Dysbiosis and Host in Periodontics
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This document discusses the complex relationship between the host and microbes in the context of periodontal disease. It addresses three levels of interaction: (1) at the microbial level where controlled inflammation benefits commensals; (2) at the host tissue level where the host responds to biofilm formation through immune and inflammatory factors as well as genetic factors; and (3) at the systemic level where dysbiosis can lead to conditions in other parts of the body. The document questions whether periodontal pathogens are generalists or specialists and whether the goal of treatment is to resolve the infection or the inflammation. It ultimately emphasizes that the host plays a key role in driving pathogen variation and the development of periodontal disease.
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Dysbiosis and Host in Periodontics
- 1. HOST and DYSBIOSIS Dr R VISWA CHANDRA MDS; DNB;PhD
- 2. HOST or MICROBE? Are Periodontopathogens Generalists or Specialists? Baumler A & Fang FC. Host Specificity of Bacterial Pathogens. Cold Spring Harb Perspect Med 2013;3:a010041 The Host as Driver of Pathogen Variation
- 3. MICROBE HOST
- 4. * *Hajishengallis G. Periodontitis: from microbial immune subversion to systemic inflammation. Nat Rev Immunol. 2015 January ; 15(1): 30–44. +Lamont and Hajishengallis. Polymicrobial synergy and dysbiosis in inflammatory diseases. Trends Mol Med. 2015 March ; 21(3): 172–183. Keystone pathogen + Inflammophilic Pathobiont Microbiota feast on ‘inflammatory spoils’ …….in a susceptible host HOST or MICROBE?
- 5. At Microbial Level “Controlled Inflammation” At Host Tissue Level Response to Biofilm Formation Immuno- inflammatory factors Genetic Factors At Systemic Level Dysbiosis in various systemic diseases LEVELS OF HOST SUSCEPTIBILITY Hajishengallis G. Periodontitis: from microbial immune subversion to systemic inflammation. Nat Rev Immunol. 2015 January ; 15(1): 30–44.
- 6. AT MICROBIAL LEVEL “Controlled” inflammation ὰ commensals Roberts FA & Darveau RP (2015) Commensal colonization is NOT REQUIRED to guide neutrophils into the sulcus Rovin S et al (1966); Tonetti MS et al (1994); Roberts FA & Darveau RP (2015) JE is host-defence driven even in the absence of bacterial signals Heymann R et al (2001); Hayashi Y et al (2010) CEACAM1 SLPI
- 7. AT HOST TISSUE LEVEL- Response to Biofilm Formation Roberts FA, Darveau RP. Microbial Protection and Virulence in Periodontal Tissue as a Function of Polymicrobial Communities: Symbiosis and Dysbiosis. Periodontol 2000. 2015 October ; 69(1): 18–27. • HBD3 HBD1 HBD3
- 8. AT HOST TISSUE LEVEL- Immuno-inflammatory factors Uriarte SM et al. (2016); Lira-Junior R & Figueredo CM. (2016); Hajishengallis G & Lamont R . (2016) IL-1β, HBD, LL-37 NET CXCL2 NE/PR3 vs Pg
- 9. AT HOST TISSUE LEVEL- Genetic Factors *Divaris K, et al. Hum. Mol. Genet. 2013; 22:2312–2324 Larsson L et al. J Periodontol 2015;86:556-568..
- 10. At Systemic Level Swallowed P gingivalis Endotoxemia F nucleatum TNF, IL-1ß, IL-6 Reduced oxygen pressure “spillover” Song JY et al. (2014); Topcuoglu et al. (2012); Liu H et al. (2014); Hajishengallis G. (2015) Salivary dysfunction
- 11. How is the host a driver of pathogen variation? Questions Bartold PM & Van Dyke TE. (2013); Baumler A & Fang FC. (2013) Is there such a thing as a periodontal pathogen? Do you resolve the inflammation or the infection?
