Oral microbiome as a co-mediator of halitosis and periodontitis: a narrative review

Objective Halitosis or oral malodor is an unpleasant odor from the oral cavity. However, although patients with periodontitis often complain of halitosis, their relationship has not been fully elucidated. We reviewed previous literature based on the hypothesis that the relationship between halitosis and periodontitis is mediated by the oral microbiome. Materials and methods This narrative review sought to provide insight into the causative role of the oral microbiome in influencing halitosis and periodontitis. In addition, we tried to deepen knowledge related to the relationship between halitosis and periodontitis generated by the oral microbiome accumulated over the past 40 years. Results From 1984 to 2023, a total of 106 papers that carefully and scientifically dealt with halitosis and periodontitis were included in this narrative review. Based on previous results, halitosis and periodontitis were closely related. For decades, researchers have taken an intriguing approach to the question of whether there is a relationship between halitosis and periodontitis. Central factors in the relationship between halitosis and periodontitis include volatile sulfur compounds (VSCs), the oral microbiota that produce VSCs, and the inflammatory response. Conclusions Taken together, the more severe periodontitis, the higher the level of VSC in halitosis, which may be mediated by oral microbiome. However, the relationship between the occurrence, maintenance, and exacerbation of periodontitis and halitosis is not a necessary and sufficient condition for each other because they are complex interplay even in one individual.


Introduction
Halitosis or oral malodor is an unpleasant odor from the mouth and has various intraoral and extraoral causes.Patients with periodontitis often complain of halitosis, but the relationship between halitosis and periodontitis has not been fully elucidated.We reviewed previous literature based on the hypothesis that the relationship between halitosis and periodontitis is mediated by the oral microbiome.A narrative review was performed based on a search of PubMed and Google Scholar databases for articles on the role of the oral microbiome as an intermediary in halitosis and periodontitis.Keywords used in the search to find related articles are: "microbiome", "microbiota", "oral", "oral cavity", "saliva", "halitosis", "oral malodor", "bad breath", "volatile sulfur compounds", "periodontitis", "periodontal disease", "bacteria", "virus", and "fungi".Papers published in English in the last 40 years between January 1984 and March 2023 were filtered in this search.A total of 1,601 articles were retrieved from the PubMed and Google Scholar databases.Original researches and review articles that were related to our hypothesis and could directly or indirectly verify the hypothesis were selected.Articles were included allowing access to the abstract and full-text as well as the title of the article.Among the articles with the accessibility of full text, non-English articles were excluded.Conference papers, and working papers, web resources and bibliographic databases were also excluded.Finally, 106 articles were selected.The authors reviewed repeatedly over a 2-week period and mainly tried to verify the content and study design to determine whether the paper was suitable for this study.

Halitosis 2.1. Definition and prevalence of halitosis
Human breath is made up of very complex substances with various odors that can cause unpleasant situations such as halitosis.Halitosis is a word derived from the Latin words halitus (breathable air) and osis (pathological change), and refers to an unpleasant odor from the air and breath that originates from the mouth (1).Because halitosis affects conversations with others and furthermore, human relationships, it has caused many personal and social problems for millennia in worldwide.This undesirable halitosis is very common in both men and women and people of all ages (2).In meta-regression analysis, the combined prevalence of halitosis was 31.8% (3).In children, the prevalence of halitosis in the literature has been reported to range from 5% to 75% (4).The male:female ratio of halitosis prevalence ranges from 1.1:1 to 1.27:1, and halitosis is slightly more prevalent in males than in females (5,6).Although the prevalence of halitosis varies depending on the diagnostic criteria or research method, there is no doubt that the prevalence is high, and understanding and exploration of halitosis should be continued.

Etiology of halitosis
The etiology of halitosis is multifactorial and the source is largely divided into oral and non-oral origin.Intra-oral origin of halitosis account for 80%-90% of all cases (4).First of all, tongue coating has been considered as a major factor in halitosis.The tongue coating contains food debris, desquamated epithelial cells, and blood cells, creating a perfect environment to nourish bacteria that produce volatile sulfur compounds (VSC) (7).Hydrogen sulfide and methyl mercaptan account for approximately 90% of VSCs (8).Self-cleaning of the tongue is difficult because of the complex anatomy of the tongue, especially at the posterior part of the tongue.The rough dorsal surface of the tongue with many papillae and deep fissures is easy for bacteria to adhere to, and it is difficult for saliva to selfpurify (9, 10).Over time, the anaerobic environment of the tongue may change to facilitate colonization of Gram negative anaerobes (11).Conversely, a decrease in tongue coating thickness was associated with a decrease in the amount of Porphyromonas gingivalis and Fusobacterium nucleatum (12).With tongue cleaning with tongue scraper, a 75% reduction in VSCs was achieved (13).
