Role of Oral Microbiome Signatures in Diagnosis and Prognosis of Oral Cancer

“The majority of HNSCC are cancers of oral cavity (OC) and oropharynx.(1) Oral squamous cell carcinoma 1 Department of Life Sciences, Central University of Tamil Nadu, Thiruvarur, Tamil Nadu, India 2 Epidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institut…”

“A typical biofilm is made up of mono- or polymicrobial cells, polysaccharide, proteins, nucleic acids, and lipids.(22) Oral biofilms are composed of 700 different microbial species; extracellular matrix that is composed of DNA, proteins, polysaccharides, and lipids; and salivary glycoproteins, GCF, albumin, and host c…”

“Oral administration of Bifidobacterium enhances antitumor immunity and alters the efficacy of check-point inhibitors as an immunotherapeutic agent by changing the composition of intestinal microorganisms.(35) Bacteriocins of Streptococcus dentisani inhibit the growth of cariogenic bacterial species.”

“Tongue, buccal mucosa, supragingival and subgingival surfaces of the teeth, soft and hard palates, and saliva of OC may represent different ecological niches or habitats.(13) The warm and moist environment and host-derived nutrients, such as saliva proteins, gingival crevicular fluid (GCF), and glycoproteins, favor th…”

“FadA adhesion molecule of F nucleatum binds to E-cadherin and activates b-catenin signaling that regulates cell proliferation and inflammatory responses in oncogenesis (Figure 2).(94,104,105) Fusobacterium nucleatum synergistically with other bacteria fungi and viruses may induce proinflammatory microenvironment throu…”

“Activated p65 subunit of NF-kB inhibits transcriptional activation of IL-8.(20)”

“The predominant oral microbial communities belonged to Firmicutes (genus Streptococcus, family Veillonellaceae, genus Granulicatella), Proteobacteria (genera Neisseria, Haemophilus), Actinobacteria (genera Corynebacterium, Rothia, Actinomyces), Bacteroidetes (genera Prevotella, Capnocytophaga, and Porphyromonas), and…”

“FadA adhesion molecule of F nucleatum binds to E-cadherin and activates b-catenin signaling that regulates cell proliferation and inflammatory responses in oncogenesis (Figure 2).(94,104,105) Fusobacterium nucleatum synergistically with other bacteria fungi and viruses may induce proinflammatory microenvironment throu…”

“Thirtytwo percent of these species remain uncultivated, and 14% have not been named.(21) A typical biofilm is made up of mono- or polymicrobial cells, polysaccharide, proteins, nucleic acids, and lipids.”

“These receptors interact with periodontal microbial-associated molecular patterns (eg, lipoproteins, LPS, fimbriae, Bacteroides surface protein A, and nucleic acids) and damage/danger-associated molecular patterns (DAMPs; eg, fibrinogen, heat-shock proteins, and nucleic acids).(47) Stratified squamous epithelium in pe…”

“Bacteria play an important role in these mucosal diseases.(49) Higher abundance of Porphyromonas and Solobacterium and lower abundance of Haemophilus, Corynebacterium, Cellulosimicrobium, and Campylobacter were reported in patients with OLP when compared to healthy controls.”

“Bacterial infection is one of the major causes of chronic inflammation which facilitates increased cell proliferation, mutagenesis, oncogene activation, and angiogenesis that lead to development of oral cancer.(6) Numerous bacterial species are involved in oral cancer.”

“Cigarette smoking also increases and decreases in the abundance of common taxa of oral microbiome.(78) a and b bacterial diversity showed significant difference between betel nut users with and without chewing of tobacco.”

“Microorganisms are classified based on their oxygen requirements as obligate aerobes; obligate anaerobes such as Fusobacterium and Veillonella; facultative anaerobes such as Actinomyces and Streptococci; microaerophiles that grow best at low concentrations of O2 (2%-10%); and capnophiles such as Neisseria that grow be…”

“Mager et al reported the presence of F periodonticum in saliva of patients with OSCC.(18) Capnocytophaga gingivalis, P melaninogenica, and S mitis were highly abundant in saliva of patients with OSCC and served as potential diagnostic markers for oral cancer.”

