Pre and Probiotics Involved in the Modulation of Oral Bacterial Species: New Therapeutic Leads in Mental Disorders?

This systematic review aims to identify probiotics and prebiotics for modulating oral bacterial species associated with mental disorders. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guideline, we search the electronic MEDLINE database published till January 2021 to identify the studies on probiotics and/or prebiotics for preventing and treating major oral dysbiosis that provokes mental disorders. The outcome of the search produces 374 records. After excluding non-relevant studies, 38 papers were included in the present review. While many studies suggest the potential effects of the oral microbiota on the biochemical signalling events between the oral microbiota and central nervous system, our review highlights the limited development concerning the use of prebiotics and/or probiotics in modulating oral dysbiosis potentially involved in the development of mental disorders. However, the collected studies confirm prebiotics and/or probiotics interest for a global or targeted modulation of the oral microbiome in preventing or treating mental disorders. These outcomes also offer exciting prospects for improving the oral health of people with mental disorders in the future.


Introduction
The oral cavity is an important bacterial gateway that plays a crucial role in the firststep digestion. Food entering the mouth is chewed and mixed with saliva before being swallowed. Microorganisms from the air pass through the nose and mouth into the trachea and lungs, and colonize the oral cavity. They spread to the epithelial surfaces and the body via the bloodstream. Thus, oral cavity is colonized by 50 to 100 billion bacteria [1], and they are responsible for many infectious diseases in the mouth, which include caries (tooth decay) and periodontitis (gum disease) [2,3]. Evidence confirms that oral bacteria are linked to many systemic diseases [4], such as cardiovascular disease [5], stroke [6], premature birth [7], diabetes [8], pneumonia [9], cancer development [10], kidney diseases [11], and mental disorders [12].
In reverse, Bifidobacterium dentium in the oral cavity may offer health benefits to the host [13]. Benefits include the barrier against pathogens or immunomodulating properties [14]. Thus, many bacterial strains are identified as probiotics-microorganisms whose ingestion in adequate quantities is beneficial to the health of the host. According to the International Scientific Association for Probiotics and Prebiotics, Bifidobacterium (adolescentis, animalis, bifidum, breve and longum) and Lactobacillus (acidophilus, casei, fermentum, gasseri, johnsonii, paracasei, plantarum, rhamnosus and salivarius) represents a core group of ternational Scientific Association for Probiotics and Prebiotics, Bifidobacterium (adolescentis, animalis, bifidum, breve and longum) and Lactobacillus (acidophilus, casei, fermentum, gasseri, johnsonii, paracasei, plantarum, rhamnosus and salivarius) represents a core group of well-studied species likely to impart some general benefits [15]. Similarly, prebiotics are substrates, such as fructans and galactans, selectively used by host microorganisms and offered a health benefit by modulating the microbiome of individuals. [16].
In 2001, Joshua Lederberg introduced the term "microbiome" [17] referred to as dynamic communities of microbes that colonized the body and provided many metabolic functions and molecular signals to maintain good health. With the concept of the microbiome, microbiologists have refocused on microbial communities rather than on individual organisms in pure culture, as in Koch's postulates. In this case, the consortia of organisms in a biofilm rather than a single pathogen are responsible for many infections like caries, periodontitis, and others [18]. As many people never develop dental caries, some authors suggest that certain bacterial species have a potential antagonistic effect against cariogenic bacteria [19]. Thus, replacing pathogens with harmless isolates obtained from healthy strains prevent health disorders. A metagenomic approach confirms that the bacteria with a protective effect against cariogenic species offers probiotic benefits for the oral health of the host [20]. From an ever-growing understanding of how the microbiome affects health and disease, the human microbiome offers new therapeutic pathways like reversing or rebalancing the microbiome towards health. In this context, this study focuses on the oral microbiome and its correlation to mental disorders, named the "Oral-Brain Axis" [12] to highlight new therapeutic perspectives for mental disorders (Figure 1). The identification of a specific microflora in patients with mental disorders suggests that these disorders could be influenced by the oral microbiome. For example, the inflammatory process induced from the Gram-negative periodontal pathogen Porphyromonas gingivalis is evoked in individuals with dementia or Alzheimer's Disease [21,22]. In Autism Spectrum Disorder, the specific oral dysbiosis observed in the oral microbial community of these patients suggests a potential role for microorganisms in the progression of this disease [23]. The microflora of individuals with Down's Syndrome (DS) with periodontitis show similarities with those of patients without DS with periodontitis, including the main periodontal pathogens (Aggregatibacter actinomycetemcomitans, P. gingivalis, Tannarella forsythia, Prevotella intermedia, Parvimonas micra, Fusobacterium nucleatum, Campylobacter rectus, etc.). In addition, patents with DS have increased colonization of some The identification of a specific microflora in patients with mental disorders suggests that these disorders could be influenced by the oral microbiome. For example, the inflammatory process induced from the Gram-negative periodontal pathogen Porphyromonas gingivalis is evoked in individuals with dementia or Alzheimer's Disease [21,22]. In Autism Spectrum Disorder, the specific oral dysbiosis observed