Dysbiosis and Rebiosis of the Periodontal Microbiome

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The human body supports the growth of a wide array of microbial communities in the gastro-intestinal and urogenital tracts and on the surface of the skin. Together, these communities of bacteria are referred to as the human microbiome. It is widely acknowledged that the human microbiome plays a significant role in human biology through its influence on human development, physiology, immunity and nutrition. Although the composition of the human microbiome has received considerable attention in recent years, the precise mechanisms whereby the microbial communities mediate disease and maintain health remain uncertain. However, recent studies have shown that several chronic diseases of the mouth and gastro-intestinal tract are associated with alterations to the composition of the entire microbiome. This is referred to as dysbiosis where there are major and harmful shifts in the relative abundancies of individual components of the microbiome compared to the abundancies found in health. Periodontal disease is an example of these conditions where dysbiosis of the normal microbiology takes place. This disease is one of the most common inflammatory diseases of humans leading to tooth loss in approximately 20% of the population and a significant cost to the NHS. It is also thought to be a risk factor for the development of other diseases including cardiovascular disease and type II diabetes. Current treatment methods involve thorough cleaning of the tooth surfaces below the gum margin, sometimes supplemented by antibiotic therapy. However, even with regular treatment episodes this is not always successful. There is, therefore, an urgent unmet clinical need to develop newer methods of both diagnosis, prevention and treatment of this condition. Given the current concerns about the development of resistance to antibiotics, newer treatments for periodontal disease should aim to avoid the use of these valuable agents for more acute and life threatening conditions. Attempts to study these processes in humans have had limited success to date - possibly because of the large variation in clinical disease in human populations and because of the need for longitudinal studies over a long time scale: disease in humans is a slowly progressive disease. We have shown in studies using mice that introduction of the human periodontal organism, Porphyromonas gingivalis, into the mouth causes dysbiosis of the oral microbiome and the development of periodontal disease. P. gingivalis causes these major shifts to the normal microbiology even though it is present in very low quantities. We therefore refer to this bacterium as a keystone pathogen able to manipulate the composition of the normal bacteria in the mouth even though it is present in low abundance. Similar keystone pathogens have now been described in other inflammatory diseases of humans. We have also shown that the P. gingivalis disease- associated microbiome is very stable and can be transferred into healthy recipient mice and cause disease. This system therefore provides an ideal experimental model to determine mechanisms of dysbiosis of the oral microbiome and how this may be reversed in order to restore health. Specifically, in this investigation, we aim: 1. To determine how a keystone pathogen - in this case P. gingivalis - causes microbial dysbiosis2. To establish what are the functional properties of a dysbiotic periodontal microbiome compared to the microbiome in health3. To determine which component(s) or properties of a normal symbiotic microbiome may be used to reverse dysbiosis and hence restore health in a diseased individualThe overall aim of these investigations is to form a basic understanding of the mechanisms of dysbiosis of the periodontal microbiome and its potential reversal to a symbiotic state (rebiosis). Through these experiments we aim to provide the basis for the development of novel approaches to the treatment and prevention of human disease.