“Saliva is used as a transporting medium of nutrients, peptides, and partially dissolved carbohydrates in the formation of oral biofilms.(17) Factors such as age of host; environmental conditions such as pH, oxygen levels, and nutrition in the habitats of the OC; lifestyle of the host such as food habit, tobacco, and a…”

“The GCF contains iron that enhances probable pathogenic mechanisms in oral bacteria associated with periodontal disease.(29) Salivary components such as immunoglobulin A, lactoferrin, lactoperoxidase, lysozyme, statherin, and histatins are nutritional source for the oral microbiome.”

“The taxa Megasphaera, Stomatobaculum, Granulicatella, Lautropia, Veillonella, Streptococcus, Scardovia, Rothia, and Actinomyces were significantly abundant in oral swabs of controls.(56) The abundance of Rothia, Haemophilus, Corynebacterium, Paludibacter, Porphyromonas, and Capnocytophaga significantly reduced and the…”

“Smokers have more bacterial diversity in OP region when compared to nonsmokers.(79) No significant differences in microbial diversity had been observed between smokers and nonsmokers groups with no history of betel nut use.”

“Fusobacterium nucleatum activates p38 which in turn activates HSP-27 and induces secretion of MMP-9 and MMP-13 (collagenase 3) that drive tumor invasion and metastasis.(9,103) Lipopolysaccharide of F nucleatum is involved in inflammation and cytokine-mediated damaging lesions of the GECs through the activation of tran…”

“The bacterial taxa Veillonella, Fusobacterium, Prevotella, Porphyromonas, Actinomyces, and Clostridium belonging anaerobes, and Haemophilus, Enterobacteriaceae, and Streptococcus subspecies belonging to aerobes were highly abundant in tumor sites of patients with OSCC.(43,58) Capnocytophaga, Pseudomonas, and Atopobium…”

“Functional prediction showed that methane metabolism, oxidative phosphorylation, and carbon fixation were significantly higher in patients with stage 4 OSCC (Table 2).(62) Filifactor alocis has genes that encode bisulfur proteins and a ferrous iron transport system that is efflux of reactive oxygen species.”

“Due to high ADH activity, Neisseria produce more ALD than Streptococcus subspecies, Stomatococcus subspecies, or Moraxella subspecies Neisseria may play an essential role in alcohol-related oral carcinogenesis.(63) Terrimonas is involved in tumorigenic anthracene degradation.”

“This type of interspecies biofilm formation upregulates host protease m calpain that increases tissue invasion through degradation of cadherin junctions.(28)”

“The bacterial taxa Veillonella, Fusobacterium, Prevotella, Porphyromonas, Actinomyces, and Clostridium belonging anaerobes, and Haemophilus, Enterobacteriaceae, and Streptococcus subspecies belonging to aerobes were highly abundant in tumor sites of patients with OSCC.(43,58) Capnocytophaga, Pseudomonas, and Atopobium…”

“Chronic periodontal disease is considered to be an important risk factor for oral premalignant lesions and OSCC.(41) Chronic periodontitis enhances the risk of oral premalignant lesions that lead to OSCC and oropharyngeal squamous cell carcinoma (OPSCC).”

“Kingella dentificans and Streptococcus sanguinis were associated with reduced risk of larynx cancer; Actinomyces oris and V denticariosi were associated with reduced risk of pharynx cancer, whereas P micra and Neisseria sicca were associated with reduced risk of oral cancer.(67) Tobacco smoking induces loss of microbi…”

“Lipopolysaccharide induces cancer-promoting inflammatory reactions.(65) Lipopolysaccharide of F nucleatum Table 3.”

“TNF-a is responsible for the generation of free radicals during sepsis.(90) Bacterial products such as endotoxins (LPS), enzymes (eg, proteases, collagenases, fibrinolysin, and phospholipase), and metabolic byproducts (eg, H2S, ammonia, and fatty acids) may induce permanent genetic alterations in epithelial cells of t…”

“Abundance of genus Streptococcus, Rothia, Gemella, Peptostreptococcus, Porphyromonas, Micromonas, Dialister, Tannerella, Veillonella, and Lactobacillus was reported in tumor tissues of patients with OSCC, whereas Prevotella, Neisseria, Leptotrichia, Capnocytophaga, Actinobacillus, and Oribacterium were more abundant i…”

“Poor oral hygiene acts synergistically to enhance the risk of oral cancer.(3,4) Human papilloma virus (HPV) infection is another known risk factor for oropharyngeal cancer (OPC).”

