Microbiolog COACTION REVIEW ARTICLE Modulation of host responses by oral commensal bacteria Deirdre A. Devine", Philip D Marsh and Josephine Meade Department of Oral Biology, School of Dentistry, University of Leeds, Leeds, United Kingdom Immunomodulatory commensal bacteria are proposed to be essential for maintaining healthy tissues, having multiple roles including priming immune responses to ensure rapid and efficient defences against pathogens. The default state of oral tissues, like the gut, is one of inflammation which may be balanced by regulatory mechanisms and the activities of anti-inflammatory resident bacteria that modulate Toll-like receptor (Tlr) signalling or NF-KB activation, or influence the development and activities of immune cells. However, the widespread ability of normal resident organisms to suppress inflammation could impose an unsustainable burden on the immune system and compromise responses to pathogens. Immunosuppressive resident bacteria have been isolated from the mouth and, for example, may constitute 30% of the resident streptococci in plaque or on the tongue. Their roles in oral health and dysbiosis remain to be determined. A wide range of bacterial components and/or products can mediate immunomodulatory activity, raising the possibility of development of alternative strategies for therapy and health promotion using probiotics, prebiotics, or Keywords: immunomodulation; homeostasis; immunosuppression; NFKB inhibition; resident microbiota; dysbiosis; probiotics *Correspondence to: Deirdre A. Devine, Department of Oral Biology, University of Leeds School of Dentistry, Level 7 Wellcome Trust Brenner Building, St. James' University Hospital, Leeds LS9 7TF, United Kingdom, Email: d a.devine@leeds. ac uk Received: 10 December 2014; Accepted: 7 January 2015; Published: 6 February 2015 any human tissues support large, resident mi- Immunomodulation by commensal bacteria crobial populations(1)which confer significant Commensal bacteria display pro-inflammatory and anti benefits. While much of the evidence for the inflammatory activities, and both are important in main- neficial and homeostatic activities of the resident micro- taining host-microbe homeostasis at heavily colonised biota is derived from studies of the gut, this also informs sites. Some immunomodulatory commensals in the gut our understanding of oral ecology and oral host-microbe (termed autobionts)are able to regulate the activities, de- homeostasis. Although beneficial under normal circum- velopment, and/or deployment of host immune cells, pro- stances. imbalances in the resident human microbiota. or viding subtle effects on immune responses and immune our responses to them, (dysbiosis) make a major contribu status(6 tion to the incidence of some significant, multifactorial Effects on cells of the immune system diseases(2,3). The role of dysbiosis in the development Multiple commensal species induce tolerance within the of periodontal diseases and dental caries has long been gut, limiting inflammatory responses by ensuring an ap- recognised, in that they are due to alterations in the bal- propriate balance of intestinal T cell populations (7, 8).In ance and composition of the resident plaque communities. the case of Bacteroides fragilis, extracellular polysacchar- In periodontal diseases, tissue damage occurs due to the ide(PSA)stimulation of CD4+ T cells via TLR-2 is the failure of the immune system to limit both the microbial mechanism, whereby tolerance is induced through initial community and the local host immune response(4, 5). TREG expansion Commensal lactic acid bacteria regulate In health, heavily colonised tissues do not normally enter communication between nK cells and dendritic cells a state of permanent damaging inflammation, and retain thereby helping to direct the adaptive immune response the ability to respond adequately to pathogenic challenges. in the gut (9). In the mouth, neutrophils are key in the It is proposed that this balance is maintained in health by defence of the gingival tissues, and chemokines such homeostatic mechanisms that include regulation or mod CXCLl, 2, and CXCL8(IL-8)establish a gradient ulation of host responses by commensal organisms. neutrophils in gingival tissues and gingival crevicular fluid Joumal of oral micr 5 Deirdre A. Devine et al. This is an Open Access article distributed under the terms of the Creative Commons 1 Attribution-noncommercial3.0unPortedLicensehttp://creativecommons.org/licenses/by-nc/3.0),permittingallnon-commercialusedistributionand CitationJournalofOralMicrobiology2015.7:26941-http://dx.doi.org/10.3402/jom.v7.26941 page number not for citation purpose