- 12. THANK YOU
Editor's Notes
- Evidence is strong for the likelihood that the periodontal pathogens identified to date represent commensal organisms that can only cause disease if a change occurs in the host that allows them to flourish, resulting in a microbial shift and leading to association with periodontitis (6). However, whether periodontal pathogens actually cause, or merely associate, with the disease still needs to be determined (23). In host–pathogen interactions, pathogens called generalists are capable of infecting a wide range of host species, whereas others referred to as specialists establish an intimate relationship with only a single-host species. Most pathogens are capable of infecting multiple hosts. HOST SPECIFICITY is very important. The Host as Driver of Pathogen Variation
- Figure 2: Porphyromonas gingivalis-induced dysbiosis and periodontal disease.Porphyromonas gingivalis subverts complement (step 1) and impairs host defence (step 2), leading to overgrowth of oral commensal bacteria, which causes complement-dependent inflammation (steps 3 and 4). Inflammatory tissue destruction (step 5) is favourable to further bacterial growth, as it provides a nutrient-rich gingival inflammatory exudate (containing degraded host proteins and hemin, a source of essential iron). These environmental changes are well exploited by, and thus favour, proteolytic and asaccharolytic bacteria, leading to compositional changes in the bacterial community. Moreover, inflammatory bone resorption (step 6) provides the dysbiotic microbiota with new niches for colonization (step 7). These alterations collectively lead to and sustain periodontal disease. Numbers indicate a possible sequence of events that sets off a self-feeding 'vicious cycle'.
- Polymicrobial synergy and dysbiosis in periodontitis model Periodontitis is induced in susceptible hosts by a polymicrobial community, in which different members fulfil distinct roles that converge synergistically to cause destructive inflammation. Keystone pathogens, the colonization of which is facilitated by accessory pathogens, initially subvert the host response leading to a dysbiotic microbiota, in which pathobionts over-activate the inflammatory response and cause periodontal tissue destruction, including resorption of the supporting alveolar bone. Inflammation and dysbiosis positively reinforce each other because inflammatory tissue breakdown products are used as nutrients by the dysbiotic microbiota. The lower panel depicts the progression from periodontal health (swallow gingival crevice; ≤2 mm) to gingivitis (periodontal inflammation without bone loss; gingival crevice ≤3 mm) to periodontitis (formation of periodontal pockets ≥4 mm and inflammatory bone loss). Polymicrobial synergy and dysbiosis drives periodontitis in a susceptible host • Dysbiosis involves specialized accessory and keystone pathogens and pathobionts • Microbial immune subversion is central to the persistence of dysbiotic communities • The dysbiotic microbiota sustains itself by feasting on the ‘inflammatory spoils Inflammophilic Refers to bacteria that thrive on inflammation as they feed off inflammatory tissue breakdown products; literally meaning attracted to inflammation, from the combined meaning of inflammation and the Greek suffix philic denoting fondness. Pathobiont Commensal with the potential to induce pathology under conditions of disrupted homeostasis. (e.g. Filifactor alocis, Peptostreptococcus stomatis and species from the genera Prevotella, Megasphaera, Selenomonas, and Desulfobulbus. Accessory pathogen S. gordonii
- “controlled” inflammation that Roberts and Darveau stated normally exists in the intestine has been attributed to both the quality and quantity of commensal microorganisms. Indeed studies have revealed that healthy human junctional epithelium, the tissue in closest contact with the polymicrobial oral community, express an interleukin-8 gradient to guide neutrophils through periodontal tissue toward the sulcus, and it was postulated that oral commensal colonization was the stimulus [62]. However, initial studies in germ-free rats demonstrated that neutrophils were found transiting in junctional epithelial tissue, indicating that commensal bacterial colonization was evidently not required for this key protective mechanism. the expression of carcinoembryonic antigen-related cell adhesion molecule-1, a cell adhesion molecule postulated to contribute the structural integrity of this loosely organized tissue, and secretory leukocyte protease inhibitor, a molecule that protects the host from host-mediated protease-induced tissue damage, is specifically expressed in the junctional epithelium, yet studies in germ-free mice demonstrated that bacterial colonization was not required for their expression. These observations demonstrate that certain structural and functional aspects of periodontal tissue, specifically the junctional epithelium, the tissue in closest contact with the oral polymicrobial community, are host developmentally driven even in the absence of bacterial signals.
