ARTICLE IN PRESS

G Model
YPHRS 2533 1–7

Pharmacological Research xxx (2012) xxx–xxx

Contents lists available at SciVerse ScienceDirect

Pharmacological Research
journal homepage: www.elsevier.com/locate/yphrs

1 Invited review

2 The oral microbiome in health and disease

3 Q1 William G. Wade ∗
4 King’s College London Dental Institute, Microbiology Unit, Floor 17, Tower Wing, Guy’s Campus, London SE1 9RT, UK
5

6 a r t i c l e i n f o a b s t r a c t
7
8 Article history: The human mouth harbours one of the most diverse microbiomes in the human body, including viruses,
9 Received 30 September 2012 fungi, protozoa, archaea and bacteria. The bacteria are responsible for the two commonest bacterial dis-
10 Received in revised form eases of man: dental caries (tooth decay) and the periodontal (gum) diseases. Archaea are restricted to
11 14 November 2012
a small number of species of methanogens while around 1000 bacterial species have been found, with
12 Accepted 15 November 2012
representatives from the phyla Actinobacteria, Bacteroidetes, Firmicutes, Proteobacteria, Spirochaetes, Syn-
13
ergistetes and Tenericutes and the uncultured divisions GN02, SR1 and TM7. Around half of oral bacteria
14 Keywords:
are as yet uncultured and culture-independent methods have been successfully used to comprehensively
15 Microbiome
16 Dental caries
describe the oral bacterial community. The human oral microbiome database (HOMD, www.homd.org)
17 Gingivitis provides a comprehensive resource consisting of descriptions of oral bacterial taxa, a 16S rRNA iden-
18 Periodontitis tification tool and a repository of oral bacterial genome sequences. Individuals’ oral microbiomes are
highly specific at the species level, although overall the human oral microbiome shows few geograph-
ical differences. Although caries and periodontitis are clearly bacterial diseases, they are not infectious
diseases in the classical sense because they result from a complex interaction between the commen-
sal microbiota, host susceptibility and environmental factors such as diet and smoking. Periodontitis, in
particular, appears to result from an inappropriate inflammatory reaction to the normal microbiota, exac-
erbated by the presence of some disease-associated bacterial species. In functional terms, there appears
to considerable redundancy among the oral microbiota and a focus on functional rather than phylogenetic
diversity may be required in order to fully understand host–microbiome interactions.
© 2012 Published by Elsevier Ltd.

19 Contents

20 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
21 2. Composition of the oral microbiome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
22 2.1. Viruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
23 2.2. Protozoa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
24 2.3. Fungi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
25 2.4. Archaea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
26 2.5. Bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
27 3. Role of oral microbiome in health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
28 4. Oral microbiome-related oral diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
29 4.1. Dental caries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
30 4.2. Endodontic infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
31 4.3. Periodontal diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
32 4.3.1. Gingivitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
33 4.3.2. Periodontitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
34 4.4. The oral microbiome and non-oral diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
35 5. Functional aspects of the oral microbiome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
36 6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
37 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
38

∗ Tel.: +44 20 7188 3872.

E-mail address: william.wade@kcl.ac.uk

1043-6618/$ – see front matter © 2012 Published by Elsevier Ltd.

http://dx.doi.org/10.1016/j.phrs.2012.11.006

Please cite this article in press as: Wade WG. The oral microbiome in health and disease. Pharmacol Res (2012),
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39 1. Introduction 2.3. Fungi 96

40 The human mouth is heavily colonised by microorganisms, Candida species are carried symptomlessly by around half of 97

41 including viruses, protozoa, fungi, archaea and bacteria. In contrast individuals with the prevalence increasing with age, and also 98

42 to the commensal microbiota found at other body sites, which typ- cause a wide range of acute and chronic infections [8]. A culture- 99

43 ically live in harmony with the host, the normal microbiota of the independent survey of the oral mycobiome in healthy individuals 100

44 mouth is responsible for the two commonest diseases of man – found 85 fungal genera in the mouths of 20 healthy individuals 101

45 dental caries and the periodontal diseases. Because of this, humans, [9]. The predominant genera were Candida, Cladosporium, Aureoba- 102

46 particularly in developed countries engage in regular oral hygiene sidium, Saccharomycetales, Aspergillus, Fusarium, and Cryptococcus. 103

47 practices, typically brushing with toothpastes and/or rinsing with Whether the detection of these, and the more rarely found gen- 104

48 mouthwashes. Why this should be necessary remains unknown era, represents colonisation by the vegetative forms of the fungi 105

49 although it is likely that soft and sugar-rich diets are largely respon- is unclear. It is possible that the method used detected airborne 106

50 sible. The bacterial communities found in the mouth are highly spores or transient colonisation from food. 107

51 complex with around 1000 species present [1] and has been shown
52 to be the second most complex in the body, after the colon [2]. 2.4. Archaea 108

53 The use of culture-independent methods of determining the com-

54 position of the oral microbiome, allied with next generation DNA The Archaea make up only a minor component of the oral micro- 109

55 sequencing methods is providing a far deeper analysis than hitherto biome and the archaeal community is restricted to a small number 110

56 possible. Species-level identification may not be sufficient how- of species/phylotypes, all of which are methanogens. They can be 111

57 ever, because of the genetic heterogeneity of bacterial species and detected in health but their prevalence and numbers are raised 112

58 the strong influence of the environment on phenotype. A combi- in subjects with periodontitis. The species found are Methanobre- 113

59 nation of phylogenetic, metagenomic, transcriptomic, proteomic vibacter oralis and two un-named Methanobrevibacter phylotypes, 114

60 and metabolomic approaches may be required to fully dissect oral Methanobacterium curvum/congolense and Methanosarcina mazeii 115

61 host–microbiome interactions relevant to health and disease. In [10,11]. 116

62 this review, the progress made towards this goal will be described
63 and discussed. 2.5. Bacteria 117