REVIEW ARTICLE Modulation of host responses by oral commensal bacteria Deirdre A. Devine*, Philip D. Marsh and Josephine Meade Department of Oral Biology, School of Dentistry, University of Leeds, Leeds, United Kingdom Immunomodulatory commensal bacteria are proposed to be essential for maintaining healthy tissues, having multiple roles including priming immune responses to ensure rapid and efficient defences against pathogens. The default state of oral tissues, like the gut, is one of inflammation which may be balanced by regulatory mechanisms and the activities of anti-inflammatory resident bacteria that modulate Toll-like receptor (TLR) signalling or NF-kB activation, or influence the development and activities of immune cells. However, the widespread ability of normal resident organisms to suppress inflammation could impose an unsustainable burden on the immune system and compromise responses to pathogens. Immunosuppressive resident bacteria have been isolated from the mouth and, for example, may constitute 30% of the resident streptococci in plaque or on the tongue. Their roles in oral health and dysbiosis remain to be determined. A wide range of bacterial components and/or products can mediate immunomodulatory activity, raising the possibility of development of alternative strategies for therapy and health promotion using probiotics, prebiotics, or commensal-derived immunomodulatory molecules. Keywords: immunomodulation; homeostasis; immunosuppression; NFkB inhibition; resident microbiota; dysbiosis; probiotics *Correspondence to: Deirdre A. Devine, Department of Oral Biology, University of Leeds School of Dentistry, Level 7 Wellcome Trust Brenner Building, St. James’ University Hospital, Leeds LS9 7TF, United Kingdom, Email: d.a.devine@leeds.ac.uk Received: 10 December 2014; Accepted: 7 January 2015; Published: 6 February 2015 Many human tissues support large, resident microbial populations (1) which confer significant benefits. While much of the evidence for the beneficial and homeostatic activities of the resident microbiota is derived from studies of the gut, this also informs our understanding of oral ecology and oral hostmicrobe homeostasis. Although beneficial under normal circumstances, imbalances in the resident human microbiota, or our responses to them, (dysbiosis) make a major contribution to the incidence of some significant, multifactorial diseases (2, 3). The role of dysbiosis in the development of periodontal diseases and dental caries has long been recognised, in that they are due to alterations in the balance and composition of the resident plaque communities. In periodontal diseases, tissue damage occurs due to the failure of the immune system to limit both the microbial community and the local host immune response (4, 5). In health, heavily colonised tissues do not normally enter a state of permanent damaging inflammation, and retain the ability to respond adequately to pathogenic challenges. It is proposed that this balance is maintained in health by homeostatic mechanisms that include regulation or modulation of host responses by commensal organisms. Immunomodulation by commensal bacteria Commensal bacteria display pro-inflammatory and antiinflammatory activities, and both are important in maintaining hostmicrobe homeostasis at heavily colonised sites. Some immunomodulatory commensals in the gut (termed autobionts) are able to regulate the activities, development, and/or deployment of host immune cells, providing subtle effects on immune responses and immune status (6). Effects on cells of the immune system Multiple commensal species induce tolerance within the gut, limiting inflammatory responses by ensuring an appropriate balance of intestinal T cell populations (7, 8). In the case of Bacteroides fragilis, extracellular polysaccharide (PSA) stimulation of CD4 T cells via TLR-2 is the mechanism, whereby tolerance is induced through initial TREG expansion. Commensal lactic acid bacteria regulate communication between NK cells and dendritic cells, thereby helping to direct the adaptive immune response in the gut (9). In the mouth, neutrophils are key in the defence of the gingival tissues, and chemokines such as CXCL1, 2, and CXCL8 (IL-8) establish a gradient of neutrophils in gingival tissues and gingival crevicular fluid. ournal of ral icrobiology i r Journal of Oral Microbiology 2015. # 2015 Deirdre A. Devine et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 3.0 Unported License (http://creativecommons.org/licenses/by-nc/3.0/), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 1 Citation: Journal of Oral Microbiology 2015, 7: 26941 - http://dx.doi.org/10.3402/jom.v7.26941 (page number not for citation purpose)