“Numerous bacterial species are involved in oral cancer.(7) Despite advancement in cancer treatment, OSCC has a poor prognosis with 5-year survival rates of <50%.”

“The staining intensity of P gingivalis in gingival carcinoma tissues was significantly enhanced when compared to noninvasive bacteria such as S gordonii.(110) Porphyromonas gingivalis is responsible for damaging local periodontal tissues and evade host immune system.”

“Porphyromonas gingivalis enhances Bcl2 (antiapoptotic); Bax (pro-apoptotic) ratio and inhibits release of cytochrome c from mitochondria.(95,96) Porphyromonas gingivalis colonizes inside GEC of oral tissues and prevents apoptosis by inducing ligation of ATP with purinergic receptor P2X7 receptors.”

“Smokers have unstable microbial colonization and are more susceptible to bacterial infection through alterations in innate and adaptive immune response.(83,84) Higher abundance of periodontopathogenic bacteria such as Prevotella tannerae, F nucleatum, and P intermedia and lower abundance of Streptococcus tigurinus wer…”

“A number of useful genes and metabolic pathways such as bacterial chemotaxis, flagellar assembly, and toxin biosynthesis were found to be enriched in the microbiomes of periodontal disease.(46) Periodontitis-associated microorganisms induce inflammation and destruction of tissue through degradation of collagen and rel…”

“Alistipes, Bacteroides, Blautia, Clostridium, Dorea, Escherichia, Faecalibacterium, Megamonas, and Phascolarctobacterium showed positive correlations between patients with epithelial precursor lesion and OSCC.(51) Furquim et al reported about the influence of salivary microbiome for developing Fanconi anemia (FA).”

“In OSCC, bacterial genes that encode enzymes such as transketolase, pyruvate formate lyase-activating enzyme, formate C-acetyltransferase, aspartokinase/homoserine dehydrogenase, and nitroreductase/dihydropteridine reductase were significantly overrepresented, whereas bacterial genes that encode iron complex transport…”

“Aerobic and anaerobic bacteria together form oral biofilms that prevent changes in their environment.(11) The oral microbiome population varies with saliva and different habitats (buccal mucosa, supragingival, and subgingival plaque) of OC.”

“Saliva is the primary nutrient source for bacteria that reside in supragingival biofilm, while GCF provides nutrient for bacteria of the subgingival biofilms.(23) Formation of oral biofilms first occurs at the supragingival region and formation of subgingival biofilms second.”

“Periodontal pathogens such as P gingivalis, P intermedia, and F nucleatum produce highest levels of AI-2.(26) The competence signaling peptide is responsible for the formation of biofilm, bacteriocins, stress response, acid tolerance, and genetic conversion by S mutans.”

“Prevotella nanceiensis, Capnocytophaga leadbetteri, and Selenomonas sputigena were inversely related to HNSCC. Porphyromonas gingivalis, T forsythia, and A actinomycetemcomitans and S mutans were positively related to risk of HNSCC. Kingella dentificans and Streptococcus sanguinis were associated with reduced risk of…”

“Abundance of periodontal pathogens Fusobacterium, Prevotella, and Alloprevotella were progressively increased, whereas the abundance of Streptococcus was progressively decreased in progression of OSCC.(75) Numerous bacterial insertion sites were reported in host genes such as mycobacterium genomic element integrations…”

“Porphyromonas gingivalis accelerates progression through the S-phase of the cell cycle by preventing activity of p53 tumor suppressor gene.(100) Induced expression of B7-H1 and B7-DC receptors on OSCC cells and primary GECs by P gingivalis has been reported earlier.”

“Streptococcus salivarius, S intermedius, S mitis, and nonpathogenic Neisseria subspecies possess alcohol dehydrogenase (ADH) that is responsible for the production of carcinogenic compounds such as ALD, hydroxyl ethyl radicals, and hydroxyl radicals from ethanol.(80,81) Streptococcus anginosus was frequently reported…”

“Presence of Clavibacter michiganensis, Plantibacter flavus, Tepidimonas aquatica, and Thermus scotoductus were predominant in deep tumor tissues.(71) Exiguobacterium oxidotolerans, C gingivalis, P melaninogenica, Staphylococcus aureus, Veillonella parvula, Capnocytophaga ochracea, Eubacterium saburreum, L buccalis, an…”

“It has been reported that b diversity significantly differed between chewers and nonchewers with excessive alcohol consumption.(61) Smokers have more bacterial diversity in OP region when compared to nonsmokers.”