The oral cavity contains multiple habitats, and the microbiome is diversely distributed in the tongue coating, saliva, teeth, buccal mucosa, soft and hard palate, gingival sulcus, tonsils, pharynx, and lips.There are 500-700 bacterial species found in the mouth, most of which can produce malodorous compounds that can cause bad breath (14, 15).In fact, the oral cavity is optimized for colonization and growth of microorganisms.The temperatures in the mouth can reach up to 37°C (changing between 34°C and 37°C).Humidity during exhalation can reach up to 96% (changing between 91% and 96%) in oral exhalation (16).These conditions can provide a suitable environment for bacterial colonization and growth.
Approximately 5%-9% of halitosis originates from non-oral structures such as the respiratory and gastrointestinal tract, and only 1% of bad breath is caused by medicine (Table 1) (17).Even among healthy people who do not have a history of halitosis and do not have periodontal disease, some people have halitosis because bacteria remain on the surface of the tongue (20).Oral bacteria break down organic substrates (such as glucose, mucins, peptides, proteins present in saliva, fissure fluid, oral soft tissue, and residual debris) and produce odorous compounds (18,19).Halitosis is mainly formed by volatile organic compounds caused by pathological or non-pathological causes.These volatile organic compounds are sulfur compounds, aromatic compounds, nitrogen-containing compounds, amines, short-chain fatty acids, alcohols or phenyl compounds, aliphatic compounds and ketones (Table 2) (22).
Among volatile compounds, VSCs are mainly responsible for bad breath from the oral cavity.Of course, organoleptic method performed by experts is considered the gold standard for diagnosing halitosis, but measurement of VSC levels using gas chromatography is objective and highly reliable (25,26).Oral microbiome associated with halitosis, particularly gram-negative bacterial species and proteolytic anaerobes, inhabit and are active primarily in the tongue coating and periodontal pockets, and produce VSCs including hydrogen sulfide, methyl mercaptan, and dimethyl sulfide (23,24).VSCs are produced by an enzymatic reaction by these bacteria of the sulfur-containing amino acids L-cysteine and L-methionine.Some bacteria also produce hydrogen sulfide and methyl mercaptan in serum (19,27).Bacteria, the most active VSC producers, are presented in Table 3 (28).
Wearing face masks during the Coronavirus Disease 2019 pandemic has increased concerns about the occurrence of halitosis (33,34).Poor oral hygiene can be a key factor in the growth of the bacteria responsible for VSC production (17,35).Oral-derived anaerobes can proliferate in chambers confined by face masks.Although the proliferation of microorganisms was observed on the inner surface of the mask, the amount of microbiome and VSC level did not significantly increase as the mask wearing time increased (33,36).Additional research is needed to scientifically investigate whether wearing a mask in turn increases microorganisms and VSC levels.

Oral microbiome and halitosis
Recent research results are accumulating the fact that oral mircobiota can be a biomarker that distinguishes pathological conditions such as halitosis and periodontitis from oral health conditions.The oral bacteria species most related to halitosis are Actinomyces spp., Bacteroides spp., Dialister spp., Eubacterium spp., Fusobacterium spp., Leptotrichia spp., Peptostreptococcus spp., Porphyromonas spp., Prevotella spp., Selenomonas spp., Solobacterium spp., Veillonella spp., and Tannerella forsythia (32, 37, 38).Increased hydrogen sulfide and methyl mercaptan levels were associated with oral microbiota including Prevotella spp., Peptostreptococcus spp., Eubacterium nodatum and Alloprevotella spp (38).VSCs, such as hydrogen sulfide and methyl mercaptan, are the main constituents of oral malodor and are produced as end products of proteolytic processes by oral microorganisms.The main pathway of protein degradation is by metabolism of sulfur-containing amino acids by Gram-negative anaerobic bacteria.Especially, the most active producers of hydrogen sulfide are Gram-negative anaerobic bacteria such as Prophyromonas gingivalis, Treponema denticola, and Tannerella forsythia, which are members of the red complex that are associated with deep periodontal pockets (39)(40)(41)(42)(43).However, Gram-positive bacteria also play a crucial role in halitosis, by cleaving sugar chains from glycoproteins to provide protein, ultimately resulting in promotion of the production of VSCs by gram-negative anaerobes (44).
