Epigenetics: New Explanations for Old Problems?

Surveillance Spotlight: Current Concepts in Oral–Systemic Health

The International Centre for Oral–Systemic Health, based at the University of Manitoba’s faculty of dentistry, was launched in January 2008. The centre is proud to partner with JCDA to provide summaries of contemporary literature and news in oral–systemic health that may affect modern dental practice

In previous columns, I discussed the importance of considering the role of oral biofilms and systemic inflammatory burden when studying the link between periodontal disease and chronic inflammatory diseases or conditions.^1,2 As our scientific knowledge continues to grow, additional potential mechanisms linking the biofilm to disease processes are being described. Epigenetics is perhaps the most exciting new field of investigation in this area, and it is starting to change the way we think about mechanisms of disease, individual susceptibility and response to treatment.^3,4

Epigenetics refers to changes in gene expression that are not mediated by alterations of the genetic code itself (mutations). Epigenetic changes are caused by biochemical modifications of the nucleotide bases that alter the 3-dimensional structure of DNA, thereby preventing the genetic code from being read (silencing or reducing gene expression). Thus, epigenetic changes cause some genes that were previously expressed to become hidden or less accessible to the transcription system that converts the genetic code into functional proteins.

In the case of biofilm bacteria, epigenetic changes in host tissue are often very specific for certain genes that are important for tissue resistance to colonization and breakdown. For infectious and inflammatory processes like periodontal disease, these changes often take the form of shutting down host defenses or lowering resistance to tissue breakdown. It is important to note that once epigenetic changes occur, they are conserved during cell division and the host tissue is permanently altered.

The oral biofilm is a unique structure that undergoes a maturational process characterized by early colonizers, intermediate colonizers (orange complex bacteria) and late colonizers (red complex bacteria). The early colonizers create an appropriate environment for late colonizers to thrive. Bacteria within the biofilm communicate with each other and resist host defenses and antibiotics. The orange and red complex bacteria (especially Porphyromonas gingivalis and Campylobacter rectus) appear to be the most virulent as they tend to be ulcerative, release toxins that kill immune cells and avoid the lymphatic system. Because gingival tissue is highly vascular, the circulating blood serves as a systemic portal of entry.

Recent evidence indicates that certain orange and red complex bacteria (especially C. rectus) can cause epigenetic changes in cells and tissues.³ The organisms gain significant survival advantages as these changes shut down genes involved in local defenses and healing (facilitating colonization and dissemination), in the regulation of vascular endothelial function (decreasing tissue perfusion and increasing inflammatory damage), and in host metabolism (providing bacteria with more carbohydrates to fuel growth and reproduction).

These findings will have a direct bearing on the traditional clinical indices (e.g., plaque index, gingival index or bleeding on probing, pocket depth, loss of attachment) and risk factors (smoking, genetics, systemic disease and age) used to diagnose periodontal disease and identify patients at risk. We may need to consider a completely new paradigm based on individualized medicine that will take into consideration biofilm, persistence of orange or red complex bacteria, bleeding regardless of pocket depth (or lack of bleeding with deep pockets) and epigenetic modification of the periodontal tissues.

Epigenetic changes in periodontal tissues may facilitate the rapid reestablishment of a virulent biofilm and may help to explain refractory cases of periodontitis. In such cases, periodontal surgery might be justified if it is deemed beneficial to remove epigenetically modified tissues that may serve to maintain active disease.

In addition to epigenetic modification of local periodontal tissues, biofilm bacteria (especially C. rectus) have also been shown to cause alterations in target tissues throughout the body.³ The most notable example involves the placenta, where epigenetic changes have been linked to adverse pregnancy outcomes. It appears that C. rectus causes changes in the developing placenta that impair perfusion, causing inflammation which leads to contraction of uterine smooth muscle, membrane rupture and neonatal inflammatory syndrome. C. rectus is an important “abortive” organism in veterinary medicine (especially within the equine industry) and new data link exposure to a 3-fold risk in humans.³ In addition, C. rectus has beenshown to reduce growth factor expression in utero, which may be a major factor in fetal growth restriction.

The importance of epigenetics in the pathogenesis of diseases is likely to be as significant as that of traditional genetic mutations. With advances in technology, our understanding of this area of biology is increasing rapidly, and emerging evidence suggests that epigenetic modification plays a key role in inflammatory diseases like periodontitis.

THE AUTHOR

Dr. Iacopino is dean and professor of restorative dentistry, and director of the International Centre for Oral–Systemic Health, at the faculty of dentistry, University of Manitoba, Winnipeg, Manitoba. Email: iacopino@cc.umanitoba.ca.

The views expressed are those of the author and do not necessarily reflect the opinions or official policies of the Canadian Dental Association.