Initial knowledge of the composition of the oral bacterial 118

biome came from microscopy with the well-known observations 119

64 2. Composition of the oral microbiome
of Leeuwenhoek [12], who showed a diverse collection of bacte- 120

rial morphotypes in dental plaque. Following the development of 121

65 2.1. Viruses
bacterial culture media by Koch, Pasteur and others, the character- 122

isation of the cultivable component of the mouth’s microbiota was 123

66 A range of viruses can be found in the mouth, which are primar-
effected and found to comprise a diverse collection of organisms, 124
67 ily disease-associated. For example, the mumps and rabies viruses
including obligate aerobes and facultative and obligate anaerobes 125
68 infect the salivary glands and thus those viruses will be found in
and a wide range of metabolic potential including the ability to 126
69 saliva in affected individuals. Similarly, blood-borne viruses such
degrade sugars and proteins, and complex substrates derived from 127
70 as the hepatitis viruses and HIV can enter the mouth via gingival
them. This culture-based work led to the identification of specific 128
71 crevicular fluid and viruses causing upper respiratory tract infec-
organisms thought to play a causative role in caries and periodon- 129
72 tions will clearly be present in the mouth during the acute phase.
titis and which could be treated with antimicrobials [13]. Culture 130
73 Herpes simplex causes gingivostomatitis or a sub-clinical infection
alone gives a highly distorted view of the composition of the oral 131
74 in the majority of neonates and the virus can subsequently enter a
microbiome, however. 132
75 dormant state in the trigeminal ganglion. The virus can reactivate
It has long been known that a substantial proportion of bac- 133
76 in response to external factors such as stress, cold weather or other
terial life on earth cannot be cultivated in the laboratory [14]. In 134
77 virus infection, and cause herpes labialis (cold sores) [3]. Human
the mouth, approximately half of the bacteria present have yet 135
78 papilloma virus HPV is responsible for a number of oral conditions,
to be cultured [15]. Complex bacterial communities such as the 136
79 including papillomas, condylomas and focal epithelial hyperplasia
oral microbiota have been characterised by culture-independent 137
80 [4] and has also been implicated in head and neck squamous cell
methods based on the analysis of the sequences of conserved 138
81 carcinoma [5].
housekeeping genes directly isolated from samples of saliva or oral 139
82 A survey of the oral virome in five subjects revealed that the
biofilms. The gene most commonly used for this purpose has been 140
83 majority of virus sequences detected had homology with bacterio-
that encoding the 16S rRNA [16]. The 16S rRNA itself can be isolated 141
84 phages which is perhaps not surprising, given the dense and diverse
directly and sequenced [17] but more typically the gene encoding 142
85 community of bacteria found in the mouth [6].
the 16S rRNA is amplified by PCR using “universal” primers tar- 143

geting the ultra-conserved regions of the gene and then cloned by 144

incorporation into a plasmid vector [18]. The use of this method 145
86 2.2. Protozoa has allowed the comprehensive description of the oral bacterial 146

biota [1]. The method is time-consuming and relative costly, how- 147
87 Two protozoon species are found as part of the normal micro- ever, and typically only around 100 cloned genes are sequenced per 148
88 biome: an amoeba Entamoeba gingivalis and the more structured sample, a relatively shallow analysis of a highly complex commu- 149
89 Trichomonas tenax. The numbers of these organisms is raised nity. 150
90 in subjects with poor oral hygiene and gingival disease and A major advance to this technique has been the adoption of 151
91 were once considered as potential pathogens. They are cur- high-throughput next generation sequencing methods such as 152
92 rently regarded as harmless saprophytes and the apparent link pyrosequencing. In the 454 system (Roche) [19], 16S rRNA genes 153
93 with disease is nutritional, in that poor oral hygiene leads to are amplified by PCR from samples with universal primers and 154
94 increased amounts of food debris and bacteria, both food sources for then mixed in equal proportions. The mixture is then amplified in 155
95 protozoa [7]. an emulsion and distributed among wells on a plate to which are 156

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157 added beads containing the sequencing reagents. Nucleotide incor- identification for the members of many genera. Indeed, it is 223

158 poration is detected by a CCD camera imaging system and around unfortunate that even full-length 16S rRNA sequences have insuf- 224

159 0.8 million sequences, up to 750 base pairs long can be obtained ficient resolution for confident identification of species comprising 225

160 in a single run. To enable multiple samples to be sequenced in the some of the important and predominant oral genera such as Acti- 226

161 same run, primers with unique barcodes are used, typically 8–12 nomyces, Streptococcus, Neisseria, Veillonella, Porphyromonas and 227

162 nucleotides, incorporated into the initial PCR primer. These bar- Selenomonas. In part, this is due to genetic exchange between mem- 228

163 codes are then incorporated into the final sequences obtained and bers of these genera which have led to recombination within the 229

164 can be easily sorted and assigned to source samples after sequenc- 16S rRNA gene, making the interpretation of phylogenetic relation- 230

165 ing. ships derived from this gene difficult [29]. 231

166 The use of pyrosequencing and alternative high through- Because of these limitations, the Ribosomal Database Project 232

167 put methods such as the Illumina system, which provides even Classifier [30], one of the most commonly used analysis pipelines, 233

168 higher numbers of sequences, although of shorter length, has only allows identification of sequences to genus level. This may be 234

169 revolutionised culture-independent analyses and has been the cor- informative when applied to highly diverse bacterial communities 235

170 nerstone of that part of the Human Microbiome Project devoted but for a well-studied microbiome such as the oral microbiome, it 236

171 to determining the composition of the microbiomes at different is a severe limitation. Thus, genera such as Porphyromonas, Aggre- 237

172 human body sites [2]. These studies have shown that each body gatibacter and Tannerella all include some species that are strongly 238

173 site studied was colonised by a microbiome characteristic of that associated with disease and others that are health-associated. Data 239

174 site but that the individual was the primary factor influencing the from next generation sequencing studies targeting the 16S rRNA 240

175 composition of the microbiome i.e. each individual is colonised gene should therefore be interpreted with caution to avoid drawing 241

176 by a unique microbiome. Within the mouth, samples from seven erroneous inferences because of the deficiencies of current analysis 242

177 different surfaces were found to be colonised by three distinct bac- pipelines. For the oral microbiota, it is possible to use the mothur 243

178 terial communities: the buccal mucosa, gingivae and hard palate analysis suite [31] in conjunction with the HOMD reference set to 244

179 had similar microbiota while the saliva, tongue, tonsils and throat, obtain species-level identifications for most oral bacterial genera 245

180 and supra- and sub-gingival plaque each had distinctive communi- [32]. An alternative approach is used in the SpeciateIT programme, 246

181 ties [20]. The oral microbiota was found to be only second to that of based on the construction of hidden Markov models, and has been 247

182 the colon in terms of species-richness and, while there are similar- shown to improve species-level identification of the endodontic 248

183 ities between individuals oral microbiomes at the genus level [21], and vaginal microbiota [33,34]. 249

184 at the species level, the composition of the microbiota is more vari- The bacterial community of the mouth is dominated by the phyla 250

185 able in different individuals with, in one study, 47% of species-level Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, Spirochaetes 251

186 OTUs shared between three individual [22]. There appears to be and Fusobacteria which account for 96% of species detected [1]. The 252

187 some evidence, then, for a core oral microbiome common to most key features of the predominant bacterial taxa have been described 253

188 individuals. previously [1] and are available from the Human Oral Microbiome 254

189 Interestingly, a study of 120 individuals from 12 worldwide loca- Database website at www.homd.org [35]. 255

190 tions found no significant geographical differences between their Defining the precise composition of the oral microbiome is 256

