Looking in the Porphyromonas gingivalis’ Cabinet of Curiosities: The Microbium, the Host and Cancer Association

The past decades of biomedical research have yielded massive evidence for the contribution of microbiome in the development of a variety of chronic human diseases. There is emerging evidence that Porphyromonas gingivalis, a well-adapted opportunistic pathogen of the oral mucosa and prominent constituent of oral biofilms, best known for its involvement in periodontitis, may be an important mediator in the development of a number of multifactorial and seemingly unrelated chronic diseases, such as rheumatoid arthritis and orodigestive cancers. Orodigestive cancers represent a big portion of the total malignancies worldwide, and include cancers of the oral cavity, gastro-intestinal tract, and pancreas. For prevention and/or enhanced prognosis of these diseases, a good understanding of the pathophysiological mechanisms and the interaction between P. gingivalis and host is much needed. With this review, we introduce the currently accumulated knowledge on P. gingivalis’ plausible association with cancer as a risk modifier, and present the putative cancer promoting cellular and molecular mechanisms that this organism may influence in the oral mucosa. “Knowledge is made by oblivion, and to purchase a clear and warrantable body of truth, we must forget and part with much we know” Sir Thomas Browne (1605–1682) Introduction The last few decades of biomedical research have accumulated a large knowledge base on the etiopathogenic mechanisms of numerous chronic diseases and conditions of man. In many of these chronic pathologies, bacteria have been shown to play a major role either as singular etiologic factors, or as synergistic contributors in the multifaceted stimulation of the host immune system that can tip the scales towards chronic or autoimmune disease development. Recent advances in metagenomic tools have heightened the importance of resident microbiome in mammalian development, metabolism, immune response and behavior during all stages of life, which has led to the initiation of several world-wide projects to determine the species diversity and genetic make-up of the human microbiome in health and disease (Diaz Heijtz et al., 2011, Cox et al., 2013, Erturk-Hasdemir & Kasper, 2013, Guinane & Cotter, 2013, Mavrommatis et al., 2013, Ridaura et al., 2013). Multiple specific examples may be given for the growing role of the human microbiome in development of chronic pathological conditions. These include chronic inflammatory diseases of the lung, liver, cardiovascular and digestive systems, as well as of periodontium (Berry & Reinisch, 2013, Chassaing et al., 2013). The human microbiome contains a number of adaptable pathogenic species that are now identified to be closely involved in the etiology of various chronic diseases. One of the best documented examples is a Gram-negative bacterium, Helicobacter pylori, primarily known for its involvement in gastric and gastro-intestinal cancers, and more recently in other chronic diseases, including asthma, type2 diabetes, and obesity (Wang et al., 2013). Furthermore, increasing evidence suggests that the establishment of a variety of chronic diseases could result from a polymicrobial interactions within the underlying microbiome, in concert with host genetic and metabolic risk factors (Michaud, 2013, Wroblewski et al., 2010, Fox & Sheh, 2013). The human body represents a multitude of mucosal sites, each comprising a specific milieu of highly adapted, commensal and opportunistic-pathogen organisms. One of the most complex and highly variable communities is the oral microbiome, which has long been implicated in the development of tooth decay and periodontal disease (Jenkinson, 2011). The oral microbiome represents a unique and vastly dynamic multidimensional biochemical network, formed by the interaction among the proteomes and metabolomes of the comprising organisms, the behavioral, hygienic and dietary habits of the host, and the genetic and immunologic host factors (Jenkinson, 2011, Khalili, 2008, Teles et al., 2013, Wright et al., 2013). Some of these interactions yield potentially pathogenic compounds that may have effect on the mucosal lining, the surrounding tissues and even on the distant organs and systems of the body (Hooper et al., 2009, Jenkinson, 2011, Ahn et al., 2012a). Those noxious metabolic products or molecules include lipids, lipopolysaccharides (LPS), free oxygen and nitrogen radicals, pro-inflammatory mediators and host and/or bacteria derived enzymes. Hence, the oral microbiome has been proposed to impact the etiology and progression of diabetes, cardiovascular disease, and lately a number of studies have indicated the association among distinct consortia of microbial species, periodontal disease and