similar substances. Their activity and role in vivo has been questioned, but studies of mutans streptococci in gnotobiotic rats showed that bacteriocin- producing strains were more competitive and able to prevent the establishment of A. V ~ S C O S U S , ' ~ ~ ~ ~  or of non-bacteriocinogenic S. mutans, l8  in plaque. Host factors Antibodies enter the oral cavity via saliva and crevicular fluid. Components of the cellular immune system are also found in crevicular fluid. Immunological control of the oral commensal flora is therefore likely, by inhibiting or promoting microbial adherence to surfaces, and possibly by changing microbial metabolism. Immunocompromised patients are more prone to overgrowth by minor components of the oral flora or by extraneous organisms. Saliva Saliva is the main component of the pelli- cle that coats oral surfaces and acts as a source of microbial nutrients, especially in the absence ofdiet- ary carbohydrates. Many dental plaque bacteria can utilise glycoproteins as a carbon source and saliva also provides minerals, vitamins, and a buf- fering system. However, saliva contains many non- specific antimicrobial substances, such as lysozyme, lactoferrin, and peroxidase, to which the normal commensal flora is relatively resistant. Salivary peroxidase converts salivary thiocyanate and mi- crobially-produced hydrogen peroxide to hypothio- cyanite (OSCN-), the inhibitor of the 'salivary peroxidase system'. Extraneous organisms, such as coliforms, can be killed by the salivary peroxidase system, whereas plaque streptococci and actinomy- cetes are only inhibited temporarily.' The peroxi- dase system can protect organisms from the toxic effects of hydrogen peroxide, and in the model mouth this led to a greater accumulation of S. mutans when grown with 'S .  mitior'.6 Exogenous factors Diet Host diet had little effect on the growth rate of plaque bacteria in rats3 or  monkey^,^ The immune system H. D. DONOGHUE although in starved rats the microbial accumulation declined sooner. Using the model mouth, the colon- isation resistance of a three-species mixture to S. mutans implantation was greatest in the absence of any dietary supplement, with saliva as the only nu- trient source (Donoghue & Perrons, unpublished observations). Antimicrobial agents Any disturbance of the commensal flora usually results in decreased colonis- ation resistance. However, an example is given below in which bacterial overgrowth was prevented in patients receiving penicillin. HOW MAY COLONISATION RESISTANCE BE ENHANCED? Pre-emptive colonisation It is unlikely, as mentioned in the Introduction, that any particular ecological niche can be filled by only one specific organism. The principle of pre- emptive colonisation is therefore to fill an ecological niche with a harmless or potentially beneficial organism, before the undesired organism has an opportunity to colonise and become established. The initial coloniser becomes integrated into the ecosystem and the pathogen is thereby excluded. For example, overgrowth of enteric Gram- negative bacteria in the oropharynx of patients due to receive large doses of penicillin was prevented by pre-dosing with low doses of the antibiotic, to select penicillin-resistant, or penicillin-tolerant strepto- cocci.23 The streptococci excluded the Gram- negative rods, although the authors were aware of the potential hazard ofcreating a partially penicillin- resistant flora. There have been several attempts to use pre- emptive colonisation in caries prevention. Low- virulence mutants of S. mutans have been produced, deficient in glucosyltransferases, l 4  intracellular polysaccharide synthesis,25 or lactate dehydro- genase.' However, wild-type revertants tend to occur, and the effectiveness of mutant strains depends on the animal host.28 Competitive displacement A more competitive organism should be able to displace a pre-existing microorganism in the same ecological niche. Competitive displacement is thus of potentially greater clinical use, as it is not depen- dent on treatment at or before colonisation with the undesired organism. REPORT OF OMIG WORKSHOP 1989 Several workers have tried to use this technique in caries prevention, i.e. in excluding virulent S. mutans from dental plaque. For example, an unusual strain of S. salivarius was shown to displace S.  mutans from the teeth of specific pathogen-free rats and to inhibit tooth decay.26 However, this organism was much less effective when attempts were made to implant it into dental plaque of adult humans.8 An S .  mutans strain which produced a high level of bac- teriocin was able to persistently colonise the teeth of three adult human volunteers'2 and a bacteriocin- producing mutant of S. mutans, avirulent because of its deficiency in lactate dehydrogenase, is currently under investigation as a possible effector strain for replacement therapy.' In conclusion, colonisation resistance can be enhanced, and the phenomenon has potential clini- cal applications. However, it is essential to investi- gate thoroughly the characteristics and stability of any effector strains, and to understand the ecology of the microbial flora. 