in the oral microbial community of these patients suggests a potential role for microorganisms in the progression of this disease [23]. The microflora of individuals with Down's Syndrome (DS) with periodontitis show similarities with those of patients without DS with periodontitis, including the main periodontal pathogens (Aggregatibacter actinomycetemcomitans, P. gingivalis, Tannarella forsythia, Prevotella intermedia, Parvimonas micra, Fusobacterium nucleatum, Campylobacter rectus, etc.). In addition, patents with DS have increased colonization of some bacterial species in the subgingival flora (Selenomonas noxia, Propionibacterium acnes, Streptococcus gordonii, Streptococcus mitis, Streptococcus oralis, Treponema socranskii and Streptococcus constellatus). S. gordonii, S. mitis, and S. oralis initiate early microbial colonization and contribute to the development of microbial plaque. The presence of P. acnes (normally found on the skin) at high levels in the subgingival microbiota of subjects with DS may be related to the habit of putting fingers to the mouth [24]. S. gordonii contains genes that facilitate the attachment of free-floating P. gingivalis to the adherent plaque biofilm [25]. S. noxia is associated with periodontal disease activity at interproximal sites [26] and T. socranskii has been associated with the severity of periodontal tissue destruction [27]. Finally, S. constellatus is associated with refractory forms of periodontitis [28]. Although this overall periodontal dysbiosis may be influenced by oral hygiene habits and deficient immune status of DS patients, it could contribute to an increased susceptibility to periodontitis in patients with DS [29]. Bipolar disorder was correlated with an increased risk of periodontitis, a higher frequency of periodontopathogens, and a higher total bacterial load like A. actinomycetemcomitans and P. gingivalis [30]. Finally, the oropharynx microbiome in schizophrenics is significantly different from that of healthy controls, with some bacterial species more abundant in schizophrenic patients than in controls (Lactobacillus gasseri, Lactobacillus salivarius, Bifidobacterium pseudocatenulatum) [31].
Therefore, the concept of the "oral-brain axis" refers to the role of the oral microbiota in the biochemical signaling events between the oral microbiota and central nervous system [10]. The bacterial species associated with mental disorders through the "oralbrain axis" are mainly periodontopathogen bacteria (A. actinomycetemcomitans, P. gingivalis, T. forsythia, Treponema denticola, C. rectus, P. intermedia, etc.). Figure 2 presents the main bacterial species that may be potentially associated with mental disorders through the "oral-brain axis" [10,22,29,30,32,33].
bacterial species in the subgingival flora (Selenomonas noxia, Propionibacterium acnes, Streptococcus gordonii, Streptococcus mitis, Streptococcus oralis, Treponema socranskii and Streptococcus constellatus). S. gordonii, S. mitis, and S. oralis initiate early microbial colonization and contribute to the development of microbial plaque. The presence of P. acnes (normally found on the skin) at high levels in the subgingival microbiota of subjects with DS may be related to the habit of putting fingers to the mouth [24]. S. gordonii contains genes that facilitate the attachment of free-floating P. gingivalis to the adherent plaque biofilm [25]. S. noxia is associated with periodontal disease activity at interproximal sites [26] and T. socranskii has been associated with the severity of periodontal tissue destruction [27]. Finally, S. constellatus is associated with refractory forms of periodontitis [28]. Although this overall periodontal dysbiosis may be influenced by oral hygiene habits and deficient immune status of DS patients, it could contribute to an increased susceptibility to periodontitis in patients with DS. [29]. Bipolar disorder was correlated with an increased risk of periodontitis, a higher frequency of periodontopathogens, and a higher total bacterial load like A. actinomycetemcomitans and P. gingivalis [30]. Finally, the oropharynx microbiome in schizophrenics is significantly different from that of healthy controls, with some bacterial species more abundant in schizophrenic patients than in controls (Lactobacillus gasseri, Lactobacillus salivarius, Bifidobacterium pseudocatenulatum) [31].
Therefore, the concept of the "oral-brain axis" refers to the role of the oral microbiota in the biochemical signaling events between the oral microbiota and central nervous system [10]. The bacterial species associated with mental disorders through the "oral-brain axis" are mainly periodontopathogen bacteria (A. actinomycetemcomitans, P. gingivalis, T. forsythia, Treponema denticola, C. rectus, P. intermedia, etc.). Figure 2 presents the main bacterial species that may be potentially associated with mental disorders through the "oralbrain axis" [10,22,29,30,32,33]. Similar to the "gut-brain axis" that emphasizes the bidirectional communication between the central and enteric nervous systems [34], the possible relationship between the oral microbiome and mental disorders suggests that probiotics or prebiotics use could prevent and manage mental disorders by modulating oral dysbiosis and its inflammatory Similar to the "gut-brain axis" that emphasizes the bidirectional communication between the central and enteric nervous systems [34], the possible relationship between the oral microbiome and mental disorders suggests that probiotics or prebiotics use could prevent and manage mental disorders by modulating oral dysbiosis and its inflammatory and immune consequences. Prebiotics are a type of fiber that the human body cannot digest. They serve as food for probiotics, which are microorganisms. Both prebiotics and probiotics may support helpful bacteria and other organisms in the gut, and we hypothesized in the oral cavity.
The objective of this systematic review is to identify probiotics and prebiotics involved in modulating oral bacterial species associated with mental disorders.