orodigestive cancers (Koren et al., 2011, Ahn et al., 2012a, Meyer et al., 2008). The evidence accumulated from those studies has specified strong correlation among a number of chronic periodontal bacteria containing Prevotella, Porphyromonas Fusobacterium, and Streptococcus spp., and squamous cell carcinoma of the orodigestive tract, which encompasses the oral cavity, gastro-intestinal tract and pancreas (Nagy et al. 1998, Mager et al., 2005,, Ahn et al., 2012b). Among these specific species, an opportunistic pathogen, Porphyromonas gingivalis, has emerged as a potential mediator in the etiology of a variety of presumably unrelated chronic diseases, such as rheumatoid arthritis, cardiovascular diseases, diabetes, and more recently different types of orodigestive cancers (Ahn et al., 2012b, Hitchon et al., 2010, Totaro et al., 2013, Ishikawa et al., 2013, Aemaimanan et al., 2013, Katz et al., 2011,, Michaud, 2013, Hajishengallis et al., 2012). In the case of rheumatoid arthritis, P. gingivalis’ peptidylarginine deiminase (PAD) has been recently suggested to assume a key role in the citrullination of arginine residues in host proteins, thus altering their normal folding and creating conditions for the induction of auto-antibodies against host cartilage-specific antigens. P. gingivalis’ ability to activate host matrix metalloproteases (MMPs) and the organisms’ role in altering cytokine responses have also been implicated in the protein degradation, observed in arthritic joints (Mangat et al., 2010, Hitchon et al., 2010, Detert et al., 2010). Conjointly, prolonged systemic cytokine elevation and inflammation have been especially attributed to P. gingivalis in the context of the multifactorial periodontal disease as contributing and/or amplifying factor in the development and progression of diabetes mellitus. The poor glycemic control in diabetes, on the other hand, has been shown to exacerbate chronic periodontitis (Lalla & Papapanou, 2011). A significant statistical association has been also observed between P. gingivalis-carriage in saliva samples and non-alcoholic fatty liver disease, further strengthening P. gingivalis’ role as a risk factor in multiple chronic conditions (Yoneda et al., 2012). On the cancer front, multiple clinical and experimental studies have displayed various degrees of associations between P. gingivalis and cancers of the oral cavity, orodigestive tract or pancreatic tissues (Katz et al., 2011, Groeger et al., 2011, Michaud, 2013, Michaud et al., 2012, Ahn et al., 2012b). P. gingivalis, which has been shown to have the plenitude of virulence factors, can also be present in healthy individuals’ periodontal pockets, affluently survives within oral epithelial tissues, and is successfully able to evade the host immune response (Yilmaz, 2008, Choi et al., 2013, Yilmaz et al., 2008, Singh et al., 2011, Yao et al., 2010, Yilmaz et al., 2010). Accordingly, P. gingivalis has recently been attributed as a key-stone pathogen based on its ability to orchestrate inflammatory disease by remodeling the oral microbiome (Hajishengallis et al., 2012). P. gingivalis, can invade primary cultures of oral epithelial cells (OECs), render them resistant to cell death, and alter the chemokine and cytokine secretion (Spooner & Yilmaz, 2011, Choi et al., 2013, Yilmaz et al., 2010, Yao et al., 2010, Hung et al., 2013, Takeuchi et al., 2013). OECs that form the outer lining of the oral mucosa are the initial targets for colonizing bacteria, and stand an important arm of the host innate immune response by secreting antimicrobial, pro-inflammatory and chemotactic signals, and modulating apoptosis upon sensing invading organisms (Takeuchi et al., 2013, Yilmaz et al., 2010, Hung et al., 2013). Therefore, the ability of P. gingivalis to colonize in the oral cavity and modulate both the epithelial cell and systemic responses potentially places the organism not only in the category of central contributors in the multifactorial etiology of the periodontal disease, but also orodigestive cancers and other chronic diseases (Figure 1). Figure 1 Schematic representation of the complex interrelationships between different human genetic, behavioral and immunologic factors, as well as microbiome-related factors, that are proposed to take part in the multifactorial etiology of orodigestive cancers ... The prospective multiple roles of P. gingivalis in the above mentioned conditions, however, remain incomplete and there is a clear need for mechanistic determination of these newly observed associations in order to better understand and possibly control those severe chronic conditions. Therefore, this review aims to offer a fresh perspective on the putative role of P. gingivalis in the orodigestive cancers, and its plausible use as a biomarker for the identification of at “high-risk” populations.