Compared to studies on halitosis and the species level of specific microbes, there are fewer studies on the relationship between halitosis at the genus and phylum level.The most dominant genera amongst the oral cavity microorganisms are Alloprevotella, Leptotrichia, Peptostreptococcus, Prevotella, and Stomatobaculum (38).The basic oral microbiota consists of the following phyla: Actinobacteria, Bacteroidetes, Firmicutes, Fusobacteria, and Proteobacteria (32).In recent deep learning approach, the genera Rothia, Streptococcus, and Granulicatella were more abundant in the healthy controls, whereas Porphyromonas, Peptostreptococcus, and Veillonella were more abundant in individuals with halitosis (45).At the genus level of bacteria involved in oral VSC production, representative hydrogen sulfide producers were genus Fusobacterium, Neisseria, and Porphyromonas, and methyl mercaptan producers were genus Atopobium, Megasphaera, Prevotella, Selenomonas, and Veillonella, respectively (46).
In the oral cavity, the anatomical part most associated with halitosis is the tongue.The microbiome of tongue coating, the main cause of halitosis, is reported more consistently at the phylum level, but at the species level may vary depending on  (51).Fungi also has the potential to increase VSC levels, and methyl mercaptan concentration was related with the presence of Candida albicans (52).Escherichia coli (E.coli) is a candidate microorganism that causes halitosis by converting cysteine to ammonia using cysteine dehydratase and reducing nitrate to ammonia (53,54).In addition, one of the major contributors to trimethylamine production is E. coli (55).
Given the relationship between viral infections and bad breath, bad breath emerged as a problem during the coronavirus disease 2019 (COVID-19) pandemic.Halitosis has been reported in cases actively infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) (56).Even, some have had newonset halitosis during infection with SARS-CoV-2 (57).In acutely infected patients with COVID-19, decreased salivary flow may cause xerostomia and thus more likely mediate the occurrence of halitosis (58).Halitosis was strongly associated with epithelial structural alterations with degeneration of the keratinized epithelium (59).Epithelial changes in the tongue dorsum may be caused by the highly expressed angiotensin converting enzyme 2 receptor, the SARS-CoV-2 binding site (60).
However, as there are many factors that influence the formation of the oral microbiota, including temperature, humidity, salivary volume, pH, oxygen level, and the rate of mucosal cell shedding (61), additional studies on microorganisms affecting halitosis are needed.According to a recent sex-stratified metagenome-genome-wide-association study, dental calculus, bleeding frequency of gums, and high-fat and high-sugar diet frequency were factors influencing oral microbiome compositions, and sex differences of saliva microbiome composition was observed (62).hormonal profiles were the main cause of sex differences in the phylum-level of the gutmicrobiome (63).However, the distribution of the oral microbiome did not differ according to the hormonal cycle and menopause of healthy women (64).Further research is needed to determine whether there are sex-specific differences in the oral microbiome in halitosis patients.
In oral cancer, the changed profile of the oral microbiota is considered as a reservoir of a diagnostic and prognostic biomarkers (65).Additionally, the abundant genus Porphyromonas has been associated with the development of oral and digestive tract cancers, as well as halitosis and periodontitis (66,67).A peculiarly pungent halitosis was confirmed in the breath of patients with oral malignancies (68).Malodorous agents responsible for carcinogenesis are hydrogen sulfide and acetaldehyde.Another VSC is dimethyl sulfide, which is primarily responsible for extraoral or bloodborne halitosis, but can also contribute to oral malodor (21).Ketones, such as acetone, benzophenone, and acetophenone, are present both in the alveoli of the lungs and in the mouth air.Indole and dimethyl selenide also cause bad breath.Halitosis creates social and psychological disadvantages for individuals, and these situations affect individual's relation with other people (16).To re-establish the symbiosis of the oral cavity in patients with halitosis and to develop new strategies to help substantially reduce VSCs, it is necessary to identify predictive microbiome biomarkers.

Definition and prevalence of periodontitis
Periodontitis is a chronic inflammatory condition in the supporting tissues of tooth that causes progressive destruction of attachment apparatus including alveolar bone, periodontal ligament and cementum.It is manifested as clinical attachment loss, periodontal pocketing, gingival bleeding and radiographic alveolar bone loss (69).Characteristics of irreversible destruction in periodontal tissues might result in tooth loss when the progression of the disease was severed, which leads to the problems in esthetics, impaired oral function and quality of life.