Materials and Methods
The present systematic review was conducted according to the PRISMA guidelines for Systematic Reviews [35].

Search Strategy
To identify studies that met the inclusion criteria, an electronic search was conducted through the MEDLINE (PubMed) database up to January 2021 without restriction. While modulation of the microbiome represents an innovative therapeutic axis to treat or prevent human pathologies [36], the impact of probiotics on human health has long been documented [37]. Consequently, the search was performed without time restriction to identify the studies that explore the application of probiotics and/or prebiotics in preventing and treating major oral dysbiosis potentially involved in mental disorders. The search terms were used in combination with Boolean operator "AND"/"OR" according to the following equations:

Study Detection
A manual reference check of eligible studies on the subject was performed by two operators who reviewed the studies according to the inclusion/exclusion criteria.

Inclusion and Exclusion Criteria
The bacterial species associated with mental disorders (Alzheimer diseases, Autism Spectrum Disorders, Down Syndrome, and Bipolar Disorders) through the oral-brain axis are mainly periodontopathogen bacteria (A. actinomycetemcomitans, P. gingivalis, T. forsythia, T. denticola, C. rectus, P. intermedia, etc.). We included experimental or clinical studies (longitudinal, cross-sectional, or randomized) that identified the effects of probiotics strains or prebiotics compounds on these bacterial species or the host response associated. Conferences, abstracts, reviews, and editorials were excluded.

Data Collection
Two independent reviewers (M.G. and Y.M.) screened titles and abstracts to identify the relevant papers based on the inclusion criteria. The full studies were reviewed to decide whether they should be included when the abstract information was judged to be insufficient. The reviewers reached a consensus on the eligibility criteria for selecting the studies. In case of discrepancy, a third reviewer (F.D.) resolved the conflicts regarding the eligibility.

Study Selection
The initial studies retrieved from the databases were first selected. We selected 38 studies from 285 studies (Figure 3), and we reviewed and analyzed studies that met the eligibility criteria.

Prebiotics
From our search, three recent studies on prebiotics were identified [38][39][40] (Table 1). Each demonstrated an oral microbiome modulation. In an in vitro study, Slomka et al. [38] identified two bacterial nutritional compounds, beta-methyl-D-galactoside and N-acetyl-D-mannosamine, that induced a beneficial composition in dual-species biofilm communities (beneficial and pathogen). Beta-methyl-D-galactoside decreased F. nucleatum and P. gingivalis in the biofilm by stimulating Streptococcus salivarius. N-acetyl-D-mannosamine stimulated S. mitis and Streptococcus sanguinis resulting in a reduction of A. actinomycetemcomitans and Streptococcus sobrinus. Rosier et al. [39] demonstrated that in vitro exposure to the ecological factors such as Nitrate favored the flora associated with oral health (Genera Neisseria and Rothia). This is achieved by limiting periodontitis-associated genera