“Fusobacterium nucleatum in GECs activates NLRP3 inflammasome that includes HMGB1 (high-morbidity group box-1 protein), apoptosis-associated speck-like protein, and caspase-1.(37) FadA adhesion molecule of F nucleatum binds to E-cadherin and activates b-catenin signaling that regulates cell proliferation and inflammato…”

“Among them, Peptostreptococcus is known to be a potential pathogen for periodontitis.(45) Prevotella intermedia, F nucleatum, Selenomonas noxia, A actinomycetemcomitans, and Eubacterium nodatum, P gingivalis, T denticola, and T forsythia were also associated with pathogenesis of periodontal disease.”

“Streptococcus mitis induces the breakdown of mucus in the human OC that drive translocation of pathogen into the lamina propria and recruitment of inflammatory cells.(114) Radiotherapy is used for the treatment of head and neck cancer.”

“Nucleoside diphosphate kinase of P gingivalis inhibits apoptosis and promotes survival of host epithelial cells.(97) Porphyromonas gingivalis reduces ATP activation of P2X7 receptors on dendritic cells that disrupt activation of the NLRP3/ASC/caspase-1 inflammasome.”

“The existence of viable bacteria in deep parts of OSCC favored the hypothesis that bacteria survived in the tumor microenvironment.(69,70) The bacterial taxa Veillonella, Fusobacterium, Prevotella, Porphyromonas, Actinomyces, and Clostridium belonging anaerobes, and Haemophilus, Enterobacteriaceae, and Streptococcus s…”

“Changes in environmental conditions increase the potential of pathogenic bacteria to create oral diseases.(12) Tongue, buccal mucosa, supragingival and subgingival surfaces of the teeth, soft and hard palates, and saliva of OC may represent different ecological niches or habitats.”

“The existence of viable bacteria in deep parts of OSCC favored the hypothesis that bacteria survived in the tumor microenvironment.(69,70) The bacterial taxa Veillonella, Fusobacterium, Prevotella, Porphyromonas, Actinomyces, and Clostridium belonging anaerobes, and Haemophilus, Enterobacteriaceae, and Streptococcus s…”

“Bacteriocins of Streptococcus dentisani inhibit the growth of cariogenic bacterial species.(36) Antimicrobial peptides such as bacteriocins produced by S mutans and S salivarius in the OC kill other bacteria.”

“Higher percentage of P intermedia was reported in betel quid chewers and alcohol users, whereas higher abundance of F nucleatum was reported in smokers.(85) The relative abundances of Periodontopathogenic genera Porphyromonas, Tannerella, and Treponema showed no significant positive correlations with cytokine concentr…”

“Bacterial products such as endotoxins (LPS), enzymes (eg, proteases, collagenases, fibrinolysin, and phospholipase), and metabolic byproducts (eg, H2S, ammonia, and fatty acids) may induce permanent genetic alterations in epithelial cells of the host that drive proliferation and/or survival of epithelial cells.(91) Mi…”

“Chronic periodontitis enhances the risk of oral premalignant lesions that lead to OSCC and oropharyngeal squamous cell carcinoma (OPSCC).(42) Periodontal bacteria such as P gingivalis, P intermedia, and F nucleatum are essential for developing OSCC.”

“Snail, Slug, and b-catenin enhances expressions of Zeb1, Vimentin, and MMP-2, -7, and -9.(108) Microbial organisms induce immune inflammation response in host cells that enhances mutation rate in normal cells and triggers malignant transformation of normal cells of host.”

“Treponema, Porphyromonas, Parvimonas, and Fusobacterium were considered as a core microbiota in periodontitis.(50) Abundance of Bacillus, Enterococcus, Parvimonas, Peptostreptococcus, and Slackia were significantly different between epithelial precursor lesion and OSCC.”

“Abundance level of S anginosus, Peptoniphilus, and Mycoplasma were significantly decreased in HPV-positive cancers.(64) Smokers have unstable microbial colonization and are more susceptible to bacterial infection through alterations in innate and adaptive immune response.”