Deirdre A. Devine et al The balance of expression of neutrophil chemokine re- keratinocytes by modulating the activity of IkB-a,an ceptors such as CXCR1, 2, and 4 can also be modulated inhibitor of NFKB (25) by chemokines and cytokines to favour neutrophil cruitment to mucosal tissue or homing to bone marron Effector molecules causing immunosuppression Resident bacteria in subgingival plaque may influence Dissecting the mechanisms underlying the immunomodu- neutrophil deployment by regulating low levels latory, particularly anti-inflammatory, ability of commensal pression of intracellular adhesion molecule 1 (ICAM-1), bacteria will increase understanding of host-microbe home- E-selectin, and CXCL8; oral commensals also promote stasis and health, and may also provide opportunities expression ofIL-1B mRNA in the oral mucosa(10, 11).An for developing therapeutic or health-promoting immuno absolute requirement for CXCR2 in periodontal neutro- modulatory molecules based on microbial components. phil recruitment was recently reported, and commensal colonisation increased the recruitment of neutrophils to Metabolites gingival tissues via the up-regulation of the CXCR2 ligand, Metabolites from commensal bacteria may mediate im- CXCL2(11) munomodulation and contribute to the balance of p and anti-inflammatory responses. Commensal lactobacilli Effects on inflammatory responses with tryptophanase activity generate indole derivatives that can function as aryl hydrocarbon(AhR) ligand Many gut commensal bacteria initiate pro-inflammatory AhR activation promotes anti-inflammatory treg de- responses and contribute to health by stimulating and priming'the immune system(12). Conversely, other com- velopment(26). Short chain fatty acids(SCFAs; e.g mensal organisms inhibit or suppress epithelial cell inflar butyrate, propionate, acetate)are produced by members matory responses by a functional modulation of immunity of the resident microbiota and a range of immune cells are through Toll-like receptor (TLR) or NOD-like receptor targets for SCFA-mediated immunomodulation by act- NLR)expression and signalling, while others suppress ivation of GRP43(which is highly expressed by neutro- inflammatory responses by inhibiting activation of NE-KB phils, macrophages, and monocytes), epigenetic control or by increasing the secretion of anti-inflammatory cyto- via inhibition of histone deacetylases and regulation of kines, such as ILlO (2, 13, 14) autophagy (7, 27, 28) The default position in the gut is thought to be one Proteins and peptides of inflammation, balanced by regulatory mechanisms and Cell-associated and secreted proteins or peptides from the activities of anti-inflammatory, or immunosuppressive various bacterial genera have been linked with immuno- members of the microbiota (3, 15). However, the wide- suppressive abilities. The most studied genus in this re- spread possession of anti-inflammatory ability by resident spect is Lactobacillus, and their abilities to inhibit NeKB mucosal bacteria could be detrimental, by imposing an activation or promote IL-10 secretion have been attrib- unsustainable burden on the host immune system and uted to cell-associated and secreted peptides (14, 29 compromising the ability to respond effectively to patho- The cellular product mediating immunosuppression by wo S. salivarius strains was a secreted peptide of sponses is also a strategy employed by the red comple KDa(21) periodontopathogens Porphyromonas gingivalis and Trepo- nema denticola(4, 17). However, P gingivalis utilises multiple Nucleic acids mechanisms to cause extensive inhibition of local immune Bacterial and viral DNA motifs(detected by TLR3, responses, while the limiting, immunomodulatory effects of TLR7, and TLR9 ) differ in their ability to produce pro- oral commensals are more subtle(11, 18). or anti-inflammatory responses. The genomes of com- Gingival tissues, in a similar