Prebiotics
From our search, three recent studies on prebiotics were identified [38][39][40] (Table 1). Each demonstrated an oral microbiome modulation. In an in vitro study, Slomka et al. [38] identified two bacterial nutritional compounds, beta-methyl-D-galactoside and N-acetyl-Dmannosamine, that induced a beneficial composition in dual-species biofilm communities (beneficial and pathogen). Beta-methyl-D-galactoside decreased F. nucleatum and P. gingivalis in the biofilm by stimulating Streptococcus salivarius. N-acetyl-D-mannosamine stimulated S. mitis and Streptococcus sanguinis resulting in a reduction of A. actinomycetemcomitans and Streptococcus sobrinus. Rosier et al. [39] demonstrated that in vitro exposure to the ecological factors such as Nitrate favored the flora associated with oral health (Genera Neisseria and Rothia). This is achieved by limiting periodontitis-associated genera (Porphyromonas, Fusobacterium, Leptotrichia, Prevotella, and Alloprevotella) without affecting biofilm growth. In 2019, Jiménez-Hernández et al. show that consumption of a mixture of bacterial growth substrates (short-chain galacto-oligosaccharides (5 g), longchain fructo-oligosaccharides (10 g), and glutamine (5 g) for six weeks by 32 patients change the structure of the oral microbiota. This is characterized by a decrease in alpha diversity and a change in beta diversity, with no clear orientation towards a healthy microbiota [40].
Identification of potential oral prebiotics that selectively stimulate commensal albeit beneficial bacteria of the resident oral microbial community while suppressing the growth of pathogenic bacteria

Not relevant
Beta-methyl-D-galactoside and Nacetyl-D-mannosamine could be identified as potential oral prebiotic compounds, triggering selectively beneficial oral bacteria throughout the experiments and shifting dual species biofilm communities towards a beneficial dominating composition. Beta-methyl-D-galactoside selectively stimulated S. salivarius causing a decrease of F. nucleatum and of P. gingivalis in the biofilm. N-acetyl-D-mannosamine was the only compound that in all beneficial-pathogen combinations did not lead to an outgrowth of any of the pathogenic species. Besides, S. mitis and S. sanguinis were significantly stimulated causing a reduction of A.
actinomycetemcomitans and S. sobrinus * in vitro, oral prebiotic compounds need to be confirmed in multi-species environments Rosier et al. (2020) [39] In vitro Nitrate Evaluation of the short-term effect of a single dose of nitrate on pH, oral biofilm growth and bacterial composition

Not relevant
Signifcantly higher levels of the oral health-associated nitrate (6.5 mM) -reducing genera Neisseria (3.1×) and Rothia (2.9×) were detected in the nitrate condition already after 5 h. Periodontitis-associated genera (Porphyromonas, Fusobacterium, Leptotrichia, Prevotella, and Alloprevotella) were significantly reduced after 5 h and 9 h. The addition of 6.5 mM nitrate did not show signifcant changes in real-time impedance measurements of bioflm formation compared to the control condition. * in vitro study

Jiménez-Hernández et al. (2019) [40]
Cross sectional study (n = 32) Mixture of short-chain galacto-oligosaccharides, long-chain fructo-oligosaccharides and glutamine Characterization of the compositional changes associated with prebiotic intervention on salivary microbiota in HIV-infected individuals. Study of the interplay between oral and gut microbiota determining the bacterial co-occurrences in both habitats.
Prebiotic intervention modified the microbiota structure Drastic decrease in alpha diversity parameters, as well as a change of beta diversity, without a clear directionality toward a healthy microbiota. * Sample size, study design Investigation of the effects of an oral probiotic bacterium, Lactobacillus reuteri on the composition of nascent plaques (grown in short-term hydroxyapatite disc models) and in steady-state, continuous culture, in vitro dental plaques. Determination of the ecological fate of the probiotic bacterium in continuous culture in vitro plaques.