“Streptococcus anginosus was frequently reported in OSCC and caused DNA damage in oral mucosa due increased synthesis of NO and cyclooxygenase 2.(82) Overrepresentation of the commensal bacterial genera, Corynebacterium and Kingella, showed reduced risk of HNSCC.”

“Expression of B7-H1 receptor induces immune evasion in oral cancers.(101) ERK1/2-Ets1, p38/HSP27, and PAR2/NF-KB pathways are activated by P gingivalis infection to induce the expression of pro-MMP-9.”

“Nitrite that is produced by oral microbiome is further reduced to nitric oxide that prevents the growth of cariogenic bacteria.(14,30) Veillonella subspecies metabolizes lactate into weaker acids that reduce local pH, whereas Streptococcus subspecies and Actinomyces subspecies generate the alkali, ammonia, by cataboli…”

“Long-term exposure of P gingivalis induces cell proliferation, migration, and invasion through regulation of tumor-related genes such as FLI1, GAS6, PDCD1LG2, CD274, and lncRNACCAT1.(111) Whether profiling of expression of these genes could be used as biomarkers remain to be investigated.”

“well as the contributor to carcinogenesis.(88,89) Lipopolysaccharide from a potential pathogen such as P gingivalis and F nucleatum is responsible for the activation immune system at the cellular level in periodontal diseases.”

“Periodontal bacteria such as P gingivalis, P intermedia, and F nucleatum are essential for developing OSCC.(18,43,44) Periodontitis is associated with the subgingival microbiota such as Peptostreptococcus, Synergistes, Filifactor, Mycoplasma, and Olsenella.”

“Actinomyces subspecies may inhibit tumorigenesis through the secretion protease inhibitors.(60) Genus Streptococcus, Dialister, and Veillonella can be used to segregate HNSCC from healthy individuals.”

“Bacterial flagella were considered as key inflammatory structures in regulating OSCC-related inflammation.(92) It has been reported that F nucleatum subspecies polymorphum, Campylobacter subspecies, and P aeruginosa showed significant association with OSCC, whereas S mitis, R mucilaginosa, and H parainfluenzae were th…”

“High prevalence of L buccalis was reported in Chinese patients with gingivitis and necrotizing ulcerative gingivitis.(38) Prevotella subspecies, Lactobacillus subspecies, Dialister subspecies, and Filifactor subspecies are related to pathogenesis and progression of dental caries.”

“Four genera Fusobacterium, Porphyromonas, Treponema, and Prevotella showed dynamic synchronous variations in their relative abundances during treatment.(113) Oral microbial community is altered in the patients with nasopharyngeal carcinoma (NPC) who develop mucositis due to radiotherapy (RT).”

“A positive correlation between HPV infection and the abundance of Haemophilus and Gemella has also been reported in OP cancer.(66) The abundance of Capnocytophaga was significantly higher in patients with recurrent OSCC when compared to controls.”

“Rothia, Streptococcus, and Prevotella produce oral ALD that promote oral carcinogenesis (Table 3).(57) Streptococcus, Neisseria, and Veillonella are considered as anti-inflammatory mediators, whereas Selenomonas, Parvimonas, and Campylobacter are considered as pro-inflammatory mediators.”

“Most of the bacteria in saliva are attached to exfoliated human epithelial cells.(15) Microorganisms are classified based on their oxygen requirements as obligate aerobes; obligate anaerobes such as Fusobacterium and Veillonella; facultative anaerobes such as Actinomyces and Streptococci; microaerophiles that grow bes…”

“Microbial organisms induce immune inflammation response in host cells that enhances mutation rate in normal cells and triggers malignant transformation of normal cells of host.(109) The staining intensity of P gingivalis in gingival carcinoma tissues was significantly enhanced when compared to noninvasive bacteria suc…”

“Subgingival biofilms are mainly dominated by gram-negative obligate anaerobes.(24) Gram-positive aerobic bacteria, such as Actinomyces subspecies and oral Streptococci (S intermedius and S oralis) are responsible for the initial colonization in teeth surfaces.”

“The OSCC is often detected at late stage, and there is a high risk of having second primary tumors.(8) To overcome these challenges, investigators should search for early diagnostic and prognostic biomarkers.”

“Lactobacillus gasseri/ L johnsonii, H parainfluenza, L fermentum, and F periodonticum can be used as a diagnostic biomarker for HNSCC.(55) Reduction in levels of Lactobacillus subspecies induces microbial dysbiosis in patients with tongue cancer.”