191 salivary microbiota [23]. This suggests that diet and the environ- difficult because the mouth is an open system and frequently 257

192 ment do not significantly influence the composition of the oral exposed to exogenous bacteria in food, in water, in air and the 258

193 microbiome and that the host species is the primary determinant. normal microbiota of other mammals including humans via social 259

194 Some novel taxa were found, however, in a study of the oral micro- contact and kissing. It is often difficult to determine whether 260

195 biota in South American Amerindians living in a remote village long-term colonisation with a particular species occurs. How- 261

196 [24], although the lack of a control group makes interpretation of ever, most non-oral bacteria are not routinely isolated from the 262

197 these data difficult. The primary source of nutrients for oral bacte- mouth. Why this should be so is unclear but exogenous bacte- 263

198 ria is endogenous in the form of saliva and gingival crevicular fluid. ria may lack adhesins and receptors that would enable them 264

199 When food is placed in the mouth and chewed, saliva production is to bind to oral surfaces or co-aggregate with other bacteria. 265

200 increased and the food is quickly swallowed, which may explain There may also be immune exclusion. Evidence for this is pro- 266

201 why, in general, diet has little effect on the composition of the vided by the observation that gut coliforms are rarely found 267

202 oral microbiota. One exception is fermentable carbohydrate; some in health but often found in immunocompromised individuals 268

203 oral bacteria are adept in taking up sugars and fermenting them to and those with reduced salivary flow [36,37]. Another group 269

204 produce acid, resulting in dental caries, as described below. Sus- of organisms that fall into this category is the methylotrophs 270

205 tained high intake of dietary carbohydrates can result in altered that can use 1-carbon substrates for growth. By performing 271

206 microbiota, dominated by aciduric species [25], and the salivary enrichment culture of oral samples using a range of 1-carbon sub- 272

207 microbiome in caries-active subjects differs from that found in strates, representatives of a number of genera including known 273

208 caries-free subjects [26]. methylotrophs such as Methylobacterium and Hyphomicrobium and 274

209 Next generation sequencing methods undoubtedly have the other organisms including Brachybacterium, Gordonia, Leifsonia, 275

210 potential to revolutionise our view of the composition of the Microbacterium and Micrococcus were isolated, in which methy- 276

211 microbiomes but do suffer from some disadvantages compared to lotrophy had not previously been demonstrated [38,39]. Most 277

212 conventional Sanger sequencing. Early data suffered from a high of these organisms had not previously been isolated from the 278

213 error rate due to the formation of heterduplexes and homopoly- mouth and were not among those detected in 16S rRNA gene 279

214 meric tracts during sequencing which led to the detection of clone libraries. They are frequently found in tap water and the 280

215 spurious diversity and excessively high estimates of species rich- environment, so it is possible that when applying the power- 281

216 ness in saliva and plaque [27]. This problem has now been ful selection of enrichment culture, organisms that were only 282

217 successfully addressed bioinformatically [28] and estimates of present in the mouth transiently, but were not permanent colonists, 283

218 species richness from recent studies are now of the same order were isolated. These species are also all mainly obligate aer- 284

219 as hitherto, with the advantage that the depth of coverage that can obes. As has been described above, these are a rare group in the 285

220 be achieved for each individual sample has been greatly increased. mouth because of the highly anaerobic nature of oral bacterial 286

221 Another significant issue is that, at present, only relatively biofilms after a short period of development. It is possible that 287

222 short sequences can be obtained which precludes species-level methylotrophic bacteria could transiently but repeatedly colonise 288

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289 the exposed aerobic surfaces of the mouth and use 1-carbon regarded as a specific pathogen. It is now recognised, however, that 349

290 substrates while there. However, further work is needed to confirm there are a large number of species naturally present in the oral 350

291 this. plaque biofilm that produce acid from dietary carbohydrate and 351

292 An additional problem in the interpretation of data from that the consequent caries-associated microbiota is complex [51]. 352

293 culture-independent surveys is that PCR reagents are frequently In addition to S. mutans and lactobacilli, members of the genera Bifi- 353

294 contaminated with DNA from environmental bacteria which can dobacterium, Propionibacterium and Scardovia have been found to 354

295 then be amplified by the universal primers used in such studies [40]. be caries-associated [52–55]. In addition to acid production, some 355

296 Pre-treatment with ultra-violet light has been found to be effective bacteria can raise pH by producing ammonia from urea and arginine 356

297 in the reduction of such contamination [41]. [56], which provides a mechanism for balancing acid production 357

from dietary sugars by other bacteria and thus maintaining homeo- 358

stasis. There is a wide variation in the metabolic activity of strains 359

298 3. Role of oral microbiome in health
within species, however, and the environment has a marked effect 360

