Graphical abstract

The field of human microbiome research has undergone a revolution in its approach toward understanding how microorganisms influence the physiology of their host. 1 Development of culture-independent methods has resulted in increased detection and classification of microbial species within microbial communities. 2 technologies, biomarker sequencing, and shotgun metagenomics have become standard tools used to determine the composition and genetic makeup of the human microbiome. 3 Other "-omics" technologies, such as proteomics and metabolomics, support mechanistic hypotheses involved in causal microbial pathways that are related to states of health and disease. 4,5 Since Antonie van Leeuwenhoek first discovered the existence of microbes in the 1700s while analyzing dental plaque under a microscope, the composition of oral microbial communities has been extensively studied. 6 Over 250 species from the oral cavity have been isolated in culture and characterized, including several key pathogens, such as Streptococcus mutans, Porphyromonas gingivalis, Tannerella forsythia, and Aggregatibacter actinomycetemcomitans, involved in the etiology of dental caries and periodontal disease. [7][8][9] An integrated approach toward understanding states of oral disease from the polymicrobial perspective has emerged over time, attributing disease pathology not only to key pathogens but rather to networks of co-occurring microbes, the collective activities of which contribute to pathogenesis. [9][10][11][12] As such, the importance of understanding the divergences, between oral health and disease, in the microbes comprising the system as well as their relative abundance and functional activity, in addition to genetic factors and ecological pressures that drive such changes, is a primary focus of research within the field of oral health research. 9,[13][14][15][16][17] In recent decades, genetic approaches have shed light on the functional capacity of members of oral microbiomes, the mechanistic underpinnings of caries and periodontal disease pathogenesis, and the complex dynamics and fitness factors of key organisms in oral microbiomes. 3,18 The oral microbial ecosystem is constantly exposed to exogenous foreign substances. 17 Such circumstances are defining factors for founding microbes and their ability to persist in this environment, and make for distinct relationships between microbe and host that rely on selective pressures. Pioneer microbial colonizers of the oral cavity, such as Streptococcus mitis, Streptococcus sanguinis, Streptococcus gordonii, and Streptococcus salivarius, display core characteristics that make them well suited to this specific niche as they are able to bind selectively to tongue and cheek cells before the teeth emerge and can outcompete other microbial species. 17,19 Emerging teeth acquire a protective glycoprotein coat, which sets in motion successional microbial colonization, resulting in the development of complex polymicrobial biofilm communities, namely dental plaque. 20 These complex dental plaque m...

Oral and periodontal health impact systemic health, and vice versa.Epidemiologic and large population studies, clinical studies, and in vitro animal studies underscore the critical importance of oral health to systemic health. These inextricable connections come to the forefront as oral diseases, such as periodontal disease, take root. Special at-risk populations bring to bear this bidirectional relationship between oral and systemic health. The concept of a risk or susceptible host, which emerged from the classic longitudinal studies on the natural history of periodontal disease in tea laborers and in studies on identical twins, highlights a genetic basis/predisposition to periodontal disease. 1,2 Thus, in susceptible hosts, as periodontal disease affects major organ systems and conditions (kidney, liver, heart, gastrointestinal tract, respiratory tract, adipose tissue, brain, neuroendocrine system/stress, reproductive system, skeletal system/joints, aging, cancer), associations between periodontal disease and systemic diseases or conditions affecting special populations emerge. Specifically, periodontal disease has been associated with diabetes, metabolic syndrome, obesity, eating disorders, liver disease, cardiovascular disease, Alzheimer disease, rheumatoid arthritis, adverse pregnancy outcomes, and cancer (Figure 1). Although bidirectional relationships are discussed, the potential for multiple comorbidities, relationships, and connections (multimodal relationships) also exists.This 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 is non-commercial and no modifications or adaptations are made.

Epidemiological studies reveal significant associations between periodontitis and oral cancer. However, knowledge about the contribution of periodontal pathogens to oral cancer and potential regulatory mechanisms involved is limited. Previously, we showed that nisin, a bacteriocin and commonly used food preservative, reduced oral cancer tumorigenesis and extended the life expectancy in tumor-bearing mice. In addition, nisin has antimicrobial effects on key periodontal pathogens. Thus, the purpose of this study was to test the hypothesis that key periodontal pathogens (Porphyromonas gingivalis, Treponema denticola, and Fusobacterium nucleatum) promote oral cancer via specific host-bacterial interactions, and that bacteriocin/nisin therapy may modulate these responses. All three periodontal pathogens enhanced oral squamous cell carcinoma (OSCC) cell migration, invasion, tumorsphere formation, and tumorigenesis in vivo, without significantly affecting cell proliferation or apoptosis. In contrast, oral commensal bacteria did not affect OSCC cell migration. Pathogen-enhanced OSCC cell migration was mediated via integrin alpha V and FAK activation, since stably blocking alpha V or FAK expression abrogated these effects. Nisin inhibited these pathogen-mediated processes. Further, Treponema denticola induced TLR2 and 4 and MyD88 expression. Stable suppression of MyD88 significantly inhibited Treponema denticola-induced FAK activation and abrogated pathogen-induced migration. Together, these data demonstrate that periodontal pathogens contribute to a highly aggressive cancer phenotype via crosstalk between TLR/MyD88 and integrin/FAK signaling. Nisin can