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 purpindirectly 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 homeo￾stasis at tissues colonised by bacterial communities (34). Concluding comments Understanding of the gut microbiome in gastrointes￾tinal 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 pop￾ulations is compartmentalised. Darveau (4) has high￾lighted 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 benefi￾cial via both immunostimulatory and immunosuppres￾sive mechanisms; most likely, the relative balance of pro-inflammatory and immunosuppressive resident or￾ganisms 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 immuno￾suppressive 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 antimicro￾bial 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 path￾ways 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 destruc￾tion. 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. Science 2011; 331: 33741. 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 commensal of the human microbiota. Science 2011; 332: 9747. 9. Rizzello V, Bonaccorsi I, Dongarra ML, Fink LN, Ferlazzo G. Role of natural killer and dendritic cell crosstalk in immuno￾modulation by commensal bacteria probiotics. J Biomed Biotechnol 2011; 2011: 473097. 10. Dixon DR, Bainbridge BW, Darveau RP. Modulation of the innate immune response within the periodontium. Periodontol 2000 2004; 35: 5374. 11. Zenobia C, Luo XL, Hashim A, Abe T, Jin L, Chang Y, et al. Commensal bacteria-dependent select expression of CXCL2 contributes to periodontal tissue homeostasis. Cell Microbiol 2013; 15: 141926. 12. Hooper LV, Macpherson AJ. Immune adaptations that main￾tain homeostasis with the intestinal microbiota. Nat Rev Immunol 2010; 10: 15969. Modulation of host responses by oral commensal bacteria Citation: Journal of Oral Microbiology 2015, 7: 26941 - http://dx.doi.org/10.3402/jom.v7.26941 3 (page number not for citation purpose)