on bacterial phenotype. Species-level identifications may therefore 361

299 The commensal microbiota plays an important role in maintain-
not be of value in understanding the disease process; functional 362
300 ing oral and systemic health. Commensals in the gut are known
characterisation is required which takes environmental influences 363
301 to be essential for the development of the structures of the gut
into account [57]. 364
302 and for appropriate development of local and systemic immunity.
303 Lymphoid follicles do not develop in the small intestine of germ-
4.2. Endodontic infections 365
304 free mice and mucosal IgA is produced only in the presence of the
305 microbiota [42,43]. The simple presence of the oral microbiota in
If dental carious lesions are left untreated, the lesion can 366
306 the mouth inhibits colonisation by pathogens, the phenomenon of
progress through dentine and into the pulp where the pulp 367
307 colonisation resistance [44]. Because all surfaces of the mouth are
becomes infected and dies. The microbiota associated with 368
308 colonised by commensals there are few binding sites available for
untreated endodontic infections are primarily anaerobic proteo- 369
309 pathogens. The importance of this effect can be seen when the com-
lytic bacteria [41]. Interestingly, endodontic infections that persist 370
310 mensal microbiota is disrupted, for example by antimicrobials [45].
after treatment frequently include enterococci which are not nor- 371
311 Infections by opportunistic pathogens such as Candida species and
mally found in the mouth in health. The source of these organisms 372
312 Staphylococcus aureus can occur.
has long been debated but it has been recently shown that are found 373
313 Some health-associated bacteria have been shown to be antag-
in cheese, both pasteurised and unpasteurised, and can persist in 374
314 onistic to oral pathogens. For example Streptococcus salivarius
the mouth for some time after cheese has been eaten [58]. In an 375
315 strain K12 produces a bacteriocin which inhibits the growth of
in vitro model, it was shown that enterococci could gain access to 376
316 Gram-negative species which are associated with periodontitis and
the root canal via microleakage through the type of temporary fill- 377
317 halitosis in vitro [46], and has been shown to have beneficial effects
ings that are placed between visits during endodontic therapy [59]. 378
318 on halitosis in vivo [47].
It is possible then that cheese, and perhaps other dairy and fer- 379
319 An interesting property of the oral microbiome relates to
mented meat products, are the source of the enterococci that can 380
320 nitrate metabolism and cardiovascular health. Around a quarter of
cause endodontic infection once the root canal has been opened for 381
321 ingested nitrate is returned to the mouth via an entero-salivary cir-
treatment. It appears that enterococci can colonise the root canal 382
322 cuit. Oral bacteria reduce nitrate to nitrite which is taken up into
and cause infections there but are not able to compete with the 383
323 the bloodstream via gastric absorption, and converted into nitric
normal microbiota away from this habitat, elsewhere in the mouth. 384
324 oxide. Nitric oxide is essential for vascular health, and helps to keep
Patients receiving endodontic treatment should be advised to avoid 385
325 blood vessels pliant and supple and thus has an anti-hypertensive
consumption of foods known to be colonised by enterococci. 386
326 effect. Dietary nitrate supplements lower blood pressure by stim-
327 ulating this mechanism [48]. The central role of oral bacteria has
4.3. Periodontal diseases 387
328 been confirmed by the observations that the increase in plasma
329 nitrite following nitrate ingestion is markedly reduced by the use
4.3.1. Gingivitis 388
330 of an antimicrobial mouthrinse [49], and, in rats, antimicrobial use
Gingivitis is perhaps the most common bacterial disease of man 389
331 abolishes the blood pressure lowering effect of ntirate [50]. This
with a prevalence in adults of over 90% [60]. Dental plaque forms 390
332 may, then, have implications for oral hygiene. Over-zealous oral
continuously on tooth surfaces. Salivary glycoproteins are selec- 391
333 hygiene could have negative implications for what appears to be
tively adsorbed onto the teeth to form the salivary pellicle. Oral 392
334 an important natural mechanism for maintaining cardiovascular
bacteria then attach to the tooth surface by adhering to epitopes 393
335 health.
in the pellicle [61,62]. Primary colonisers can then co-aggregate 394

with other bacteria joining the developing biofilm via coaggrega- 395

336 4. Oral microbiome-related oral diseases tion interactions [63]. In general, primary colonisers tend to be 396

Gram-positive aerobes and facultative anaerobes such as strepto- 397

337 4.1. Dental caries cocci and Actinomyces species [64], while among the predominant 398

anaerobic organisms in mature plaque are Gram-negatives such 399

338 Dental caries, or tooth decay, is the dissolution of tooth structure as Fusobacterium, Treponema and members of the phylum Syner- 400

339 by acid produced as a result of the fermentation of dietary car- gistetes [65]. A variety of oral hygiene measures have been used 401

340 bohydrates by oral bacteria. In individuals who repeatedly ingest throughout human history to remove dental plaque [66]. Brush- 402

341 high levels of carbohydrates, the frequency of acid production leads ing with a toothpaste is the primary method in industrialised 403

342 to the erosion of the buffering capacity of saliva and frequent and countries but the use of chewing sticks is perhaps the most com- 404

343 sustained reductions in pH. In turn this changes the composition monly used method of oral hygiene worldwide. If tooth cleaning 405

344 of the oral microbiota to one that favours aciduric species [25]. is practised regularly, dental plaque is kept in an immature state 406

345 These species, particularly Streptococcus mutans and lactobacilli, and in relatively small amounts. If an individual does not practice 407

346 continue to produce acid under acidic conditions and thus exac- oral hygiene, then the proportion of Gram-negative and anaero- 408

347 erbate the damage to the dental hard tissues. S. mutans has been bic species increases and endotoxin and other enzymes pass into 409

348 studied intensively for its cariogenic properties and has even been the gingivae and cause irritation and inflammation by activating 410

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411 pro-inflammatory pathways. The clinical signs of gingivitis are fluid in the form of glycoproteins. There are probably no bacte- 472

412 swollen and inflamed gums which bleed on probing or spon- ria that can digest oral glycoproteins in their entirety on their 473

413 taneously. The disease is entirely reversible if oral hygiene is own but consortia of bacteria can work together to degrade com- 474

414 reinstated [67]. There are no specific bacteria associated with gin- plex substrates to the benefit of the whole community [82]. For 475

415 givitis but the amount of plaque present, the plaque load, and its example, it has been shown that certain streptococci have both 476

416 maturity are correlated with disease severity [68]. glycosidic and endopeptidase activity and are thus able both to 477

remove the oligosaccharide sidechains and attack the protein core 478

417 4.3.2. Periodontitis of glycoproteins [83,84]. Many Gram-negative anaerobic bacte- 479

418 In susceptible individuals, attachment is lost between the gin- ria such as members of the genera Prevotella and Porphyromonas 480

419 givae and the teeth with the formation of a periodontal pocket, also have endopeptidase activity which results in the cleavage of 481

420 which becomes heavily colonised with anaerobic bacteria. The host proteins to peptides [85]. Many frequently detected oral bacte- 482

421 response is ineffectual and actually contributes to the development ria including Fusobacterium and Peptostreptococcus and relatives 483

422 of the lesion with host proteases making a significant contribution have aminopeptidase activity [86,87], and can ferment amino acids 484

423 to tissue damage [69]. The alveolar bone which supports the teeth producing short chain fatty acids. The connective tissue found in 485

424 resorbs ahead of the infection, the teeth become mobile in their the periodontium is rich in sulphur-containing glycosaminoglycans 486

425 sockets and are eventually lost. Dental plaque-associated periodon- [88] and sulphate accumulates as a result of tissue breakdown in 487

426 titis is classified into two main categories – chronic and aggressive, disease. Bacterial species regarded as terminal degraders are found 488

427 with the latter being characterised by increased severity and rate in periodontal pockets. For example the methanogens use short 489

428 of progression and generally earlier onset [70]. These general chain fatty acids in the production of methane [10], and a number 490

429 descriptions are likely to encompass a spectrum of related diseases, of species of sulphate-reducing bacteria, including Desulfobulbus, 491

430 however, which are clinically difficult to differentiate. A specific Desulfomicrobium and Desulfovibrio can be found [89,90]. 492

431 microbiota is associated with advanced periodontitis [13], although Oral bacteria vary widely in their sensitivity to oxygen. There 493

432 whether certain species are responsible for the initiation of the dis- are relatively few species of obligate aerobes in the mouth. The 494

433 ease or the inflammation and pocket formation create conditions principal genera are Neisseria and Rothia species which are among 495

434 that periodontitis-associated bacteria prefer remains unclear. Host the earliest colonisers of tooth surfaces [91]. Many are faculta- 496