Not relevant
The introduction of L. reuteri bacteria to in vitro oral models resulted in alterations in both nascent and developed plaque ecosystems, which included increases in numbers of exogenous lactobacilli but also in increases in streptococci and Gram-negative anaerobes. L. reuteri bacteria persisted and potentially integrated into continuous culture dental plaque biofilms for at least 20 days following cessation of dosing.   [48] placebo-controlled, parallel study (n = 12; 5 in control group, 7 in probiotic group)

Lactobacillus delbrueckii subsp. bulgaricus, Lactobacillus paracasei
Assessment of the impact on the overall saliva microbiome structure of a short-term probiotic intervention 100 g of a commercial probiotic product containing milk fermented (1 day).
Short-term probiotic intake significantly increases the complexity of the community with Steptococcus and Actinomyces as the most involved genera. Absence of significant changes detected in the metabolic structure of probiotic versus control samples. The two Lactobacillus strains present in the probiotic product were not detected in probiotic-intake samples.

Lactobacillus delbrueckii subsp. bulgaricus, Lactobacillus paracasei
Verification of the hypothesis that the intake of commercially available probiotic products has a directly effect on the diversity and composition of the saliva microbiome.
100 g of a commercial probiotic product containing milk fermented (1 day).
The intake of commercially available probiotic products has a directly effect on the diversity and composition of the saliva microbiome, at least at short timescales. The overall taxonomic and abundance distribution of bacterial genera is however minimally influenced by probiotic intake. Investigation of the effects of a probiotic tablet containing Lactobacillus reuteri in peri-implantitis patients.
One tablet a day for 6 months with 1 × 10 8 CFU L. reuteri strains DSM 17938 and ATCC PTA 5289.
Negligible changes were observed in the bacterial flora around implants * Sample size, No evaluation of L. reuteri colonization.

Not relevant
The commensal oral microbiota is considered to induce a beneficial oral immune response or to interfere with periodontopathogen colonization. Probiotics showed a stronger inhibition of P. gingivalis and P. intermedia, and the oral isolated strains showed a clearly stronger inhibition of F. Investigation of the competition between probiotics and periodontal pathogens in vitro.
Not relevant Probiotics are capable of inhibiting specific periodontal pathogens but have no effect on the periodontal protective bacteria (S. sanguinis). Competition between probiotics and periodontal pathogens depended on the sequence of inoculation. * In vitro study  Evaluation of the effects of L. reuteri as an adjunct to scaling and root planning.
One lozenge at the morning and one at the night during 12 weeks (L. reuteri 1 × 10 8 CFU for each strain) L. reuteri lozenges resulted in significant additional clinical improvements primarily for initially moderate to deep pockets when compared to SRP alone. The microbiological differences were more moderate and primarily restricted to P. gingivalis numbers. * Sample size, No evaluation of L. reuteri colonization. 50g of petit-suisse cheese daily from Monday to Friday, and the following week from Monday to Thursday (3% de L. casei) The product with added L. casei was shown to be able to reduce A. actinomycetemcomitans, and able to maintain lower density of P. gingivalis in post treatment two weeks later. * No evaluation of probiotic change after introduction in food.

L. salivarius WB21
Evaluation of the impact of oral administration of lactobacilli on the bacterial population in supra/subgingival plaque.
L. salivarius WB21 administration successfully decreased the numerical sum of A. actinomycetemcomitans, P. intermedia, P. gingivalis, T. denticola, and T. forsythia in subgingival plaque at 4 weeks. No significant difference between the WB21 and the placebo groups in the direct count of any specific periodontopathic bacteria at 8 weeks. * Sample size The probiotic mouthwash was able to substantially affect the levels of dental pathogens in saliva (S. mutans) and periodontal pathogens in subgingival plaque (C. rectus and P. gingivalis) * Sample size, Young and orally healthy adults poupulation Alanzi et al. (2018) [68] Randomized placebo-controlled study (n = 108, 54 placebo group, 54 probiotic group)

L. rhamnosus GG, B lactis BB12
Determination of the effect of a probiotic combination on the gingival health, dental plaque accumulation, and the oral carriage of four putative periodontal pathogens in healthy adolescents LG2055 treatment significantly reduced alveolar bone loss, detachment and disorganization of the periodontal ligament, and bacterial colonization by subsequent P. gingivalis challenge. The expression and secretion of TNF-α and IL-6 in gingival tissue was significantly decreased in LG2055-administered mice after bacterial infection. * Experimental design Experimental study in mice (n = 6; 3 probiotic, 3 placebo group) L. brevis CD2 Determination of the Lactobacillus brevis CD2 potential on inhibit periodontal inflammation and bone loss in experimental periodontitis.
Lyopatch with L. brevis CD2 (8 × 10 5 CFU in 1-mm 2 ) L. brevis CD2-treated mice exhibited significantly decreased expression of all proinflammatory cytokines tested (TNF, IL-1β, IL-6, and IL-17A). L. brevis CD2 treatment resulted in significantly higher counts of aerobic bacteria and, conversely, significantly lower numbers of anaerobic bacteria, as compared to the placebo-treated control group. Evaluation of the effects of probiotic supplements in adjunct to conventional management of peri-implant mucositis Topical oil application (2 × 10 7 CFU of each strain) followed by twice-daily intake of lozenges for 3 months (1 × 10 8 CFU of each strain) Topical treatment and daily intake of probiotic lozenges as an adjunct to mechanical debridement and oral hygiene instructions did not improve clinical, microbial or inflammatory variables of peri implant mucositis as compared to the use of placebo. * Sample size CFU: colony forming units.