111 Fisher J, Tanzer JM. (1984). Implantation of Streptococcus salivarius strain TOVE-R onto adult human teeth. Journal of Dental Research 63, 201 (abstract 275). Fitzgerald RJ, Adams BO, Sandham HJ, Abhyankar S. (1989). Cariogenicity of a lactate dehydrogenase- deficient mutant of Streptococcus mutans serotype c in gnotobiotic rats. Infection and Immunity 57, Hamilton WA. (1984). Energy sources for microbial growth: an overview. In: Codd GA (ed) Aspects of Microbial Metabolism and Ecology. Academic Press, London, pp 35-57. Hillman JD, Socransky SS, Shivers M. (1985) The relationships between streptococcal species and periodontopathic bacteria in human dental plaque. Archives of Oral Biology 30,791-795. Hillman JD, Dzuback AL, Andrews SW. (1987). Colonization of the human oral cavity by a Strepto- coccus mutans mutant producing increased bacterio- cin. Journalof Dental Research 66, 1092-1094. Hillman JD, Shivers M. (1988). Interaction between wild-type, mutant and revertant forms of the bac- terium Streptococcus sanguis and the bacterium Actinobacillus actinomycetemcomitans in vitro and in the gnotobiotic rat. Archives of Oral Biology 33, 39540 1. Hirasawa M, Kiyono H, Babb JL, Shiota T, Michalek SM, McGhee JR. (1980). Virulence of Streptococcus mutans: in vivo reversion of a low- virulence mutant results in partial displacement and pathogenesis. InfectionandImmunity27,1003-1011. van der Hoeven JS, Rogers AH. (1979). Factors affecting the stability of the resident dental plaque microflora of specific pathogen-free rats in relation to the ability to resist colonization by Streptococcus mutans. Archives of Oral Biology 24,787-790. van der Hoeven JS, Rogers AH. (1979). Stability of the resident microflora and the bacteriocinogeny of Streptococcus mutans as factors affecting its estab- lishment in specific pathogen-free rats. Infection and Immunity 23,20&2 12. Johnson KP, Hillman JD. (1982). Competitive properties of lactate dehydrogenase mutants of the oral bacterium Streptococcus mutans in the rat. Archives of Oral Biology 27,513-5 16. Kitamura K, Masuda N, Kato K, Sobue S, Hamada S. ( 1  989). Effect of a bacteriocin-producing strain of Streptococcus sobrinus on infection and establish- ment of Streptococcus mutans on tooth surfaces in rats. Oral Microbiology and Immunology 4,65-70. Liljemark WK, Gibbons RJ. (1973). Suppression of Candida albicans by human oral streptococci. Infection and Immunity 8,846849. Perrons CJ, Donoghue HD. (1 990). Colonization resistance of defined bacterial plaques to Streptococ- cus mutans implantation on teeth in a model mouth. Journal of Dental Research (in press). 823-826. REFERENCES 1. 2. 3. 4. 5. 6. 7. Adamson M, Carlsson J. (1982). Lactoperoxidase and thiocyanate protect bacteria from hydrogen peroxide. Infection and Immunity 35,20-24. Atlas R M ,  Bartha R. (1987) Microbial Ecology: Fundamentals and Applications. 2nd Edition. The Benjamin/Cummings Publishing Co. Inc, Menlo Park, Calif., pp 72-80. Beckers HJA, van der Hoeven JS. (1984). The effects of mutual interaction and host diet on the growth rates of the bacteria Actinomyes viscosus and Streptococcus mutans during colonization of tooth surfaces in di-associated gnotobiotic rats. Archives of Oral Biology 29,231-236. Beighton D, Smith K, Hayday H. (1986). The growth of bacteria and the production of exoglyco- sidic enzymes in the dental plaque of macaque monkeys. Archives of Oral Biology 31,829-835. Donoghue HD, Tyler JE. (1975). Antagonisms amongst streptococci isolated from the human oral cavity. Archives of Oral Biology 20,381-387. Donoghue HD, Perrons CJ, Hudson DE. (1985). The role of H,O, and the lactoperoxidase-SCN -- H202  system on the interaction between two bacteria originating from human dental plaque, Streptococcus rattus (mutans) BHT and Strepto- coccus mitior LPA-I, grown on human teeth in an artificial mouth. Archives of Oral Biology 30, Donoghue HD, Perrons CJ. (1988). Establishment of defined mixed bacterial plaques on teeth in a laboratory microcosm (model mouth). Microbial Ecology in Health and Disease 1,193-200. 5 19-523. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. iv H. D. DONOGHUE 21. RogersAH,vanderHoevenJS,MikxFHM. (1978). Inhibition of Actinomyces viscosus by bacteriocin- producing strains of Streptococcus mutans in the dental plaque of gnotobiotic rats. Archives of Oral Biology 23,477483. Sprunt K, Redman W. (1968). Evidence suggesting importance of role of interbacterial inhibition in maintaining balance of normal flora. Annals of Internal Medicine 68,579-590. 23. Sprunt K, Leidy GA, Redman W. (1971). Preven- tion of bacterial overgrowth. Journal of Infectious Diseases 123, 1-10. 24. Sprunt K, Leidy G. (1988). The use of bacterial interference to prevent infection. Canadian Journal of Microbiology 34,332-338. 22. 25. Tanzer M, Fisher J, Freedman ML. (1982). Pre- emption of Streptococcus mutans 104498 coloniz- ation by its mutant 805. Infection and Immunity 35, 26. Tanzer JM, Kurasz AB, Clive J. (1985). Competitive displacement of mutans streptococci and inhibition of tooth decay by Streptococcus salivarius TOVE-R. Infection and Immunity 48,44-50. 27. Wimpenny JWT. (1981). Spatial order in microbial ecosystems. Biological Reviews 56,295-342. 28. Yaphe B, Johnson K, Shuh V, Hillman J. (1982). Replacement therapy of dental caries in irus monkeys. Journal of Dental Research 61, 252 (abstract 666). 1 38- 142. 

Can the colonisastion resistance of the oral microflora be enhanced?

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Can the colonisastion resistance of the oral microflora be enhanced?

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