manner to the gut, are mensal and probiotic lactobacilli can be enriched in probably normally mildly inflamed (19). Certain strains sequences that are immunosuppressive(15). Unmethy and species of commensal oral streptococci suppress lated CpG motifs from the resident microbiota, recog epithelial cell cytokine expression(13, 20-23). The pro- nised by TlR9, may have a role in maintaining an biotic Streptococcus salivarius K12 down-regulated CXCL8 appropriate balance of ThI/Th2 cells, and in supporting excretion from bronchial, skin, and oral keratinocytes mucosal functions in health(30). Double-stranded RNA (cell lines and primary cells), via inhibition of activation from intestinal lactic acid bacteria induces interferon-P of NFKB(13). Oral strains of S salivarius were later iso- production by dendritic cells via TLR3 activation, thereby lated that suppressed inflammatory responses in pha- promoting anti-inflammatory effects(31). Clustered reg- ryngeal cells (24). A wide range of S. salivarius and ularly interspaced short palindromic repeats(CRISPR) S. vestibularis strains suppressed responses of intestinal sequences are often adjacent to cas genes(CRISPR- epithelial cells and monocyte-like cells via NFKB inhibi- associated), which encode enzymes that can degrade tion, and S. salivarius inhibited inflammation in vivo and inactivate nucleic acids. CRISPR/Cas systems can (21, 22).S. cristatus also inhibited CXCL8 secretion by also affect gene expression in the host bacterium, thereby CitationJournalofOralMicrobiology2015,7:26941-http://dx.doi.org/10.3402/jom.v7.26941 not for citation purpose]
The balance of expression of neutrophil chemokine receptors such as CXCR1, 2, and 4 can also be modulated by chemokines and cytokines to favour neutrophil recruitment to mucosal tissue or homing to bone marrow. Resident bacteria in subgingival plaque may influence neutrophil deployment by regulating low levels of expression of intracellular adhesion molecule 1 (ICAM-1), E-selectin, and CXCL8; oral commensals also promote expression of IL-1b mRNA in the oral mucosa (10, 11). An absolute requirement for CXCR2 in periodontal neutrophil recruitment was recently reported, and commensal colonisation increased the recruitment of neutrophils to gingival tissues via the up-regulation of the CXCR2 ligand, CXCL2 (11). Effects on inflammatory responses Many gut commensal bacteria initiate pro-inflammatory responses and contribute to health by stimulating and ‘priming’ the immune system (12). Conversely, other commensal organisms inhibit or suppress epithelial cell inflammatory responses by a functional modulation of immunity through Toll-like receptor (TLR) or NOD-like receptor (NLR) expression and signalling, while others suppress inflammatory responses by inhibiting activation of NF-kB or by increasing the secretion of anti-inflammatory cytokines, such as IL10 (2, 13, 14). The default position in the gut is thought to be one of inflammation, balanced by regulatory mechanisms and the activities of anti-inflammatory, or immunosuppressive members of the microbiota (3, 15). However, the widespread possession of anti-inflammatory ability by resident mucosal bacteria could be detrimental, by imposing an unsustainable burden on the host immune system and compromising the ability to respond effectively to pathogens (16). Indeed, suppression of host inflammatory responses is also a strategy employed by the red complex periodontopathogens Porphyromonas gingivalis and Treponema denticola (4, 17). However, P. gingivalis utilises multiple mechanisms to cause extensive inhibition of local immune responses, while the limiting, immunomodulatory effects of oral commensals are more subtle (11, 18). Gingival tissues, in a similar manner to the gut, are probably normally mildly inflamed (19). Certain strains and species of commensal oral streptococci suppress epithelial cell cytokine expression (13, 2023). The probiotic Streptococcus salivarius K12 down-regulated CXCL8 secretion from bronchial, skin, and oral keratinocytes (cell lines and primary cells), via inhibition of activation of NFkB (13). Oral strains of S. salivarius were later isolated that suppressed inflammatory responses in pharyngeal cells (24). A wide range of S. salivarius and S. vestibularis strains suppressed responses of intestinal epithelial cells and monocyte-like cells via NFkB inhibition, and S. salivarius inhibited inflammation in vivo (21, 