Modulation of the Oral Microbiome
The development and degradation of oral biofilms rely on adhesion and cooperation or competition between oral bacteria [76]. Several in vitro and in vivo studies demonstrated the ability of various probiotics strains to modulate these mechanisms. In vitro models, the Lactobacillus reuteri introduction results in changes to the nascent and developed biofilm ecosystem with an increase in exogenous lactobacilli (L.), streptococci (S.) and Gramnegative anaerobes [41]. Lactobacillus rhamnosus reduces the biofilm-forming capacity of F. nucleatum, integrates into all oral biofilms [42], and shows higher adhesive properties than P. gingivalis on gingival stromal cells [43].
In rats, Bifidobacterium reduces the proportion of some Gram-negative anaerobic bacteria-like species involved in the pathogenesis of periodontal diseases in the subgingival biofilm (Veillonella parvula, Capnocytophaga sputigena, Eikenella corrodens, and Prevotella intermedia) [46]. Similar results are found in several in vivo studies. Thus, Bifidobacterium animalis subsp. lactis HN019 used for 30 days (lozanges) reduce the adhesion of P. gingivalis to buccal epithelial cells [47]. Short-term consumption (1 day) of milk fermented with probiotic strains (Streptococcus thermophilus, Lactobacillus delbrueckii, and Lactobacillus paracasei) supplemented with vitamin B6 and vitamin D increases the overall diversity of the oral cavity microbiome with an increase in the genera Steptococcus and Actinomyces. However, no substantial change in the microbiome structure is noted [48,49]. The effects of L. acidophilus, B. animalis, and L. rhamnosus combined in a probiotic milk drink on periodontopathogenic bacteria in subgingival plaque is lower than those in supragingival plaque [50]. According to Tada et al., L. reuteri fails to improve the microbial flora of the peri-implant sulcus in patients with peri-implantitis [51]
In addition, this antimicrobial activity is observed in vivo. According to Invernici et al., B. animalis inhibits the growth of P. gingivalis, P. intermedia, F. nucleatum, and A. actinomycetemcomitans [47]. A decrease in the number of P. gingivalis was also reported after oral administration of L. crispatus for four weeks [59]. Administration of L. reuteri tablets for 28 days reduced the number of P. intermedia and P. gingivalis in the subgingival microbiota [60]. In combination with scaling and root planning (SRP), the consumption of L. reuteri tablets for 12 weeks showed a limited difference in the number of P. gingivalis [61]. The association between L. plantarum, L. brevis, and Pediococcus acidilactici demonstrated a significant microbiological impact after reducing the counts of T. forsythia in patients with gingivitis [62]. From Imran et al., daily consumption of L. casei commercial fermented milk (Yakult © ) for one month reduced the numerical sum of P. gingivalis, A. actinomycetemcomitans, and P. intermedia in patients with chronic generalized mild to moderate periodontitis [63]. Consuming petit-suisse cheese for nine days, L. casei reduces the density of A. actinomycetemcomitans and maintain lowers density of P. gingivalis two weeks later [64]. Four weeks after intake of L. salivarius tablets for eight days, a significant reduction is noted in the number of A. actinomycetemcomitans, P. intermedia, P. gingivalis, T. denticola, and T. forsythia in the subgingival plaque. This reduction disappears after eight weeks [65]. Sajedinejad et al. found that oral application of L. salivarius as a mouthwash for 28 days serves as the antimicrobial activity against A. actinomycetemcomitans [66]. In a pilot study, a commercial probiotic mouthwash containing natural oral bacteria (S. oralis, S. uberis, S. rattus) shows a trend towards the reduction of periodontal pathogens in subgingival plaque (P. gingivalis and C. rectus) [67]. Daily consumption of probiotic lozenges that combined L. rhamnosus and B. animalis for four weeks decreases the bacterial load of A. actinomycetemcomitans and F. nucleatum in both saliva and plaque. The consumption also decreases the number of P. gingivalis in the plaque [68]. In patients who received non-surgical treatment (SRP), the administration of L. rhamnosus sachets (30 days) or azithromycin pills (five days) offered microbiological effects similar to SRP alone for the treatment of chronic periodontitis [69].