435 susceptibility is clearly of primary importance and tobacco smok- tive anaerobes including Streptococcus and Actinomyces, the two 497

436 ing is a strong environmental factor [71]. Species associated with most numerous genera found. As oral biofilms develop, they rapidly 498

437 periodontitis include Porphyromonas gingivalis, Treponema denti- become anaerobic which explains the high proportions and large 499

438 cola and Tannerella forsythia which were originally associated with number of species of obligate anaerobes that are found in the 500

439 the disease in culture-based studies and subsequently confirmed mouth. Interestingly, it has been shown that members of the oral 501

440 with whole-genomic DNA probes [72]. Culture-independent stud- bacterial community can cooperate to protect each other from 502

441 ies have expanded the range of disease-associated organisms to atmospheric stresses. It has been shown that the presence of the 503

442 include Anaeroglobus geminatus, Eubacterium saphenum, Filifactor obligate aerobe Neisseria enables obligate anaerobes to grow in a 504

443 alocis, Porphyromonas endodontalis, Prevotella denticola and un- mixed-culture biofilm under aerobic conditions [92]. 505

444 named Bacteroidetes and Fretibacterium phylotypes [73]. Although oral bacteria can be grouped by function in this way, 506

there must still be a reason for the extreme diversity and variability 507

445 4.4. The oral microbiome and non-oral diseases within species. Presumably, this diversity lends versatility to the 508

community and the ability to respond to environmental stresses 509

446 The oral microbiome has long been known to be a reservoir for in the most appropriate way. Recently developed genetic meth- 510

447 infection at other body sites. Oral bacteria easily and frequently gain ods are allowing the functional potential of the oral microbiome to 511

448 access to the bloodstream via the gingival crevice and untreated be assessed. Firstly, metagenomic sequencing using next genera- 512

449 carious lesions and are a significant cause of infectious endocardi- tion sequencing methods can be used to sequence large amounts 513

450 tis [74], and brain and liver abscesses [75,76]. Oral bacteria have of DNA from oral sites without the need to culture the microbiota. 514

451 been detected in the lungs in cystic fibrosis patients [77], and can For example, the metagenomes associated with periodontitis and 515

452 cause a variety of soft tissue infections following bites and clenched caries have been found to be significantly different from those seen 516

453 fist injuries [78,79]. In addition, it has been suggested that the com- in oral health and to include sequences coding for a variety of viru- 517

454 position of the oral microbiome may be linked to diseases at other lence factors [93,94]. Combined metagenomic and 16S rRNA based 518

455 body sites either in a causative way or as a reflection of systemic analyses have allowed correlations between the community struc- 519

456 changes in the body [80,81]. In the latter case, oral microbiomic ture and metabolic activity to be determined for a variety of sites 520

457 profiles could be used as diagnostic biomarkers for other diseases. from the adult digestive tract [20]. Further clues as to the function 521

of oral bacteria and archaea in health and disease will be obtained 522

458 5. Functional aspects of the oral microbiome from metaproteomic and transcriptomic studies. For example, the 523

metaproteome of salivary sediments has been successfully studied, 524

459 The complexity of the oral bacterial community is so great that with peptides identified from over 100 oral bacterial and success- 525

460 it might be considered an impossible task to assign a role for fully mapped to metabolic pathways [95]. 526

461 each organism within the community. What is important, how-

462 ever, is the functional role of each organism and it is likely that
463 the range of such functions is more limited than the phyloge- 6. Conclusion 527

464 netic range of species present. Within each habitat, and depending
465 on the health/diseases status of the site, a restricted range of The use of recently developed molecular methods has greatly 528

466 functions may be needed and could be provided by a number expanded our knowledge of the composition and function of the 529

467 of organisms. Arguably, the most important functions are nutri- oral microbiome in health and disease. Much remains to be done, 530

468 tional. The primary substrates for growth in the mouth are not however. Bacterial species are far from homogeneous and compar- 531

469 derived from the food ingested by the human host since this is isons of genomes of strains from the same species have revealed 532

470 removed quickly by the combined actions of salivary flow and the high genetic diversity of most species studied, particularly 533

471 swallowing, but are derived from saliva and gingival crevicular in relation to the presence or absence of virulence factors. As 534

Please cite this article in press as: Wade WG. The oral microbiome in health and disease. Pharmacol Res (2012),
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6 W.G. Wade / Pharmacological Research xxx (2012) xxx–xxx

535 discussed above, diseases associated with the commensal micro- [27] Keijser BJ, Zaura E, Huse SM, van der Vossen JM, Schuren FH, Montijn RC, et al. 613

536 biota are not caused by a single pathogen but result, in part, from Pyrosequencing analysis of the oral microflora of healthy adults. Journal of 614
Dental Research 2008;87:1016–20. 615
537 the concerted actions of a number of species. Investigating and [28] Quince C, Lanzen A, Curtis TP, Davenport RJ, Hall N, Head IM, et al. Accurate 616
538 understanding the interactions between organisms will be a highly determination of microbial diversity from 454 pyrosequencing data. Nature 617

539 complex task. Finally, these diseases primarily result from an inter- Methods 2009;6:639–41. 618
[29] Hanage WP, Fraser C, Spratt BG. Fuzzy species among recombinogenic bacteria. 619
540 action between the human host and the microbiome. Variations in BMC Biology 2005;3:6. 620
541 human responses to the microbiome have rarely been studied and [30] Wang Q, Garrity GM, Tiedje JM, Cole JR. Naive Bayesian classifier for rapid 621
542 the influence of environmental factors introduces a further layer of assignment of rRNA sequences into the new bacterial taxonomy. Applied and 622
Environmental Microbiology 2007;73:5261–7. 623
543 complexity. Technical advances in DNA and RNA sequencing will
[31] Schloss PD, Westcott SL, Ryabin T, Hall JR, Hartmann M, Hollister EB, 624
544 provide vast amounts of new data but analysing and interpreting et al. Introducing mothur: open-source, platform-independent, community- 625
545 the data will be extremely challenging. supported software for describing and comparing microbial communities. 626
Applied and Environmental Microbiology 2009;75:7537–41. 627
[32] Pramanik R, Thompson H, Kistler J, Wade WG, Galloway J, Peakman T, et al. 628
Effects of the UK Biobank collection protocol on potential biomarkers in saliva. Q2 629
International Journal of Epidemiology, in press. 630
546 References [33] Hsiao WW, Li KL, Liu Z, Jones C, Fraser-Liggett CM, Fouad AF. Microbial trans- 631
formation from normal oral microbiota to acute endodontic infections. BMC 632

547 [1] Dewhirst FE, Chen T, Izard J, Paster BJ, Tanner AC, Yu WH, et al. The human oral Genomics 2012;13:345. 633