22). S. cristatus also inhibited CXCL8 secretion by keratinocytes by modulating the activity of IkB-a, an inhibitor of NFkB (25). Effector molecules causing immunosuppression Dissecting the mechanisms underlying the immunomodulatory, particularly anti-inflammatory, ability of commensal bacteria will increase understanding of hostmicrobe homeostasis and health, and may also provide opportunities for developing therapeutic or health-promoting immunomodulatory molecules based on microbial components. Metabolites Metabolites from commensal bacteria may mediate immunomodulation and contribute to the balance of proand anti-inflammatory responses. Commensal lactobacilli with tryptophanase activity generate indole derivatives that can function as aryl hydrocarbon (AhR) ligands; AhR activation promotes anti-inflammatory TREG development (26). Short chain fatty acids (SCFAs; e.g. butyrate, propionate, acetate) are produced by members of the resident microbiota, and a range of immune cells are targets for SCFA-mediated immunomodulation by activation of GRP43 (which is highly expressed by neutrophils, macrophages, and monocytes), epigenetic control via inhibition of histone deacetylases and regulation of autophagy (7, 27, 28). Proteins and peptides Cell-associated and secreted proteins or peptides from various bacterial genera have been linked with immunosuppressive abilities. The most studied genus in this respect is Lactobacillus, and their abilities to inhibit NFkB activation or promote IL-10 secretion have been attributed to cell-associated and secreted peptides (14, 29). The cellular product mediating immunosuppression by two S. salivarius strains was a secreted peptide of B3 KDa (21). Nucleic acids Bacterial and viral DNA motifs (detected by TLR3, TLR7, and TLR9) differ in their ability to produce proor anti-inflammatory responses. The genomes of commensal and probiotic lactobacilli can be enriched in sequences that are immunosuppressive (15). Unmethylated CpG motifs from the resident microbiota, recognised by TLR9, may have a role in maintaining an appropriate balance of Th1/Th2 cells, and in supporting mucosal functions in health (30). Double-stranded RNA from intestinal lactic acid bacteria induces interferon-b production by dendritic cells via TLR3 activation, thereby promoting anti-inflammatory effects (31). Clustered regularly interspaced short palindromic repeats (CRISPR) sequences are often adjacent to cas genes (CRISPRassociated), which encode enzymes that can degrade and inactivate nucleic acids. CRISPR/Cas systems can also affect gene expression in the host bacterium, thereby Deirdre A. Devine et al. 2 (page number not for citation purpose) Citation: Journal of Oral Microbiology 2015, 7: 26941 - http://dx.doi.org/10.3402/jom.v7.26941
Modulation of host responses by oral commensal bacteria indirectly affecting immunomodulation, for example, probiotic organisms extend beyond the ability to modulate by down-regulating pro-inflammatory lipoproteins(32). immune responses, to also include enhancement of mucin Although CRISPR/Cas systems have been detected in production and barrier function, induction of antimicro- genomes of the commensal S. mitis, they are not present in bial host defence peptides, promotion of angiogenesis and the closely related pathogen S. pneumoniae(33). Uracil is wound healing. The oral probiotic S salivarius K12, which pro-inflammatory, it is proposed that commensal bacteria secretes bacteriocin-like inhibitory substances, not only do not secrete uracil while pathogens do and that uracil down-regulated epithelial cell inflammatory responses, but secretion is significant in determining host-microbe homeo- also up-regulated hepcidin (an antimicrobial and iron tasis at tissues colonised by bacterial communities(34). regulating peptide), actively stimulated beneficial path ways including type I and Il interferon responses, and Concluding comments exerted significant effects Understanding of the gut microbiome in gastrointes- properties of the host cells(13). An appropriate balance of tinal health or disease has shaped our views of host- immunomodulatory commensals capable of exhibiting a microbiome interactions at other body sites, but it is combination of such beneficial and homeostatic properties important to consider that microbiomes at various sites are may be essential for health distinct from each other and are determined by the unique properties