The Global Burden of Disease 2015 study reported that oral diseases are highly prevalent involving 3.5 billion people worldwide with untreated dental caries, severe periodontitis, and severe tooth loss (70).Approximately, 10.8% of the global population showed severe periodontitis that was the sixth-most prevalent health problems.In addition, complete edentulism and severe tooth loss was reported to be 2.3% and 2.4%, respectively, which led to the global burdens of direct and indirect economic costs, and intangible costs associated with social activities (71).

Etiology of periodontitis
Periodontitis is a disease mediated by dental biofilm (dental plaque) that contains hundreds of species of bacteria and possibly viruses and fungi which are together called oral microbiome, and host's immune response to the plaque biofilm.In healthy gingiva, commensal microflora in oral microbiome exists in harmony with the host, hence called symbiosis (72).When the bacterial deposits accumulate at the gingival crevice with poor oral hygiene, changes of the plaque mass and microbial compositions result in the gingivitis initially that represents inflammation in the periodontal soft tissues but no loss of periodontal support.However, chronic subgingival microbial colonization with pathogenic compositional shift (dysbiosis) can cause destruction of periodontal supporting tissue either by hyporesponsive or hyper-responsive inflammatory reaction (73).Intrinsic host genetic factors and acquired environmental stressors can modulate immune response, which affect the individual susceptibility to the disease (74).In addition, periodontitis can be associated with other chronic noncommunicable diseases such as diabetes and cardiovascular disease by sharing common inflammatory pathways (71).
In oral cavity, various habitats including tooth surface (supragingival and subgingival), crevicular epithelium, buccal mucosa, tongue, tonsil and palate have unique microenvironmental conditions to form niches for heterogenous oral microbiome.The oral microbiome comprises bacteria, archaea, fungi, protozoa and viruses, which exists as planktonic phase in saliva or attached to oral surfaces such as a plaque biofilm (72).Subgingival microbial colonization at the root surface is critical for the development of periodontal disease as it can evade shear forces and is under the microenvironmental conditions with low redox potential and gingival crevicular fluid for nutritional source that favors the growth and maintenance of various species including anaerobic pathogens (30).

Oral microbiome and periodontitis
More than 500 species of bacteria have been detected in the subgingival plaque and the current high-throughput molecular technologies are extending the information about highly diverse community in oral microbiome (31).In previous model of plaque development in healthy gingiva, gram-positive cocci and rods are dominant in subgingival microbiome.Actinomyces spp.and Streptococcus spp.are the representative species which act as early colonizers and form early dental plaque.The second most frequent species appears to be the gram-negative rod Fusobacterium nucleatum which is the second colonizer that bridges different kinds of bacteria during the plaque maturation.However, recent studies that integrated spectral imaging with high-throughput sequencing data reported a radially arranged, multigenus consortium in the microbiome of dental plaque (75-77).The spatial organization of bacterial consortium consisted of filamentous Corynebacterium as a primary framework foundation that favored growth of Streptococcus at the periphery in a "hedgehog" appearance.Other taxa identified as regular participants in periphery of hedgehog structure included Porphyromonas, Haemophilus/Aggregatibacter, Neisseriaceae, Fusobacterium, Leptotrichia, Capnocytophaga, and Actinomyces, which were localized in a well-defined zone according to the microenvironments they were engaged in (76).
Undisturbed plaque accumulation causes shifts in subgingival composition to increase gram-negative rods, filaments and spirochetes accompanied by the clinical gingival inflammation, which can be reversed to the healthy state after removal of the plaque.Prevotella spp., Selenomonas spp., and Fusobacterium nucleatum subspecies polymorphum are enriched with the development of gingivitis while relative abundance of gram-positive species such as Rothia dentocariosa decrease significantly (78).In addition, total bacterial biomass increases approximately 3-log which makes the influence of proportional changes much larger.