“Streptococcus, Neisseria, and Veillonella are considered as anti-inflammatory mediators, whereas Selenomonas, Parvimonas, and Campylobacter are considered as pro-inflammatory mediators.(93) Role of P gingivalis and F nucleatum in Progression of OSCC”

“Synergistes are responsible for microecological changes and anaerobiosis in periodontal pocket, inflammation, and destruction of gingival tissue that may drive periodontitis-mediated oral carcinogenesis.(74) Mycoplasma, Treponema, Campylobacter, Eikenella, Fusobacterium, Selenomonas, Dialister, Peptostreptococcus, Fil…”

“These may drive tumorigenesis by altering gene expression.(76)”

“Prevotella subspecies, Lactobacillus subspecies, Dialister subspecies, and Filifactor subspecies are related to pathogenesis and progression of dental caries.(39) The genera Veillonella, Bifidobacterium, Chattopadhyay et al 5”

“Fusobacterium nucleatum synergistically with other bacteria fungi and viruses may induce proinflammatory microenvironment through recruitment of tumor-infiltrating immune cells that favor tumorigenesis.(106) Antigens of P gingivalis have also been detected in gingival squamous carcinoma.”

“Human papilloma virus (HPV) infection is another known risk factor for oropharyngeal cancer (OPC).(5) Bacterial infection is one of the major causes of chronic inflammation which facilitates increased cell proliferation, mutagenesis, oncogene activation, and angiogenesis that lead to development of oral cancer.”

“Veillonella has cariogenic potential and allows acidogenic bacteria such as Streptococcus species to grow and continue to produce additional acid.(40)”

“Porphyromonas gingivalis is considered as a potential risk factor for oral cancer.(107) Infection of P gingivalis induces EMT by downregulation of E-cadherin and nucleocytoplasmic accumulation of b-catenin that drive aggressiveness and/or metastatic potential in OSCC.”

“Terrimonas is involved in tumorigenic anthracene degradation.(87)”

“The relative abundances of Periodontopathogenic genera Porphyromonas, Tannerella, and Treponema showed no significant positive correlations with cytokine concentrations.(86) Porphyromonas gingivalis, P intermedia, A actinomycetemcomitans, and F nucleatum are responsible to produce volatile sulfur compounds such as gen…”

“induces inflammation through the release of IL-1 and IL-6 in RT-induced mucositis.(115)”

“The salivary microbiome profile of patients with FA showed similar diversity pattern with oral leukoplakia and OSCC.(52) 6 Technology in Cancer Research & Treatment”

“Oral taxon 44, and F nucleatum subspecies polymorphum are associated with OSCC.(68) Moraxella osloensis, Prevotella veroralis, and species of Actinomyces were only detected in normal tissues.”

“Oral microbiome may function as synergistic risk factors along with primary risk factors such as alcohol and tobacco use.(77) Leukoplakia, erythroplakia, and oral submucous fibrosis are precursor lesion of oral cancer in betel nut chewers.”

“The competence signaling peptide is responsible for the formation of biofilm, bacteriocins, stress response, acid tolerance, and genetic conversion by S mutans.(27) Commensal bacteria live in equilibrium with the host immune response.”

“Antimicrobial peptides such as bacteriocins produced by S mutans and S salivarius in the OC kill other bacteria.(25)”

“Streptococcus is commonly found genera in the human OC, but it is highly genetically heterogeneous group.(19) Veillonella atypica, P gingivalis, Selenomonas subspecies, Actinobacillus actinomycetemcomitans, Prevotella intermedia, and Capnocytophaga are observed in tongue, whereas Streptococcus pyogenes, Streptococcus…”

“Abundance of Alphaproteobacteria and Deltaproteobacteria in saliva were higher in Indians when compared to HMP.(33) Streptococcus subspecies was the commonly observed bacterial genus in saliva of Indian populations.”

“Solobacterium subspecies, Alloprevotella subspecies, and Lachnoanaerobaculum subspecies represent core saliva microbiome in the Indian population.(34)”

“Moraxella osloensis, Prevotella veroralis, and species of Actinomyces were only detected in normal tissues.(73) The level of Parvimonas was enhanced and the level of Actinomyces was reduced in tumors relative to normal tissues.”