- Current knowledge of microbial influence on the junctional epithelium based on cumulative data from human and mouse studies. The architecture of junctional epithelium and the presence of neutrophils are similar between germ-free and conventional mice. Several molecules appear to change dramatically with the addition of bacteria but many are unchanged . (B) Overview of current knowledge of microbial influence on the intestinal epithelium. The architecture of the intestinal tissue is changed markedly with the addition of bacteria: the crypts are deeper, the capillary network is more extensive, the mucus layer is reduced, cilia are shorter, and many differences are seen with immune cells and molecules as indicated. The figure indicates the relative location and abundance of innate immune cells/molecules (*indicates changes due to microbial interactions confirmed in germ-free studies.) Furthermore, the expression of carcinoembryonic antigen-related cell adhesion molecule-1, a cell adhesion molecule postulated to contribute the structural integrity of this loosely organized tissue, and secretory leukocyte protease inhibitor, a molecule that protects the host from host-mediated protease-induced tissue damage, is specifically expressed in the junctional epithelium, yet studies in germ-free mice demonstrated that bacterial colonization was not required for their expression
- Probably the defining feature of PSD is Immunosubversion and their priming but if I were to speak about it, it would be be giving a lot of weightage to bacteria over the host factors. . Priming of neutrophils is understood as the enhanced functional response of the cell to a stimulus by previous exposure of the cell to a priming agent. Priming agents can be host-derived, like different cytokines or chemokines, such as TNFα, IL-1β, IFNα, IL-8, growth factors like GM-CSF, or bacterial-derived compounds like lipopolysaccharide (LPS). F. alocis is a Pathobiont F nucleatum is an accessory pathogen 1. Overall, several host-derived mediators contribute to a healthy periodontium. The specialized junctional epithelium participates in the release of antimicrobial peptides, like βdefensins and LL-37, which helps to maintain less diverse bacterial community that has been associated with a healthy periodontium. Bacterial presence constantly stimulates the release of IL-8 from the gingival epithelium, which generates a chemotactic gradient that continually guides neutrophils to the gingival sulcus (Fig. 2A). In addition, the local oral symbiotic microbial community induces the production of IL-1β,48 which can prime the immune system and generates a state of mild inflammation which is linked to promoting immune fitness 2. human neutrophils cope with the ‘nososymbiocity’ of periodontitis- Hajishengallis G, Lamont RJ. Dancing with the stars: how choreographed bacterial interactions dictate nososymbiocity and give rise to keystone pathogens, accessory pathogens, and pathobionts. Trends Microbiol. 2016; 24:477–489. [PubMed: 26968354] To protect against the collateral damage that neutrophil antimicrobial serine proteases such as NE and PR3 may cause the host tissue, endogenous protease inhibitors are present in the gingival tissue such as secretory leukocyte protease inhibitor (SLPI) and elafin. Analysis of crevicular fluids from chronic periodontitis patents reveals significantly lower levels of SLPI with concomitant higher activity of both NE and PR3 activity compared to periodontal healthy controls.74 Moreover, the keystone periodontal pathogen, P. gingivalis , has several virulence factors that tip the balance in favor of dysbiosis and host tissue damage. An exemplary type of virulence factor is the secreted cysteine proteolytic enzymes called gingipains. One of the many properties that makes P. gingivalis gingipains so successful is the ability to inactivate the endogenous protease inhibitors. The level of cell activation is the result of a range of increasing degree of activation states instead of an on/of switch mechanism, with priming being a reversible step that modulates neutrophils graded response to an insult. 3. importance of salivary effector functions in the preservation of a homeostatic environment, especially in the context of CGD. Not only does saliva diligently control the number of bacteria that accumulates on the tooth surface via several components with antimicrobial activity, but in response to saliva, neutrophils from healthy and CGD patents can form neutrophil extracellular traps (NETs). 4. As shown in knockout mice, the chemotactic receptor CXCR2 facilitates neutrophil recruitment to the periodontal tissue. This was found since neutrophils are absent in the junctional epithelium of CXCR2 knockout mice while the cells are present in the blood vessels. Interestingly, both CXCL1 and CXCL2, ligands of the CXCR2 receptor, are expressed in the junctional epithelium of GF mice; however, only a significant increase on CXCL2 expression levels, not of CXCL1, is observed in the epithelium of SPF mice when compared to the GF. The presence of the indigenous oral bacterial community enhanced neutrophil recruitment to the periodontal tissue by selectively stimulating the expression of the potent neutrophil chemokine CXCL2.16 In a recent study, Greer et al.21 compare the expression levels of CXCL2 and neutrophil location in different areas of the junctional epithelium across the tooth, among GF, SPF and GF mice which were gavaged with single commensal oral bacteria like Streptococcus sp. or Lactobacillus sp.21 Neutrophils show a similar location pattern in the periodontium of the SPF mice 5. Furthermore, Park et al[60] have used a T-cell transfer model of IBD, using CD4+CD45RBHigh T cells, to assess the alveolar bone metabolism. It was found that this T cell subset was sufficient for the induction of alveolar bone resorption. adapted from Gemmell & Seymour Gonasales 6. Moreover, the inflamed environment with broken homeostasis favors the overgrowth of some bacterial species called ‘infammophilic’ or pathobionts which have a fitness advantage and will try to preserve inflammation at all cost.70 One such emerging pathogen is F. alocis, a gram-positive anaerobic rod. Although cultivable, this organism is slow-growing and difficult to detect by conventional culture-based methodologies. Nonetheless, it is becoming increasingly apparent that the presence of F. alocis is indicative of oral disease, as the organism has been detected significantly more frequently and in higher numbers at periodontal disease sites compared with healthy sites. 7. e environment, such as smoking, diabetes, stress, antbiotic therapy, or colonization by keystone periodontal pathogens, the majority of the microbial composition identified in health will encounter a hostle niche