Modulation of Immunological or Inflammatory Mediators of Oral Dysbiosis
The bacterial exposure induces the synthesis of cytokine as Interleukins (IL) or TNF α and chemokine as CXCL8. This synthesis regulates inflammation and modulates cellular activities associated with the host immune response [78]. Some probiotics demonstrated in vitro ability to modulate immunoinflammatory parameters. According to Shin et al., Lactococcus lactis neutralizes and inhibits the production of IL-6 or TNF-α induced by lipopolysaccharides from F. nucleatum, P. gingivalis, and T. forsythia [56]. CXCL8 secretions from gingival stromal stem cells increase when pretreated with L. rhamnosus before P. gingivalis stimulation [43]. In gingival epithelial cells, IL-1β and TNF-α synthesis stimulation decreases when co-culture with P. gingivalis and L. rhamnosus or bifidobacteria (B. longum, B. animalis, B. pseudolongum, B. bifidum) or L. salivarius. CXCL8 secretion increases when co-cultured with P. gingivalis and L. salivarius or L. rhamnosus [45]. In mice, L. gasseri and L. brevis decrease the expression and secretion in gingival tissue of inflammatory cytokine (IL-1β, IL-6, IL-17A, and TNF α) [70,71]. B. lactis reduces levels of IL-1b and IL-1b/IL-10 ratios in rats using experimental periodontitis [46]. These observations are different from those observed in humans. In a group of 47 individuals, 4-week consumption of tablets containing a mixture of L. rhamnosus and L. curvatus showed no effect on the concentration of selected cytokines (IL1β, IL6, IL8, IL10, TNF-α) in gingival crevicular fluid [72]. In two randomized, double-blind, placebo-controlled crossover trials, three-week ingestion of L. reuteri tablets twice a day offers no difference in cytokine saliva levels (IL1β, IL6, IL8, and IL10) [73,74]. Following the management of peri-implant mucositis, probiotic supplementation with L. reuteri offered no difference in inflammatory mediator level in the crevicular fluid for 89 patients at a 26-week follow-up [75].