548 microbiome. Journal of Bacteriology 2010;192:5002–17. [34] Ravel J, Gajer P, Abdo Z, Schneider GM, Koenig SS, McCulle SL, et al. Vaginal 634

549 [2] Human Microbiome Project Consortium. Structure, function and diversity of microbiome of reproductive-age women. Proceedings of the National Academy 635

550 the healthy human microbiome. Nature 2012;486:207–14. of Sciences of the United States of America 2011;108(Suppl. 1):4680–7. 636

551 [3] Scott DA, Coulter WA, Lamey PJ. Oral shedding of herpes simplex virus type [35] Chen T, Yu WH, Izard J, Baranova OV, Lakshmanan A, Dewhirst FE. 637

552 1: a review. Journal of Oral Pathology & Medicine: Official Publication of the The human oral microbiome database: a web accessible resource 638

553 International Association of Oral Pathologists and the American Academy of for investigating oral microbe taxonomic and genomic information. 639

554 Oral Pathology 1997;26:441–7. Database: The Journal of Biological Databases and Curation 2010;2010, 640

555 [4] Kumaraswamy KL, Vidhya M. Human papilloma virus and oral infections: an http://dx.doi.org/10.1093/database/baq013. 641

556 update. Journal of Cancer Research and Therapeutics 2011;7:120–7. [36] Jobbins J, Bagg J, Parsons K, Finlay I, Addy M, Newcombe RG. Oral carriage 642
557 [5] Loning T, Ikenberg H, Becker J, Gissmann L, Hoepfer I, zur Hausen H. Anal- of yeasts, coliforms and staphylococci in patients with advanced malignant 643
558 ysis of oral papillomas, leukoplakias, and invasive carcinomas for human disease. Journal of Oral Pathology & Medicine: Official Publication of the Inter- 644
559 papillomavirus type related DNA. The Journal of Investigative Dermatology national Association of Oral Pathologists and the American Academy of Oral 645
560 1985;84:417–20. Pathology 1992;21:305–8. 646
561 [6] Pride DT, Salzman J, Haynes M, Rohwer F, Davis-Long C, White 3rd RA, et al. Evi- [37] MacFarlane TW, Mason DK. Changes in the oral flora in Sjogren’s syndrome. 647
562 dence of a robust resident bacteriophage population revealed through analysis Journal of Clinical Pathology 1974;27:416–9. 648
563 of the human salivary virome. The ISME Journal 2012;6:915–26. [38] Anesti V, McDonald IR, Ramaswamy M, Wade WG, Kelly DP, Wood AP. Isolation 649
564 [7] Wantland WW, Wantland EM, Remo JW, Winquist DL. Studies on human mouth and molecular detection of methylotrophic bacteria occurring in the human 650
565 protozoa. Journal of Dental Research 1958;37:949–50. mouth. Environmental Microbiology 2005;7:1227–38. 651
566 [8] Arendorf TM, Walker DM. Oral candidal populations in health and disease. [39] Hung WL, Wade WG, Boden R, Kelly DP, Wood AP. Facultative methylotrophs 652
567 British Dental Journal 1979;147:267–72. from the human oral cavity and methylotrophy in strains of Gordonia, Leifsonia, 653
568 [9] Ghannoum MA, Jurevic RJ, Mukherjee PK, Cui F, Sikaroodi M, Naqvi A, et al. Char- and Microbacterium. Archives of Microbiology 2011;193:407–17. 654
569 acterization of the oral fungal microbiome (mycobiome) in healthy individuals. [40] Tanner MA, Goebel BM, Dojka MA, Pace NR. Specific ribosomal DNA sequences 655
570 PLoS Pathogens 2010;6:e1000713. from diverse environmental settings correlate with experimental contami- 656
571 [10] Lepp PW, Brinig MM, Ouverney CC, Palm K, Armitage GC, Relman nants. Applied and Environmental Microbiology 1998;64:3110–3. 657
572 DA. Methanogenic archaea and human periodontal disease. Proceedings [41] Munson MA, Pitt-Ford T, Chong B, Weightman A, Wade WG. Molecular and cul- 658
573 of the National Academy of Sciences of the United States of America tural analysis of the microflora associated with endodontic infections. Journal 659
574 2004;101:6176–81. of Dental Research 2002;81:761–6. 660
575 [11] Matarazzo F, Ribeiro AC, Feres M, Faveri M, Mayer MP. Diversity and quantita- [42] Hooper LV, Littman DR, Macpherson AJ. Interactions between the microbiota 661
576 tive analysis of archaea in aggressive periodontitis and periodontally healthy and the immune system. Science 2012;336:1268–73. 662
577 subjects. Journal of Clinical Periodontology 2011;38:621–7. [43] Shroff KE, Meslin K, Cebra JJ. Commensal enteric bacteria engender a self- 663
578 [12] Porter JR. Antony van Leeuwenhoek: tercentenary of his discovery of bacteria. limiting humoral mucosal immune response while permanently colonizing the 664
579 Bacteriological Reviews 1976;40:260–9. gut. Infection and Immunity 1995;63:3904–13. 665
