Dysbiosis and Rebiosis of the Periodontal Microbiome

牙周微生物群的失调和再生

• 批准号: MR/P012175/1
• 负责人: Michael Curtis
• 金额: $ 70.34万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP012175%2F1
• 关键词: Dysbiosis; Rebiosis; Periodontal; Microbiome

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.

人体支持胃肠道和泌尿生殖道以及皮肤表面大量微生物群落的生长。总而言之，这些细菌群落被称为人类微生物群。人们普遍认为，人体微生物群通过对人体发育、生理、免疫和营养等方面的影响，在人类生物学中发挥着重要作用。虽然近年来人类微生物群的组成受到了相当大的关注，但微生物群落介导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的组成变化有关。这被称为生态失调，即与健康中发现的丰度相比，微生物组各组成部分的相对丰度发生了重大和有害的变化。牙周病就是这些情况的一个例子，在这些情况下，正常微生物会发生生物失调。这种疾病是人类最常见的炎症性疾病之一，在大约20%的人口中导致牙齿脱落，给NHS带来了巨大的成本。它也被认为是其他疾病发展的危险因素，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床边缘以下的牙齿表面，有时辅以抗生素治疗。然而，即使有规律的治疗发作，这也不总是成功的。因此，迫切需要开发诊断、预防和治疗这种疾病的新方法，这一需求尚未得到满足。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该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。到目前为止，研究人类这些过程的尝试取得的成功有限--可能是因为人类人群的临床疾病存在很大差异，而且需要进行长期的纵向研究：人类的疾病是一种进展缓慢的疾病。我们在用小鼠进行的研究中表明，将人类牙周有机体牙龈卟啉单胞菌引入口腔会导致口腔微生物群的失调和牙周病的发展。尽管牙龈假单胞菌的数量很少，但它会导致这些向正常微生物学的重大转变。因此，我们将这种细菌称为一种关键病原体，即使它的丰度很低，也能够操纵口腔中正常细菌的组成。类似的Keystone病原体现在已经在人类的其他炎症性疾病中被描述出来。我们还表明，与牙龈假单胞菌疾病相关的微生物群非常稳定，可以转移到健康的受体小鼠体内并导致疾病。因此，该系统提供了一个理想的实验模型，以确定口腔微生物组失调的机制，以及如何逆转这种机制以恢复健康。具体地说，在这项研究中，我们的目标是：1.确定Keystone病原体--在这种情况下是牙龈假单胞菌--如何导致微生物失调2。确定与健康中的微生物组相比，非生物牙周微生物组的功能特性是什么。为了确定正常共生微生物群的哪种成分(S)或其性质可以用来逆转牙周微生物群的失调，从而恢复患者的健康。这些研究的总体目标是形成对牙周微生物群失调的机制及其潜在的逆转为共生状态(再生物)的基本理解。通过这些实验，我们旨在为开发治疗和预防人类疾病的新方法提供基础。

项目成果

LptO (PG0027) Is Required for Lipid A 1-Phosphatase Activity in Porphyromonas gingivalis W50.

• DOI: 10.1128/jb.00751-16
• 发表时间: 2017-06-01
• 期刊: Journal of bacteriology
• 影响因子: 3.2
• 作者: Rangarajan M;Aduse-Opoku J;Hashim A;McPhail G;Luklinska Z;Haurat MF;Feldman MF;Curtis MA
• 通讯作者: Curtis MA

DS_10.1177_0022034519877150 - Supplemental material for Horizontal and Vertical Transfer of Oral Microbial Dysbiosis and Periodontal Disease

DS_10.1177_0022034519877150 - 口腔微生物失调和牙周病水平和垂直转移的补充材料

• DOI: 10.25384/sage.9916928
• 发表时间: 2019
• 作者: M.A. Payne

Hemin binding by Porphyromonas gingivalis strains is dependent on the presence of A-LPS.

• DOI: 10.1111/omi.12178
• 发表时间: 2017-10
• 期刊: Molecular oral microbiology
• 影响因子: 3.7
• 作者: Rangarajan M;Aduse-Opoku J;Paramonov NA;Hashim A;Curtis MA
• 通讯作者: Curtis MA

DS_10.1177_0022034519898144 - Supplemental material for The P. gingivalis Autocitrullinome Is Not a Target for ACPA in Early Rheumatoid Arthritis

DS_10.1177_0022034519898144 - 牙龈卟啉单胞菌自身瓜氨酸组的补充材料不是早期类风湿性关节炎中 ACPA 的目标

• DOI: 10.25384/sage.11536026
• 发表时间: 2020
• 作者: E. Muñoz-Atienza

The P. gingivalis Autocitrullinome Is Not a Target for ACPA in Early Rheumatoid Arthritis

• DOI: 10.1177/0022034519898144
• 发表时间: 2020-01-06
• 期刊: JOURNAL OF DENTAL RESEARCH
• 影响因子: 7.6
• 作者: Munoz-Atienza, E.;Flak, M. B.;Curtis, M. A.
• 通讯作者: Curtis, M. A.