of, and host responses at, each site(35, 36). Acknowledgements Thus, control of the immune response by commensal pop- The authors acknowledge financial support from the Leverhulme ulations is compartmentalised. Darveau(4)has high Trust (DD)and Colgate Palmolive Inc (DD, PDM) lighted the differences between the anatomy and biology of gut epithelial tissues compared with periodontal tissues, Conflict of interest and funding The contribution of oral commensals to the structure There is no conflict of interest in the present study for any and function of periodontal tissues is more subtle than of the authors hose seen in the gut, and the gingival epithelium is more porous and more exposed to microbes References than gut epithelia(11, 18). Thus, while we should learn from data emanating from studies of host responses to the 1. Huttenhower C, Gevers D, Knight R, Abubucker S, Badger Chinwalla AT, et al. Structure, function and diversity of resident gut microbiota and probiotics, it is essential that further studies are carried out with relevant oral 2. Neish AS. icrobes in gastrointestinal health and disease. organisms and tissues in order to better understand oral Gastroenterology 2009: 136: 65-80. host-microbe homeostasis 3. Morgan XC, Segata N, Huttenhower C. Bio The resident communities at each site contribute to unctional genomics in the human microbiome. Trend tissue complexity and have coevolved with their host 4. Darveau RP Periodontitis: a polymicrobial disruption of host to tune host requirements at each site and establish a homeostasis. Nat Rey microbiol 2010: 8: 481-90 threshold of activation required for immune fitness(37) 5. Graves D. Cytokines that promote periodontal tissue destruc- Immunomodulatory commensals are held to be benefi- tion. J Periodontol 2008: 79: 1585-91 6. Ivanov ll. honda k. Intestinal commensal microbes as immune cial via both immunostimulatory and immunosuppres modulators Cell Host Microbe 2012: 12: 496-508. sive mechanisms; most likely, the relative balance of 7. Atarashi K, Tanoue T, Shima T. Imaoka A, Kuwahara T pro-inflammatory and immunosuppressive resident or Momose Y, et al. Induction of colonic regulatory T cells by ganisms is critical for appropriate immune responses in digenous Clostridium species. Science 2011 331:337-41 the mouth and maintenance of host-microbe homeostasis 8. Round JL, Lee SM, Li J. Tran G Jabri B. Chatila TA. et al The Toll-like receptor 2 pathway establishes colonization by a in a manner analogous to that proposed for the gu commensal of the human microbiota Science 2011: 332: 974-7. Up to 30-40% of resident streptococci isolated from the 9. Rizzello V, Bonaccorsi I, Dongarra ML, Fink LN, Ferlazzo G ongue or plaque were able to inhibit CXCL& secretion Role of natural killer and dendritic cell crosstalk in immuno. (largely via inhibition of NFKB)from cells stimulated by modulation by commensal bacteria probiotics. J Biomed flagellin, LL-37 or by oral pathogens such as P. gingivalis Biotechnol 2011: 2011: 473097 and Aggregatibacter actinomycetemcomitans(Devine et al 10. Dixon dr. bainbridge bw darveau rp modulation of the response within the periodontium. Periodontol unpublished observations). The impact of such immuno- 20002004;35:53-74 suppressive populations on host-microbe homeostasis in 11. Zenobia C, Luo XL, Hashim A, Abe T, Jin L, Chang Y, et al. the mouth is unknown, although transient reductions in Commensal bacteria-dependent select expression of CXCL2 CXCL8 secretion in the gCf of individuals with mild contributes to periodontal tissue homeostasis. Cell Microbiol gingival inflammation were demonstrated following use of 2013:15:1419-26 2. Hooper LV, Macpherson AJ. Immune adaptations that chewing gum containing immunosuppressive probiotic tain homeostasis with the intestinal microbiota. Nat R lactobacilli(38). The beneficial effects of commensal or Immunol2010;10:15969 Citation: Joumal of oral gy2015.7:26941·http:/dx.doi.org/10.3402omv7.26941 not for citation purp