580 [13] Loesche WJ. Chemotherapy of dental plaque infections. Oral Sciences Reviews [44] Vollaard EJ, Clasener HA. Colonization resistance. Antimicrobial Agents and 666
581 1976;9:65–107. Chemotherapy 1994;38:409–14. 667
582 [14] Amann RI, Ludwig W, Schleifer KH. Phylogenetic identification and in situ [45] Sullivan A, Edlund C, Nord CE. Effect of antimicrobial agents on the ecological 668
583 detection of individual microbial cells without cultivation. Microbiological balance of human microflora. The Lancet Infectious Diseases 2001;1:101–14. 669
584 Reviews 1995;59:143–69. [46] Wescombe PA, Heng NC, Burton JP, Chilcott CN, Tagg JR. Streptococcal bacteri- 670
585 [15] Wade WG. Non-culturable bacteria in complex commensal populations. ocins and the case for Streptococcus salivarius as model oral probiotics. Future 671
586 Advances in Applied Microbiology 2004;54:93–106. Microbiology 2009;4:819–35. 672
587 [16] Pace NR, Olsen GJ, Woese CR. Ribosomal RNA phylogeny and the primary lines [47] Burton JP, Chilcott CN, Moore CJ, Speiser G, Tagg JR. A preliminary study of the 673
588 of evolutionary descent. Cell 1986;45:325–6. effect of probiotic Streptococcus salivarius k12 on oral malodour parameters. 674
589 [17] Ward D, Weller R, Bateson M. 16S rRNA sequences reveal numerous uncultured Journal of Applied Microbiology 2006;100:754–64. 675
590 microorganisms in a natural community. Nature 1990;345:63–5. [48] Kapil V, Milsom AB, Okorie M, Maleki-Toyserkani S, Akram F, Rehman F, et al. 676
591 [18] Giovannoni S, Britschgi T, Moyer C, Field K. Genetic diversity in Sargasso Sea Inorganic nitrate supplementation lowers blood pressure in humans: role for 677
592 bacterioplankton. Nature 1990;345:60–3. nitrite-derived no. Hypertension 2010;56:274–81. 678
593 [19] Rothberg JM, Leamon JH. The development and impact of 454 sequencing. [49] Govoni M, Jansson EA, Weitzberg E, Lundberg JO. The increase in plasma nitrite 679
594 Nature Biotechnology 2008;26:1117–24. after a dietary nitrate load is markedly attenuated by an antibacterial mouth- 680
595 [20] Segata N, Haake SK, Mannon P, Lemon KP, Waldron L, Gevers D, et al. Compo- wash. Nitric Oxide: Biology and Chemistry/Official Journal of the Nitric Oxide 681
596 sition of the adult digestive tract bacterial microbiome based on seven mouth Society 2008;19:333–7. 682
597 surfaces, tonsils, throat and stool samples. Genome Biology 2012;13:R42. [50] Petersson J, Carlstrom M, Schreiber O, Phillipson M, Christoffersson G, Jagare 683
598 [21] Lazarevic V, Whiteson K, Hernandez D, Francois P, Schrenzel J. Study of inter- A, et al. Gastroprotective and blood pressure lowering effects of dietary nitrate 684
599 and intra-individual variations in the salivary microbiota. BMC Genomics are abolished by an antiseptic mouthwash. Free Radical Biology & Medicine 685
600 2010;11:523. 2009;46:1068–75. 686
601 [22] Zaura E, Keijser BJ, Huse SM, Crielaard W. Defining the healthy “core micro- [51] Gross EL, Leys EJ, Gasparovich SR, Firestone ND, Schwartzbaum JA, Janies DA, 687
602 biome” of oral microbial communities. BMC Microbiology 2009;9:259. et al. Bacterial 16S sequence analysis of severe caries in young permanent teeth. 688
603 [23] Nasidze I, Li J, Quinque D, Tang K, Stoneking M. Global diversity in the human Journal of Clinical Microbiology 2010;48:4121–8. 689
604 salivary microbiome. Genome Research 2009;19:636–43. [52] Downes J, Mantzourani M, Beighton D, Hooper S, Wilson MJ, Nicholson A, et al. 690
605 [24] Contreras M, Costello EK, Hidalgo G, Magris M, Knight R, Dominguez-Bello MG. Scardovia wiggsiae sp. Nov., isolated from the human oral cavity and clini- 691
606 The bacterial microbiota in the oral mucosa of rural Amerindians. Microbiology cal material, and emended descriptions of the genus Scardovia and Scardovia 692
607 2010;156:3282–7. inopinata. International Journal of Systematic and Evolutionary Microbiology 693
608 [25] Takahashi N, Nyvad B. The role of bacteria in the caries process: ecological 2011;61:25–9. 694
609 perspectives. Journal of Dental Research 2011;90:294–303. [53] Kaur R, Gilbert SC, Sheehy EC, Beighton D. Salivary levels of bifidobacteria in 695
610 [26] Yang F, Zeng X, Ning K, Liu KL, Lo CC, Wang W, et al. Saliva microbiomes caries-free and caries-active children. International Journal of Paediatric Den- Q3 696
611 distinguish caries-active from healthy human populations. The ISME Journal tistry/the British Paedodontic Society [and] The International Association of 697
612 2012;6:1–10. Dentistry for Children 2012. 698

