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 purposeREVIEW 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 mi￾crobial populations (1) which confer significant benefits. While much of the evidence for the beneficial and homeostatic activities of the resident micro￾biota is derived from studies of the gut, this also informs our understanding of oral ecology and oral hostmicrobe homeostasis. Although beneficial under normal circum￾stances, imbalances in the resident human microbiota, or our responses to them, (dysbiosis) make a major contribu￾tion 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 bal￾ance 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 mod￾ulation of host responses by commensal organisms. Immunomodulation by commensal bacteria Commensal bacteria display pro-inflammatory and anti￾inflammatory activities, and both are important in main￾taining hostmicrobe homeostasis at heavily colonised sites. Some immunomodulatory commensals in the gut (termed autobionts) are able to regulate the activities, de￾velopment, and/or deployment of host immune cells, pro￾viding 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 ap￾propriate balance of intestinal T cell populations (7, 8). In the case of Bacteroides fragilis, extracellular polysacchar￾ide (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)