Dysbiosis associated with periodontitis can be characterized by profound compositional shifts to diverse groups of gram-negative species in subgingival microbiome which are even different from those found in gingivitis (79).Red complex triad comprising Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia described in the fundamental study by Socransky et al. is one of the enriched species and strongly associated with periodontal destruction (39).They possess virulence factors with high protease activity and act as keystone pathogens that orchestrate inflammatory process by involving with microbial shifts to diseased state, acquisition of nutrition from host and growth of pathobionts to increase host response (80).For example, P. gingivalis can trigger imbalance between bacteria and host response by avoiding host immune component Toll-like receptors and complements, which brings out changes in the relative abundance of other bacteria.Besides the increased diversity of periodontitis-associated microbiome, some species including Campylobacter gracilis and Fusobacterium nucleatum are identified consistent with the proportions in health and periodontitis which are classified as core species (79).It shows that the species associated with health state are still present and dysbiosis can be described again as shifts in the dominant species.In addition, total biomass increases significantly which aggravates the host interaction to higher microbial load for both core and periodontitis-associated species.

Oral microbiome, halitosis, and periodontitis
Clinically, oral malodor is very common in patients with periodontitis.For decades, researchers have taken an intriguing approach to presenting scientific evidence for the relationship between bad breath and periodontitis (81-83).However, the strength of scientific evidence for a link between halitosis and periodontitis is not strong.In one case-control study, in 81.7% of patients with periodontitis, halitosis was found as a comorbidity, which was significantly higher than in healthy controls (58.3%)(84).In on observational study, approximately 90% of halitosis causes were of oral origin, with tongue coating (43%) being the most common cause, followed by gingivitis or periodontitis (11%), and a combination of the two subtypes of periodontal diseases (18%) (83).However, it is controversial whether tongue coating is a direct cause of gingivitis or periodontitis.Tongue coating thickness was not significantly associated with gingivitis and bleeding on pocket probing (85).
In studies examining tongue-coating microbes, fusobacterium periodonticum, neisseria mucosa, and aggregatibacter segnis were associated with tongue coating (86).The Extended Human Oral Microbiome Database (eHOMD) was updated in 2017 and found that six major phyla including Firmicutes, Actinobacteria, Proteobacteria, Fusobacteria, Bacteroidetes and Spirochetes, constitute 96% of total oral bacteria (87).At the phylum level, the proportions of Actinobacteria and Spirochaetes were higher in the tongue coating than in other areas of the oral cavity (87).When the distribution of 7 phyla, 27 genera and 825 operational taxonomic units of dorsal tongue microbes in halitosis patients was compared with that of healthy controls, there was no difference at the phylum level, and there were significant differences in some genus and species including Aggregatibacter, Campylobacter, Capnocytophaga, Prevotella, and Treponema (88).In children, Leptotrichia wadei, Peptostreptococcus stomatis and Prevotella shahii were higher in the tongue coatings of children with halitosis than in children without halitosis (89).Microbiota related to tongue coating or oral hygiene should continue to develop microbial-based biomarkers for use in the diagnosis of periodontitis as well as halitosis.
Nevertheless, an open mind should be maintained about the possibility that microbes could be co-mediators of the halitosis and periodontitis.The term co-mediator used in this study refers to microorganisms that can be simultaneously involved in two diseases and can interplay between the two diseases.Since most of the microorganisms responsible for bad breath are involved in periodontitis, the oral microbiome may be a co-mediator of these two diseases.Central factors in the relationship between halitosis and periodontitis include VSCs, the oral microbiota that produce VSCs, and the inflammatory response.Accompanying inflamed periodontal pockets in periodontitis provide a stable habitat for the oral microbiota, which enhances hydrogen sulfide production (15).The tongue dorsum is also a major habitat for periodontal disease-associated bacteria such as Porphyromonas gingivalis and Treponema denticola (90).Among the various related oral microbiota, Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia are closely related to the progression and exacerbation of periodontitis, as well as to the occurrence of halitosis by increasing the production of VSCs (91-93).Thus, key pathogens in periodontal disease can produce VSCs and increase the incidence of halitosis, and oral dysbiosis is important in the development of halitosis, as well as in the progression of periodontal disease.Therefore, oral microorganisms can be considered as co-mediators of these two diseases (Figure 1).To the best of our knowledge, few studies have investigated the prevalence of periodontitis in patients with halitosis.Specifically, increased levels of VSCs in the oral cavity were associated with the number and extent of periodontal pockets deeper than 3 mm (94).Patients with one or more periodontal pockets greater than 5 mm in depth had a 30% increase in VSC values compared to normal subjects (95).Aggravation of the severity of periodontitis was associated with an increase in bad breath.Conversely, curettage and periodontal surgery can reduce VSC concentration (96).In a more recent study, Fusobacterium nucleatum, Capnocytophaga gingivalis, and Campylobacter showaei correlated with reduced VSC levels after periodontal therapy (97).When water-flossing and toothbrushing were performed together, the level of halitosis was lowered at week 12, and the dental plaque microbiota was changed.When water-flossing and toothbrushing were performed together, the level of halitosis was lowered at week 12, and compared to the case of toothbrushing alone, Prevotella at genus level and Prevotella intermedia at species level were significantly reduced among dental plaque microbiota (97).Gram-negative anaerobes, the main cause in both halitosis and periodontitis, mainly inhabit the posterior part of the tongue (98).It has even been suggested that the coating of tongue dorsum acts as a reservoir to periodontal pathogens (90).Therefore, tongue cleaning and maintaining good oral hygiene not only reduce gram-negative anaerobes, but also prevent nutrient supply to them, thereby reducing VSC production in healthy subjects as well as patients with periodontitis.
