Periodontal studies using transcriptomics, proteomics, and metabolomics encompass the collection of mRNA transcripts, proteins, and small‐molecule chemicals in the context of periodontal health and disease. The number of studies using these approaches has significantly increased in the last decade and they have provided new insight into the pathogenesis and host‐microbe interactions that define periodontal diseases. This review provides an overview of current molecular findings using ‐omic approaches that underlie periodontal disease, including modulation of the host immune response, tissue homeostasis, and complex metabolic processes of the host and the oral microbiome. Integration of these ‐omic approaches will broaden our perspective of the molecular mechanisms involved in periodontal disease, advancing and improving the diagnosis and treatment of various stages and forms of periodontal disease.

The oral cavity contains up to 1000 microbial species in total, comprised of bacteria, fungi, viral, archaea, and protozoan species that thrive in a very dynamic microenviroment. [1][2][3][4][5] All of these microorganisms form a complex relationship among themselves, establishing a unique microbiome, known as the oral microbiome. Interestingly, the oral microbiome forms a close symbiotic relationship with human host cells in the oral cavity. Thus, the term oralome was coined to encompass not only the oral microbiome but also the host-microbial interactions that take place in the human oral cavity. 5 In this sense, healthy symbiotic host-microbiome interactions between humans and these microorganisms are known as eubiosis. [5][6][7] The microbial composition can be dramatically affected by interspecies and host-microbial interactions. These microbial changes can impact the health and disease status of the host, since eubiosis plays an essential role both in the development of natural oral physiology and host defense mechanisms. 5,8,9 Although the oral microbiome can compensate for most overall perturbations, 5,10 some changes can profoundly affect its composition, impacting the oral commensal populations and causing an unbalanced state known as dysbiosis. 5,11 | Periodontitis and oral microbiome dysbiosisDysbiosis is an unbalanced microbiome state that is caused by internal and/or external microbial-ecologic changes to the oral microbiome. 5 This specific state has been described as capable of promoting diseases in the host. 12,13 Since periodontitis is considered an inflammatory disease that is initiated by pathogenic bacteria, the most accepted hypothesis for periodontitis initiation and progression is that there is a dysbiotic shift in the oral microbiome. 5,14 This shift is driven by an enrichment of Prevotella intermedia, Fusobacterium nucleatum, Porphyromonas gingivalis, Tannarella forsythia, and Treponema denticola species in the microbiome. [14][15][16] Specifically, a dysbiotic oral biofilm infiltrates the gingival pocket, which then triggers the host immune response. This reaction leads to gingival tissue inflammation (gingivitis) and, ultimately, tissue degradation and periodontitis. 14 Oral dysbiosis has been associated with a variety of systemic diseases and conditions, including Alzheimer's disease, diabetes, adverse pregnancy complications, and several types of cancer, including oral, gastrointestinal, lung, breast, prostate, and uterine cancer. 5,[17][18][19][20] Thus, the objective of this research is to (1) evaluate the epidemiologic evidence linking periodontitis to these types of cancer, (2) provide insights into the mechanisms by which oral microbial dysbiosis can cause these cancers, and (3) summarize the evolving evidence supporting the use of probiotics and related moleculesThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use...

Periodontal disease is driven by dysbiosis in the oral microbiome, resulting in over-representation of species that induce the release of pro-inflammatory cytokines, chemokines, and tissue-remodeling matrix metalloproteinases (MMPs) in the periodontium. These chronic tissue-destructive inflammatory responses result in gradual loss of tooth-supporting alveolar bone. The oral spirochete Treponema denticola (T. denticola), is consistently found at significantly elevated levels in periodontal lesions. Host-expressed Toll-Like Receptor 2 (TLR2) senses a variety of bacterial ligands, including acylated lipopolysaccharides and lipoproteins. T. denticola dentilisin, a surface-expressed protease complex comprised of three lipoproteins has been implicated as a virulence factor in periodontal disease, primarily due to its proteolytic activity. While the role of acylated bacterial components in induction of inflammation is well-studied, little attention has been given to the potential role of the acylated nature of dentilisin. The purpose of this study was to test the hypothesis that T. denticola dentilisin activates a TLR2-dependent mechanism, leading to upregulation of tissue-destructive genes in periodontal tissue. RNA-sequencing of periodontal ligament cells challenged with T. denticola bacteria revealed significant upregulation of genes associated with extracellular matrix organization and degradation including potentially tissue-specific inducible MMPs that may play novel roles in modulating host immune responses that have yet to be characterized within the context of oral disease. The Gram-negative oral commensal, Veillonella parvula, failed to upregulate these same MMPs. Dentilisin-induced upregulation of MMPs was mediated via TLR2 and MyD88 activation, since knockdown of expression of either abrogated these effects. Challenge with purified dentilisin upregulated the same MMPs while a dentilisin-deficient T. denticola mutant had no effect. Finally, T. denticola-mediated activation of TLR2/MyD88 lead to the nuclear translocation of the transcription factor Sp1, which was shown to be a critical regulator of all T. denticola-dependent MMP expression. Taken together, these data suggest that T. denticola dentilisin stimulates tissue-destructive cellular processes in a TLR2/MyD88/Sp1-dependent fashion.

