Dysbiosis and Rebiosis of the Periodontal Microbiome

人体在胃肠道、泌尿生殖道和皮肤表面支持大量微生物群落的生长。这些细菌群落一起被称为人类微生物群。人们普遍认为，人体微生物组通过对人体发育、生理、免疫和营养的影响，在人类生物学中发挥着重要作用。尽管近年来人类微生物组的组成受到了相当大的关注，但微生物群落调节疾病和维持健康的确切机制仍然不确定。然而，最近的研究表明，口腔和胃肠道的几种慢性疾病与整个微生物组组成的改变有关。这被称为生态失调，即微生物组中单个成分的相对丰度与健康中发现的丰度相比发生了重大和有害的变化。牙周病是正常微生物菌群失调的一个例子。这种疾病是人类最常见的炎症性疾病之一，导致大约20%的人口牙齿脱落，并对NHS造成重大损失。它也被认为是其他疾病发展的风险因素，包括心血管疾病和II型糖尿病。目前的治疗方法包括彻底清洁牙龈边缘以下的牙齿表面，有时辅以抗生素治疗。然而，即使定期治疗，这也并不总是成功的。因此，迫切需要开发诊断、预防和治疗这种疾病的新方法。鉴于目前对抗生素耐药性发展的担忧，牙周病的新治疗方法应旨在避免在更急性和危及生命的情况下使用这些有价值的药物。迄今为止，在人类身上研究这些过程的尝试取得了有限的成功——可能是因为人群中临床疾病的差异很大，也可能是因为需要进行长时间的纵向研究：人类疾病是一种缓慢进展的疾病。我们在对小鼠的研究中表明，将人类牙周微生物牙龈卟啉单胞菌引入口腔会导致口腔微生物群的生态失调和牙周病的发展。牙龈卟啉卟啉引起这些重大转变，正常微生物，即使它是在非常低的数量存在。因此，我们认为这种细菌是一种关键病原体，能够操纵口腔中正常细菌的组成，即使它的丰度很低。在人类的其他炎症性疾病中也发现了类似的关键病原体。我们还表明，牙龈卟啉卟啉菌疾病相关的微生物组是非常稳定的，可以转移到健康的受体小鼠并引起疾病。因此，该系统提供了一个理想的实验模型，以确定口腔微生物群失调的机制，以及如何逆转这一机制以恢复健康。具体来说，在本次调查中，我们的目标是：1。为了确定一种关键病原体——在本例中是牙龈卟啉单胞菌——是如何引起微生物生态失调的。与健康的牙周菌群相比，确定牙周菌群失调的功能特性。确定正常共生微生物组的哪些成分或特性可用于逆转生态失调，从而恢复患病个体的健康。这些研究的总体目的是形成对牙周微生物组生态失调机制的基本理解，以及它可能逆转到共生状态（再生）。通过这些实验，我们的目标是为开发治疗和预防人类疾病的新方法提供基础。

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.