indirectly affecting immunomodulation, for example, by down-regulating pro-inflammatory lipoproteins (32). Although CRISPR/Cas systems have been detected in genomes of the commensal S. mitis, they are not present in the closely related pathogen S. pneumoniae (33). Uracil is pro-inflammatory; it is proposed that commensal bacteria do not secrete uracil while pathogens do and that uracil secretion is significant in determining hostmicrobe homeostasis at tissues colonised by bacterial communities (34). Concluding comments Understanding of the gut microbiome in gastrointestinal health or disease has shaped our views of host microbiome interactions at other body sites, but it is important to consider that microbiomes at various sites are distinct from each other and are determined by the unique properties of, and host responses at, each site (35, 36). Thus, control of the immune response by commensal populations is compartmentalised. Darveau (4) has highlighted the differences between the anatomy and biology of gut epithelial tissues compared with periodontal tissues, and the distinct host defence strategies used at each. The contribution of oral commensals to the structure and function of periodontal tissues is more subtle than those seen in the gut, and the gingival epithelium is more porous and more exposed to microbes and their products than gut epithelia (11, 18). Thus, while we should learn from data emanating from studies of host responses to the resident gut microbiota and probiotics, it is essential that further studies are carried out with relevant oral organisms and tissues in order to better understand oral hostmicrobe homeostasis. The resident communities at each site contribute to tissue complexity and have coevolved with their host to tune host requirements at each site and establish a threshold of activation required for immune fitness (37). Immunomodulatory commensals are held to be beneficial via both immunostimulatory and immunosuppressive mechanisms; most likely, the relative balance of pro-inflammatory and immunosuppressive resident organisms is critical for appropriate immune responses in the mouth, and maintenance of hostmicrobe homeostasis in a manner analogous to that proposed for the gut. Up to 3040% of resident streptococci isolated from the tongue or plaque were able to inhibit CXCL8 secretion (largely via inhibition of NFkB) from cells stimulated by flagellin, LL-37 or by oral pathogens such as P. gingivalis and Aggregatibacter actinomycetemcomitans (Devine et al., unpublished observations). The impact of such immunosuppressive populations on hostmicrobe homeostasis in the mouth is unknown, although transient reductions in CXCL8 secretion in the GCF of individuals with mild gingival inflammation were demonstrated following use of chewing gum containing immunosuppressive probiotic lactobacilli (38). The beneficial effects of commensal or probiotic organisms extend beyond the ability to modulate immune responses, to also include enhancement of mucin production and barrier function, induction of antimicrobial host defence peptides, promotion of angiogenesis and wound healing. The oral probiotic S. salivarius K12, which secretes bacteriocin-like inhibitory substances, not only down-regulated epithelial cell inflammatory responses, but also up-regulated hepcidin (an antimicrobial and iron regulating peptide), actively stimulated beneficial pathways including type I and II interferon responses, and exerted significant effects on the cytoskeleton and adhesive properties of the host cells (13). An appropriate balance of immunomodulatory commensals capable of exhibiting a combination of such beneficial and homeostatic properties may be essential for health. Acknowledgements The authors acknowledge financial support from the Leverhulme Trust (DD) and Colgate Palmolive Inc (DD, PDM). Conflict of interest and funding There is no conflict of interest in the present study for any of the authors. References 1. Huttenhower C, Gevers D, Knight R, Abubucker S, Badger JH, Chinwalla AT, et al. Structure, function and diversity of the healthy human microbiome. Nature 2012; 486: 20714. 2. Neish AS. Microbes in gastrointestinal health and disease. Gastroenterology 2009; 136: 6580. 3. Morgan XC, Segata N, Huttenhower C. Biodiversity and functional genomics in the human microbiome. Trends Genet 2013; 29: 518. 4. Darveau RP. Periodontitis: a polymicrobial disruption of host homeostasis. Nat Rev Microbiol 2010; 8: 48190. 5. Graves D. Cytokines that promote periodontal tissue destruction. J Periodontol 2008; 79: 158591. 6. Ivanov II, Honda K. Intestinal commensal microbes as immune modulators. Cell Host Microbe 2012; 12: 496508. 7. Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y, et al. Induction of colonic regulatory T cells by indigenous Clostridium species. 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