Discussion
Many studies suggest beneficial effects of prebiotics and probiotics on brain function through the gut-brain axis [79]. In contrast, no studies demonstrate a use of prebiotics compounds or probiotics strains to prevent or treat brain disorders through oral-brain axis.
We identified 38 studies, and only three explored the effects of prebiotic compounds on the growth of beneficial bacteria. Prebiotics are a recent field of research [80], and scanty studies publish their effects on the oral microbiome. Our review shows that nutritional stimulation of the oral microbiome using various prebiotic compounds (Nitrate, betamethyl-D-galactoside, N-acetyl-D-mannosamine, etc.) may induce the composition of the dental biofilm and growth of beneficial oral bacteria at the expense of pathogenic bacteria (A. actinomycetemcomitans, F. nucleatum, P. gingivalis). Anxiolytic and antidepressant effects or enhancement in cognitive deficit and social functioning were observed with the rebalancing of gut flora through the consumption of prebiotics by patients suffering from depression, Alzheimer's disease, or autism spectrum disorders [81]. Thus, in the context of the oral-brain axis, it can be assumed that the use of prebiotics in modulating the oral microbiome could lead to improvements in mental health. As the beneficial effects of prebiotics have already been studied for the modulation of the gut microbiome [82,83], it can be assumed that research on the effects of prebiotics on the oral flora will represent an area with growing interest.
Since the 1980s, studies have explored probiotics, particularly lactobacilli of which the most popular are L. rhamnosus, L. reuteri, L. casei, and L. acidophilus [84]. Probiotic microorganisms that offer health benefits for humans are Lactobacilli and Bifidobacterium species [85]. The major probiotic mechanisms of the action of probiotics include improved adhesion to bacterial colonization sites, competing with pathogenic microorganisms, production of antimicrobial substances, and modulating the host's immune response [86].
The in vitro and in vivo confirm the effects of lactobacilli and bifidobacterium on modulating the oral microbiota associated with mental disorders (B. animalis, L. paracaseï, L. acidophilus, L. rhamnosus, L. delbrueckii). Bacterial competition excludes some pathogens without biofilm structural disruption (F. nucleatum, P. gingivalis, etc.). The biofilm enzymatic degradation capacity appears as a mechanism of action implicated in this competition.
The specific dysbiotic signature associated with patients with mental disorders suggests an influence of the central nervous system in the development of oral pathologies [12]. While the use of probiotics may appear as a complementary therapeutic means for patients with mental disorders, it is necessary to keep in mind the multifactorial character of the oral microbiome homeostasis [87]. Frequent oral alterations affect patients with mental disorders [88]. These alterations are correlated with a psychomotor impairment that prevents an adequate hygiene routine and reduces salivary flow due to various psychoactive substances (drugs, medication) and difficulty in accessing dental health services [89,90]. These mental disorders promote oral dysbiosis that can lead to dental caries and periodontal disease [91]. P. gingivalis, T. forsythia, and T. denticola represent the red complex polymicrobial community involved in the development of periodontal disease [92]. Some of these periodontopathogen bacteria (P. gingivalis, T. denticola) or their toxic proteases (gingipaïn) detected by postmortem analysis of Alzheimer's disease patients' brains suggest their pathogenesis involvement of this mental disorder [93]. Thus, the antimicrobial activity of probiotic strains against periodontal pathogens could represent an axis of prevention of oral dysbiosis and its potential implication in the development of mental disorders.
The modulation of the immune system induced by prebiotics and probiotics is one of the health benefits of increasing interest. Although the mechanisms of action are not yet clearly understood, this stimulation of the immune system can be direct by altering cytokine expression or indirect by altering the composition and population of bacterial species. The direct beneficial effects on the immune system are generally associated with an increase in the expression of anti-inflammatory cytokines (IL 4, IL 10, IL 11, IL 13) and a reduction in pro-inflammatory cytokines (IL 1β, IL 6, TNFα) [94]. Their immunomodulatory effects have been extensively studied in inflammatory diseases in the gastrointestinal tract [95][96][97] but remain poorly evaluated in periodontal pathogen-induced inflammatory diseases.
Chronic inflammation and latent infections can cause cognitive and behavioral problems [98]. Cytokines produced outside the central nervous system such as IL 1β and TNF α cause brain neurotoxicity [78]. The inflammation induced by periodontopathogen bacteria is associated with dementia and neurodegenerative lesions in patients with Alzheimer's disease [21,22]. In in vitro and animal studies, while probiotic strains seem to decrease in cytokines induced by the main periodontopathogens species (P. gingivalis, F. nucleatum, T. forsythia), the improvement of the inflammatory condition is not observed in human studies. The probiotics are not demonstrated in preventing the neurological consequences of inflammation associated with periodontal disease.

Limits and Perspectives
In this review, studies suggest that prebiotics and probiotics can prevent and treat oral dysbiosis involved in the oral-brain axis. However, several limitations are noted. These studies only use human small samples with short intake and/or follow-up, which fails to define their long-term effects. In addition, the diversity of probiotic species studied according to different modes of administration neither support the standardization of a probiotic formulation nor the definition of an adapted delivery system.
Prebiotics and/or probiotics are not shown to treat or prevent mental disorders using modulating oral dysbiosis. In addition, their effects are preventive approaches for periodontal disease. Human studies using different galenic forms (milk drinks, yogurts, and mouthwashes) should be explored in future studies for more suitable use of prebiotics and/or probiotics in patients with reduced oral hygiene habits [98]. Longitudinal studies should define a formulation of prebiotics and/or probiotics and a mode of administration in preventing oral dysbiosis and evaluating their safety.

Conclusions
Our review highlights the limited research regarding the use of prebiotics and/or probiotics in modulating oral dysbiosis in mental disorders. However, the studies confirm their interest in preventing or treating mental disorders through global or targeted modulation of the oral microbiome. Research is emerging on prebiotic compounds and probiotics for the treatment of oral dysbiosis and mental disorders. In this review, the probiotic strains belong to the genus Lactobacilli and Bifidobacterium commonly studied for the rebalancing of intestinal flora. While prebiotics and probiotics are part of the gut-brain axis, it is still difficult to envisage their preventive or therapeutic application for managing mental disorders through the oral-brain axis. Modulating oral dysbiosis can improve the oral health of patients with mental disorders.