The periodontal complex consists of the periodontal ligament (PDL), alveolar bone, and cementum, which work together to turn mechanical load into biological responses that are responsible for maintaining a homeostatic environment. However oral microbes, under conditions of dysbiosis, may challenge the actin dynamic properties of the PDL in the context of periodontal disease. To study this process, we examined host-microbial interactions in the context of the periodontium via molecular and functional cell assays and showed that human PDL cell interactions with Treponema denticola induce actin depolymerization through a novel actin reorganization signaling mechanism. This actin reorganization mechanism and loss of cell adhesion is a pathological response characterized by an initial upregulation of RASA4 mRNA expression resulting in an increase in matrix metalloproteinase-2 activity. This mechanism is specific to the T. denticola effector protein, dentilisin, thereby uncovering a novel effect for Treponema denticola-mediated RASA4 transcriptional activation and actin depolymerization in primary human PDL cells.

Periodontal disease is driven by dysbiosis of the oral microbiome, resulting in over-representation of species that induce the release of pro-inflammatory cytokines, chemokines, and tissue-remodeling matrix metalloproteinases (MMPs) in the periodontium. These chronic tissue-destructive inflammatory responses result in gradual loss of tooth-supporting alveolar bone. The oral spirochete Treponema denticola, is consistently found at significantly elevated levels in periodontal lesions. Host-expressed Toll-Like Receptor 2 (TLR2) senses a variety of bacterial ligands, including acylated lipopolysaccharides and lipoproteins. T. denticola dentilisin, a surface-expressed protease complex comprised of three lipoproteins has been implicated as a virulence factor in periodontal disease, primarily due to its proteolytic activity. While the role of acylated bacterial components in induction of inflammation is well-studied, little attention has been given to the potential role of the acylated nature of dentilisin. The purpose of this study was to test the hypothesis that T. denticola dentilisin activates a TLR2-dependent mechanism, leading to upregulation of tissue-destructive genes in periodontal tissue. RNA-sequencing of periodontal ligament cells challenged with T. denticola bacteria revealed a significant upregulation of genes associated with extracellular matrix organization and degradation, including tissue-specific inducible MMPs that may play novel roles in modulating host immune responses yet to be characterized within the context of oral disease. The Gram-negative oral commensal, Veillonella parvula, failed to upregulate these same MMPs. Dentilisin-induced upregulation of MMPs was mediated via TLR2 and MyD88 activation, since knockdown of either TLR2 or MyD88 abrogated these effects. Challenge with purified dentilisin upregulated the same MMPs, whereas a dentilisin-deficient T. denticola mutant had no effect. Finally, T. denticola-mediated activation of TLR2/MyD88 led to the nuclear translocation of the transcription factor Sp1, which was shown to be a critical regulator of all T. denticola-dependent MMP expression. Taken together, these data support that T. denticola dentilisin stimulates tissue-destructive cellular processes in a TLR2/MyD88/Sp1-dependent fashion.AUTHOR SUMMARYPeriodontal disease is driven by dysbiosis of the oral microbiome, which interacts with host tissues and thereby induces the release of pro-inflammatory cytokines, chemokines, and tissue-remodeling matrix metalloproteinases (MMPs), leading to destruction of the periodontal tissues. Even after clinical intervention, patients with severe periodontal disease are left with a persistent pro-inflammatory transcriptional profile throughout the periodontium. The oral spirochete, Treponema denticola, is consistently found at elevated levels in periodontal lesions and is associated with several pathophysiological effects driving periodontal disease progression. The T. denticola surface-expressed protease complex (dentilisin) has cytopathic effects consistent with periodontal disease pathogenesis. To date, few direct links have been reported between dentilisin and the cellular and tissue processes that drive periodontal tissue destruction at the transcriptional and/or epigenetic levels. Here, we utilize wild type and dentilisin-deficient T. denticola as well as purified dentilisin to characterize dentilisin-dependent activation of intracellular pathways controlling MMP expression and activity. Our results define a role for dentilisin in initiating this signal cascade. Also, our study identified tissue-specific inducible MMPs that may play novel roles in modulating as-yet uncharacterized host responses in periodontal disease. Lastly, T. denticola dentilisin stimulates tissue-destructive cellular processes in a TLR2/MyD88/Sp1-dependent fashion. Taken together, our study provides new insights into the molecular mechanisms underpinning periodontal disease progression which could lead to the development of more efficacious therapeutic treatments.