Please cite this article in press as: Wade WG. The oral microbiome in health and disease. Pharmacol Res (2012),
http://dx.doi.org/10.1016/j.phrs.2012.11.006
 ARTICLE IN PRESS
G Model
YPHRS 2533 1–7

W.G. Wade / Pharmacological Research xxx (2012) xxx–xxx 7

699 [54] Munson MA, Banerjee A, Watson TF, Wade WG. Molecular analysis of the [77] Rogers GB, Carroll MP, Serisier DJ, Hockey PM, Jones G, Kehagia V, et al. Use 755
700 microflora associated with dental caries. Journal of Clinical Microbiology of 16S rRNA gene profiling by terminal restriction fragment length polymor- 756
701 2004;42:3023–9. phism analysis to compare bacterial communities in sputum and mouthwash 757
702 [55] Tanner AC, Kent Jr RL, Holgerson PL, Hughes CV, Loo CY, Kanasi E, et al. Micro- samples from patients with cystic fibrosis. Journal of Clinical Microbiology 758
703 biota of severe early childhood caries before and after therapy. Journal of Dental 2006;44:2601–4. 759
704 Research 2011;90:1298–305. [78] Goldstein EJ, Citron DM, Finegold SM. Role of anaerobic bacteria in bite-wound 760
705 [56] Burne RA, Marquis RE. Alkali production by oral bacteria and protection against infections. Reviews of Infectious Diseases 1984;6(Suppl. 1):S177–83. 761
706 dental caries. FEMS Microbiology Letters 2000;193:1–6. [79] Mennen U, Howells CJ. Human fight-bite injuries of the hand. A study of 100 762
707 [57] Burne RA, Zeng L, Ahn SJ, Palmer SR, Liu Y, Lefebure T, et al. Progress dissec- cases within 18 months. Journal of Hand Surgery-British 1991;16:431–5. 763
708 ting the oral microbiome in caries and health. Advances in Dental Research [80] Ahn J, Chen CY, Hayes RB. Oral microbiome and oral and gastrointestinal cancer 764
709 2012;24:77–80. risk. Cancer Causes & Control 2012;23:399–404. 765
710 [58] Razavi A, Gmur R, Imfeld T, Zehnder M. Recovery of enterococcus faecalis from [81] Farrell JJ, Zhang L, Zhou H, Chia D, Elashoff D, Akin D, et al. Variations of oral 766
711 cheese in the oral cavity of healthy subjects. Oral Microbiology and Immunol- microbiota are associated with pancreatic diseases including pancreatic cancer. 767
712 ogy 2007;22:248–51. Gut 2012;61:582–8. 768
713 [59] Kampfer J, Gohring TN, Attin T, Zehnder M. Leakage of food-borne entero- [82] Wickstrom C, Herzberg MC, Beighton D, Svensater G. Proteolytic degradation 769
714 coccus faecalis through temporary fillings in a simulated oral environment. of human salivary muc5b by dental biofilms. Microbiology 2009;155:2866–72. 770
715 International Endodontic Journal 2007;40:471–7. [83] Byers HL, Tarelli E, Homer KA, Beighton D. Sequential deglycosylation and 771
716 [60] Coventry J, Griffiths G, Scully C, Tonetti M. ABC of oral health: periodontal utilization of the n-linked, complex-type glycans of human alpha1-acid glyco- 772
717 disease. British Medical Journal 2000;321:36–9. protein mediates growth of Streptococcus oralis. Glycobiology 1999;9:469–79. 773
718 [61] Ahn SJ, Kho HS, Lee SW, Nahm DS. Roles of salivary proteins in the adherence [84] Homer KA, Whiley RA, Beighton D. Proteolytic activity of oral streptococci. 774
719 of oral streptococci to various orthodontic brackets. Journal of Dental Research FEMS Microbiology Letters 1990;55:257–60. 775
720 2002;81:411–5. [85] Jie Bao G, Kari K, Tervahartiala T, Sorsa T, Meurman JH. Proteolytic activities 776
721 [62] Murray PA, Prakobphol A, Lee T, Hoover CI, Fisher SJ. Adherence of oral strepto- of oral bacteria on prommp-9 and the effect of synthetic proteinase inhibitors. 777
722 cocci to salivary glycoproteins. Infection and Immunity 1992;60:31–8. The Open Dentistry Journal 2008;2:96–102. 778
723 [63] Kolenbrander PE, Palmer Jr RJ, Rickard AH, Jakubovics NS, Chalmers NI, Diaz PI. [86] Ng J, Ng LK, Mayrand D, Dillon JA. Aminopeptidase activities in Peptostrepto- 779
724 Bacterial interactions and successions during plaque development. Periodon- coccus spp. Are statistically correlated to gelatin hydrolysis. Canadian Journal 780
725 tology 2006;2000(42):47–79. of Microbiology 1998;44:303–6. 781
726 [64] Nyvad B, Kilian M. Microbiology of the early colonization of human enamel and [87] Rogers AH, Gunadi A, Gully NJ, Zilm PS. An aminopeptidase nutritionally impor- 782
727 root surfaces in vivo. Scandinavian Journal of Dental Research 1987;95:369–80. tant to Fusobacterium nucleatum. Microbiology 1998;144(Pt 7):1807–13. 783
728 [65] Zijnge V, van Leeuwen MB, Degener JE, Abbas F, Thurnheer T, Gmur R, et al. Oral [88] Larjava H, Paunio K. Analyses of periodontal glycosaminoglycans and pro- 784
729 biofilm architecture on natural teeth. PLoS ONE 2010;5:e9321. teoglycans. Regulation by microbial, chemical and inflammatory factors. 785
730 [66] Fischman SL. The history of oral hygiene products: how far have we come in Proceedings of the Finnish Dental Society Suomen Hammaslaakariseuran toim- 786
731 6000 years? Periodontology 1997;2000(15):7–14. ituksia 1991;87:287–98. 787
732 [67] Loe H, Theilade E, Jensen SB. Experimental gingivitis in man. Journal of Peri- [89] Langendijk PS, Kulik EM, Sandmeier H, Meyer J, van der Hoeven JS. Isolation 788
733 odontology 1965;36:177–87. of Desulfomicrobium orale sp. Nov. And Desulfovibrio strain ny682, oral sulfate- 789
734 [68] Socransky SS. Microbiology of periodontal disease – present status and future reducing bacteria involved in human periodontal disease. International Journal 790
735 considerations. Journal of Periodontology 1977;48:497–504. of Systematic and Evolutionary Microbiology 2001;51:1035–44. 791
736 [69] Darveau RP. Periodontitis: a polymicrobial disruption of host homeostasis. [90] van der Hoeven JS, van den Kieboom CW, Schaeken MJ. Sulfate-reducing 792
737 Nature Reviews Microbiology 2010;8:481–90. bacteria in the periodontal pocket. Oral Microbiology and Immunology 793
738 [70] Armitage GC. Development of a classification system for periodontal diseases 1995;10:288–90. 794
739 and conditions. Annals of Periodontology/The American Academy of Periodon- [91] Diaz PI, Chalmers NI, Rickard AH, Kong C, Milburn CL, Palmer Jr RJ, 795
740 tology 1999;4:1–6. et al. Molecular characterization of subject-specific oral microflora dur- 796
741 [71] Van Dyke TE, Sheilesh D. Risk factors for periodontitis. Journal of the Interna- ing initial colonization of enamel. Applied and Environmental Microbiology 797
742 tional Academy of Periodontology 2005;7:3–7. 2006;72:2837–48. 798
743 [72] Socransky SS, Haffajee AD, Cugini MA, Smith C, Kent Jr RL. Microbial complexes [92] Bradshaw DJ, Marsh PD, Allison C, Schilling KM. Effect of oxygen, inoculum 799
744 in subgingival plaque. Journal of Clinical Periodontology 1998;25:134–44. composition and flow rate on development of mixed-culture oral biofilms. 800
745 [73] Kumar PS, Griffen AL, Barton JA, Paster BJ, Moeschberger ML, Leys EJ. New bac- Microbiology 1996;142(Pt 3):623–9. 801
746 terial species associated with chronic periodontitis. Journal of Dental Research [93] Alcaraz LD, Belda-Ferre P, Cabrera-Rubio R, Romero H, Simon-Soro A, Pignatelli 802
747 2003;82:338–44. M, et al. Identifying a healthy oral microbiome through metagenomics. Clinical 803
748 [74] Mylonakis E, Calderwood SB. Infective endocarditis in adults. The New England Microbiology and Infection: The Official Publication of the European Society of 804
749 Journal of Medicine 2001;345:1318–30. Clinical Microbiology and Infectious Diseases 2012;18(Suppl. 4):54–7. 805
750 [75] Marques da Silva R, Caugant DA, Josefsen R, Tronstad L, Olsen I. Characterization [94] Liu B, Faller LL, Klitgord N, Mazumdar V, Ghodsi M, Sommer DD, et al. Deep 806
751 of Streptococcus constellatus strains recovered from a brain abscess and peri- sequencing of the oral microbiome reveals signatures of periodontal disease. 807
752 odontal pockets in an immunocompromised patient. Journal of Periodontology PLoS ONE 2012;7:e37919. 808
753 2004;75:1720–3. [95] Jagtap P, McGowan T, Bandhakavi S, Tu ZJ, Seymour S, Griffin TJ, et al. 809
754 [76] Schiff E, Pick N, Oliven A, Odeh M. Multiple liver abscesses after dental treat- Deep metaproteomic analysis of human salivary supernatant. Proteomics 810
ment. Journal of Clinical Gastroenterology 2003;36:369–71. 2012;12:992–1001. 811

Please cite this article in press as: Wade WG. The oral microbiome in health and disease. Pharmacol Res (2012),
http://dx.doi.org/10.1016/j.phrs.2012.11.006