In the previous section, a significant number of studies identifying potential biomarkers for ODs were discussed. That included mostly higher molecular-weight constituents such as proteins. This section will focus specifically on the subset of potential biomarkers for ODs that are the volatile organic compounds (VOCs).
According to the most recent data reviewed by Milanowski, Pomastowski, Ligor and Buszewski
[60][78] almost 500 VOCs have been identified in the oral cavity. This includes data from reference studies as the human volatilome showing that 359 out of 1840 VOCs were identified in the saliva
[61][79] and the 317 VOCs identified in a 10-days follow up salivary analysis
[62][80]. In another study, 90 out of 166 VOCs were found common to saliva and axillary sweat samples
[63][81]. Overall, salivary VOCs derive from different sources; a part of them results from the metabolic activity of different cells in the body (review in
[60][78]) that eventually reach the serum, blood, gingival exudate, nasal cavity or the gastrointestinal reflux, among others. The acinar cells that compose the salivary glands for instance, are highly vascularized allowing the exchange of blood components including VOCs through different mechanisms as passive diffusion, ultrafiltration and active diffusion
[16][65][66][16,88,89]. However, the oral microbiota activity as well as food debris, commercial products (toothpaste for instance) and environmental contaminants have a significant contribution to the VOCs identified in saliva. The oral cavity seems to be colonized by a huge number of bacteria (50 to 100 billion bacteria from 300 to 700 different species
[63][67][68][81,90,91]). In fact, there are many salivary VOCs such as aliphatic amines, branched chain fatty acids, 2,3-butanedione, 2,3-pentanedione, pyrrole, indole, phenol, and volatile Sulphur-containing compounds (VSCs, as hydrogen sulphide, methyl mercaptan, dimethyl sulphide and dimethyl disulphide) that are produced by oral bacteria
[60][62][63][68][78,80,81,91]. In turn, the hydrocarbons which are consistently the most abundant salivary VOCs reflect their possible origin in food, fragrances and cosmetics. Finally, many of the long-chain alkane derivatives such as hexane, octane and undecane are probably environmental contaminants (air pollutants). The same applies to aromatic compounds, as benzene, toluene, xylenes and styrene
[60][78]. This metabolic characterization of the source of the VOCs identified in saliva (synthetized in
Table 1) is crucial for diagnostic purposes. In the context of the ODs, it is of paramount importance to know the source of a given VOC so we can infer if certain clinical condition is present and retain information about its progression or response to treatment. The identification of microorganisms using their volatile metabolic activity has been already reported for several clinical conditions, including pulmonary bacterial infections caused by
Escherichia coli,
Pseudomonas aeruginosa,
Staphylococcus aureus and
Klebsiella pneumoniae [69][92] as well as for
Candida fungus causing oral candidiasis
[70][86] (
Table 1). Unique VOCs signatures for bacteria species that often colonize our mouth,
S. mutans,
L. salivarius and
P. acidifaciens (
[71][93]) have been also described. These in vitro studies clearly point to the potential of salivary VOCs as putative biomarkers for ODs. In fact, several features have been associated with periodontal disease, as increased amounts of VSCs and presence of pyridines, which are absent in the saliva of healthy controls
[60][78]. These are, nevertheless, VOCs that can arise from different pathways and sources and it is likely that many confounding factors are affecting the reported results. Also, dimethyl disulphide has been associated to halitosis and different metabolites such as indole and skatole or phenol and p-cresol have been shown to be specific of the bacterial fermentation of tryptophan and phenolic amino acids, respectively (
Table 1, reviewed in
[60][78]). There is an obvious interplay between periodontal disease and halitosis because patients affected by periodontal disease are at higher risk for halitosis detection than healthy individuals. In fact, it has been reported that the posterior portion of the tongue dorsum constitutes an important source of odorous compounds, possibly produced by
P. gingivalis identified in these patients
[72][94]. Nevertheless, careful analysis of such data should be taken because alternative sources such as diet, environmental contamination or even other endogenous contributions may drive variations in some of these VOCs. Blood borne halitosis for instance, is caused by malodourous compounds generated elsewhere in the organism, carried through the blood stream to the lungs where they diffuse across the pulmonary alveolar membrane to enter the breath. Regarding this, Torsten, Gomez-Moreno and Aguilar-Salvatierra
[73][83] reported that the metabolism of at least nine medications can release dimethyl sulphide, carbon disulphide and several VSCs in breath causing a drug-related halitosis. Moreover, the metabolism of penicillamine raises the pH level favouring the proliferation of gram-negative bacteria in the oral cavity which in turn causes halitosis. Therefore, these forms of halitosis are not caused by any specific disease in the oral cavity. Anxiety is another condition that can favour changes in oral microbiota leading to significant variations in oral VSCs and consequently halitosis
[74][84].