- Contemporary model of host–microbe interactions in the pathogenesis of periodontitis, in which the host response drives an incipient dysbiosis (gingivitis). If the biofilm is not disrupted/removed, frank dysbiosis results and perpetuates a chronic nonresolving and destructive. Although a genetic basis for periodontitis is supported by twin studies and familial aggregation of severe forms of the disease, the implication of identified specific genes — such asAlthough a genetic basis for periodontitis is supported by twin studies and familial aggregation of severe forms of the disease, the implication of identified specific genes — such as IL1, IL6, TNF, FCGR2A, C5, CD14, WNT5A — is debatable. This uncertainty is probably attributed to the fact that chronic periodontitis is a polygenic disease, in which multiple genes contribute cumulatively to the overall disease risk (or protection) by influencing the host immune response and the microbiota composition and structure155. This notion stands in stark contrast to monogenic forms of the disease, such as aggressive periodontitis in young patients with leukocyte adhesion deficiency, where a single gene (ITGB2, encoding integrin β-2) invariably precipitates periodontal diseases. The subgingival presence and pathogenic relevance of specific bacteria and strains such as A. actinomycetemcomitans JP2 clone is probably modulated by age but is under a strong host genetic influence, as testified by the prevalence of this clone in people of specific ethnicity, not necessarily dependent on their geographic origin. Many biologists from the nineteenth century believed that inheritance and development was one and the same. This theory was ignored for many years until it resurfaced and flourished in the twentieth century. Conrad Waddington, a professor of "Genetics at Edinburgh University" first coined the word epigenetics from the Greek word epigenesist. DNA methylation is noted as chemical reactions that add a methyl group to a DNA molecule (hypermethylation) and demethylation (hypomethylation) as the removal of a methyl group from DNA (Yehuda & Bierer, 2009). It was found that with methylation, demethylation and acetylation, deacetylation or any combination of these worked to either express or repress genes during replication. It was found that these processes were key factors in inflammatory and neoplastic diseases. These processes triggered by environmental influences regulated cytokines such as IL-1 and IL-6 which were responsible for inflammatory tissue destruction as seen in chronic periodontitis (Wilson, 2008). Epigenetics: environmental factors to induce changes in epigenetic regulatory mechanisms of the immune response (Fig. 4). Knowledge of the role of epigenetics in development of periodontal diseases is still limited, but the studies presented in this review highlight that both DNA methylation and histone modifications occur in the oral mucosa in response to bacteria and the inflammatory processes.
- P and IBD: Large quantities of oral bacteria are constantly swallowed on a daily basis via the saliva into the gut. In this context, an alternative, or additional, mechanism linking periodontitis to systemic inflammation was recently proposed: Swallowed P. gingivalis causes alterations to the gut microbiota, thereby leading to increased gut epithelial permeability and endotoxemia, which causes systemic inflammation. independent, the depicted events are not mutually exclusive but could in principle occur simultaneously. CRP, C-reactive protein; IL, interleukin; TNF, tumor necrosis factor. Other periodontal bacteria such as Fusobacterium nucleatum have been detected in the placenta where they can cause adverse pregnancy outcomes. The pathogenesis of OME appears to be multifactorial, including immature anatomy, initiating viral infections that induce eustachian tube dysfunction, retrograde movement of bacteria from the oropharynx into the middle ear cavity, and host physiological factors (5). Eustachian tube dysfunction may create reduced oxygen pressure in the middle ear cavity and therefore this environmental change may favor the growth of anaerobes. Esophagio salivary relex maintains salivary volume and salivary volume is decreased in GERD. Acidic reflux plus biofilm formation
- As different hosts represent different environmental niches, the fitness of a pathogen may vary from host to host. Different strains of a pathogen that are highly adapted to specific hosts may evolve in what is referred to as polymorphism. As early as 1988, Genco and co-workers published a paper considering the origin of periodontal infections (27). In this paper, the authors described how it is important to determine whether the source of periodontal organisms is indigenous or exogenous. Such approaches are consistent with the principles of the ecological plaque hypothesis and represent a treatment aimed at restricting the nutrient supply to the periodontal pathogens within the commensal subgingival flora through resolving inflammation and promoting healing and health (56). By altering the subgingival environment, the subgingival flora can be manipulated. GPR. JP2 clone of AA Complex………