“Prevotella nanceiensis, Capnocytophaga leadbetteri, and Selenomonas sputigena were inversely related to HNSCC. Porphyromonas gingivalis, T forsythia, and A actinomycetemcomitans and S mutans were positively related to risk of HNSCC. Kingella dentificans and Streptococcus sanguinis were associated with reduced risk of…”

“Bacterial species Localization (206) Refs.”

“Different species of bacteria are able to trigger cell proliferation and permanent genetic mutations by their products and metabolites and inducing proinflammatory cytokines’ production, inhibition of antitumoral immune cells, malignant transformation and cellular invasion [39,40].”

“The oral microbiota induces inflammatory and immune responses in oral tissues (49, 50), which in turn affects cardiometabolic health and promotes the onset of cardiovascular disease.”

“The abundance of lactic acid bacteria and species of the genus Lactobacillus in saliva was found to be significantly higher in patients who had undergone chemoradiation or surgery [47].”

“nucleatum which activates pro-inflammatory signaling pathways [33].”

“chewing and smoking are the major factors [9].”

“Moreover, oral microbiota has also been reported to influence salivary metabolomic profiles of HNC patients (107).”

“143 Another investigation reported F. nucleatum to be twice as prevalent in the mouthwash of HNSCC patients compared to the control group.”

“Interestingly, they also play a role in enhancing tumor progression by promoting colonization of the tumor bed by other pathogens [9].”

“Its activation occurs as an essential feature of bacterial-associated tumor development [138, 169] (Figure 2C).”

“92 94 Interestingly, species from these four bacterial genera have been recently associated with the establishment and progression of oral cancer, 95–98 implicating human papillomavirus as a driver of oropharyngeal and oral cancer tumorigenesis by influencing the composition of the oral microbiome.”

“At different phases of OSCC, these variables have been shown to cause chronic in fl ammation of the oral cavity by inducing the production of pro-in fl ammatory cytokines (12, 80).”

“anginosus is responsible for inducing the nitric oxide synthesis and inflammatory cytokines causing carcinogenesis [45].”

“Capnocytophaga gingivalis, Prevotella melaninogenica, and Streptococcus mitis have been found in high abundance in the saliva of OSCC patients [57].”

“(3) P. gingivalis activates antiapoptotic pathways, such as Janus kinase 1 (JAK1)/signal transducer and activator of transcription 3 (STAT3) and phospho-inositide 3-kinase PI3K/protein kinase B (Akt) in oral epithelial cells, thus promoting OSCC [60].”

“7 of 35 Finally, a total of 72 studies were selected for this review (Figure 1).”

“Different studies have also shown that they have intron sequences with a strong self-splicing capacity within their 16S rRNA, 23S rRNA, and tRNA genes (13, 14, 24, 25).”

“The oral microbiome thrives under specific conditions, including an average temperature of 37 ◦ C and decreasing bicarbonate (HCO 3 − ) and hydrogen ions, making a saliva pH range of 6.5–7 [26], although some studies suggest a broad range of 6.2–7.6, with an average of 6.7 [27].”

“A healthy oral microbiome is essential for maintaining oral health and preventing disease, including oral cancer [144].”

“There are over 770 bacterial species in the oral cavity [82], in addition to candidate phyla radiation (CPR) of bacterial organisms, bacteriophages, fungal genera, and viruses [83].”

“Additionally, components derived from Pseudomonas aeruginosa , including its flagella and cytotoxin ExoU, exhibit potent inflammatory activity by recruiting neutrophils while simultaneously activating the NF-κB signaling pathway, consequently accelerating the progression of oral cancer [282].”

“Prevotella intermedia None identified None identified None identified (144)”

“Several bacterial species in the oral cavity whether pathogenic or commensal strains have a real role in oral cancer by involving in chronic inflammation which leads to progress of oral carcinogenesis, for example, Porphyromonas gingivalis and Fusobacterium nucleatum induce the production of cytokines inflammation, pr…”

“Thus, alteration in the oral microbiome may be able to be used as a predictive marker for malignant transformation [115].”

“Enzymes such as amylases, cystatins, histatins, mucins, and peroxidases work together to fight germs in the mouth [98].”