Two sulfide gases, hydrogen sulfide and methyl mercaptan, are the main causes of halitosis in VSCs, but methyl mercaptan seems to play a more important role in relation to periodontitis.First of all, the reason why methyl mercaptan has more adverse effects on patients with halitosis and periodontitis than hydrogen sulfide is that it has the permeability of oral mucosa (99).Particularly high concentrations of methyl mercaptan were found among VSCs in subjects with probing depths greater than 4 mm (82).Moreover, methyl mercaptan can dimerize to dimethyl sulfide, and since sulfide is considered highly cytotoxic, methyl mercaptan may accelerate periodontal disease progression (100).Tongue biofilm and plaque was the major source of higher amounts of VSC, especially methyl mercaptan, in patients with periodontitis (101, 102).Patients with periodontitis had higher VSC levels compared to healthy controls, and their greater subgingival bacterial diversity was positively associated with hydrogen sulfide levels (103).In the tongue biofilm metatranscriptome analysis, over-expression of genes related to cysteine degradation into hydrogen sulfide was observed in patients with halitosis (104).Based on previous results, it can be concluded that halitosis and periodontitis are closely related.Oral microorganisms involved in the occurrence and progression of halitosis and periodontitis can promote the production of VSCs, and subsequently, individuals affected by these diseases are affected biologically, chemically, and locally and systemically, and eventually halitosis and periodontitis may worsen.Conversely, by early detection of changes in oral microorganisms and controlling the interaction of these microorganisms, the two diseases can be effectively controlled simultaneously.
However, even within individuals, the interplay between halitosis and periodontitis is very complex, making it difficult to derive a single relationship.For example, even in one individual, the relationship between halitosis and periodontal diseases may be different according to the site of periodontitis and their local and/or systemic condition, and this relationship may change with the increase of age (105).Thus, it should be noted in the interpretation of the clinical results that halitosis may occur temporarily as part of the physiological phenomenon or mentally even in normal people, so the occurrence, maintenance, and exacerbation of the two diseases are not necessary and sufficient conditions for each other.Furthermore, halitosis is affected by several systemic diseases such as gastrointestinal disease, respiratory system problems, hepatic disease, renal disease, diabetes mellitus, and several metabolic diseases (17, 106).Therefore, when considering the oral microbiota in the relationship between halitosis and periodontitis, it is important to understand the diversity of the oral microbiota and how it fluctuates under disease/disturbing conditions.According to eHOMD results published in 2017, only 70% are culturable species, of which only 57% have been named (87).That is, much of the oral microbiome remains a mystery.To have clear conclusions, high-throughput epidemiologic investigations and analysis based on the advanced technology for oral microbiome are additionally required.

Conclusion
Taken together, specific oral microbiome profiles and dysbiosis may be associated with halitosis and periodontitis.The direct cause of bad breath is VSC produced by the oral microbiome.Changes in the oral microbiome and VSC production are also involved in the progression of periodontitis.In other words, specific microbiota can interplay and mediate the onset and progression of two diseases, halitosis and periodontitis.Although a clear relationship between halitosis and periodontitis is evident, it is unclear whether the oral microbiome mediates this relationship.Prospective, large-scale, clinical studies and animal experiments are needed to demonstrate the role of the oral microbiome in the relationship between halitosis and periodontitis.In the not-toodistant future, if biomarkers that co-mediate halitosis and periodontitis are clarified, which may have full potential to lead to early diagnosis and improve quality of life for patients with these diseases, and to lighten the burden on clinicians.