“5), Prevotella, Mitsuokella, and Treponema species are commonly detected in the subgingival plaques of patients with poor oral hygiene and chronic periodontitis, and they are possibly associated with oral cancer (Chattopadhyay et al. 2019; Zhong et al. 2021).”

“Consistent with our results, Rothia has also been reported as both enriched and depleted in HNSCC tissue and biospecimen versus that of control [23, 44, 45].”

“Changes in the proportions of these bacteria can cause oral micro-flora dysbiosis and are also associated with all systemic diseases, including cancer [5, 38, 40, 44–47].”

“Previous studies have made efforts to characterize the oral microbiome in several populations (Kilian et al., 2016; Acharya et al., 2017; Sarkar et al., 2017; Xian et al., 2018; Chattopadhyay et al., 2019; Burcham et al., 2020; Rai et al., 2021).”

“Indeed, it is now well described that alterations in the composition and function of the oral microbiota, known as dysbiosis, can contribute to carcinogenesis through various mechanisms [43,44].”

“…and saccharolytic or aciduric species in comparison to non-tumorous paracancerous mucosal tissue (Hooper et al., 2007; Zhao et al., 2017), while the abundance of Streptococcus progressively decreased with the progression of OSCC (Chattopadhyay et al., 2019; Ganly et al., 2019).”

“Oral disorders like as caries, periodontal disease, Pericoronitis, and jaw osteomyelitis are caused by an imbalance of the oral microbiota, which is also linked to cancers, diabetes, rheumatoid arthritis, and cardiovascular disease, all of which have a substantial influence on human health (Chattopadhyay et al., 2019).”

“periodontal pockets in periodontitis provide a stable habitat for the oral microbiota, which enhances hydrogen sulfide production (15).”

“In the oral cavity, where oral cancers such as oral squamous cell carcinoma were present, varieties of bacterial groups [121–129], specific bacteria [36,130], and fungi [131] increased within the oral microbiota.”

“Changes in the oral microbiome have been associated with periodontitis and oral cancer [19], but systemic diseases, including hypertension and obesity [20], also have links with the oral microbiome [21,22].”

“, Fusobacterium and Prevotella), stimulates the production of several cytokines, including interleukin-1ß (IL-1ß) and IL-6, tumour necrosis factor-α (TNF-α), and matrix metalloproteinases (MMPs) [19,48].”

“Prevotella -a taxa dominant both in periodontitis and increasing with BOP severity, has been associated to inflammation sites (Chattopadhyay et al., 2019) and has been identified in oral cancer signatures (Rovery et al.”

“(Chattopadhyay et al., 2019; Karpinski, 2019) Diabetes Capnocytophaga, Pseudomonas, Bergeyella, Sphingomonas, Corynebacterium, Propionibacterium, Neisseria Fusobacterium nucleatum, Eikenella corrodens, Veillonella parvula V. dispar Streptococcus Lactobacilli F. alocis, P. gingivalis, T. forsythia…”

“In patients with oral lichen planus (OLP), the number of Porphyromonas and Solobacterium is higher, and the number of Haemophilus , Corynebacterium , Cellulosimicrobium and Campylobacter is lower than in the healthy population [61].”

“[8] showed that detecting alterations in oral commensal microbial communities is a potential diagnostic tool for OSCC.”

“27 Also, the distance to lymphoid structures, such as the Waldeyer ring, which is an arrangement of tonsils in the oropharynx, differs per site and might influence the TIME.”

“…alters the oral microbiome 8,12,19,41,42 , and perturbations in the oral microbiome have been linked to multiple oral and non-oral diseases 73,74 , these altered microbiomes may well play a role in the development of carcinogenic and/or non-carcinogenic outcomes among tobacco users 4,63,75,76 .”

“…development is complex, and it may include chronic in fl ammation, alteration in cell homeostasis, the release of harmful substances, and compromised host response [95]. chronic inflammation, alteration in cell homeostasis, the release of harmful substances, and compromised host response [95].”

“…(especially K. denitri fi cans ), Neisseria , Abiotrophia , and Capnocytophaga is associated with a reduced risk of laryngeal cancers and the increased abundance of Actinomyces (A. oris) , N. sicca and Veillonella denticariosi species with a reduced risk of pharyngeal and other HNCs (29, 74).”

“12,204 207 F. nuleatum also intensifies TNF-α production from GECs and macrophages, contributing to free radical generation during sepsis.”