Dysbiosis of the oral microbiome in periodontal disease: host gene and pathogen effects

牙周病中口腔微生物群的失调：宿主基因和病原体的影响

• 批准号: MR/J011118/1
• 负责人: Michael Curtis
• 金额: $ 56.56万
• 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: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ011118%2F1
• 关键词: Dysbiosis; oral; microbiome; periodontal; disease

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 or protection from it remain largely uncertain. However, recent studies have shown that several chronic diseases of the gastro-intestinal tract are associated with alterations to the composition of the intestinal microbiome: referred to as dysbiosis wherein there are shifts in the relative abundancies of individual components of the microbiome compared to the abundancies found in health. Furthermore, it has been shown in animal studies that some disease-associated microbiomes can reproduce the disease when they are transferred to healthy recipients suggesting that dysbiosis of the microbiome is important in the causation of disease. In this investigation, dysbiosis of the oral microbiome will be examined in relation to the development of periodontal disease. Periodontal 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. The hypothesis for this study is that dysbiosis of the oral microbiome, induced by either the genetic status of the host or by the introduction of periodontal pathogens leads to the development of inflammatory periodontal disease and bone loss mediated through the normally benign oral microbiome. To test the hypothesis, this study will examine dysbiosis of the oral microbiome and the development of disease using a mouse model. Initially, the mouse oral microbiome will be characterised using a non-cultural approach involving DNA sequence analysis of 16S rRNA genes isolated from oral bacteria of the laboratory mice used in this study. Each 16S rRNA sequence is diagnostic for an individual bacterial species and hence they will provide a reference database which can be used for high throughput investigations of changes to the microbiome where only part of the 16S rRNA gene is sequenced. The effect of the introduction of Porphyromonas gingivalis, a periodontal bacterium frequently present in human disease, into the mouse oral microbiome will then be examined. Preliminary cultural studies have shown that introduction of only low levels of this organism leads to a major increase in the total amount of the mouse oral microbiome and changes to the major types of bacteria present but the use of a non-cultural approach will gain a better understanding of the overall changes. The influence of the host genetic status on the microbiome will also be examined using mice which have been genetically engineered to remove genes important in the immune status of the periodontal tissues. Some of these genetically engineered mice are far more susceptible to periodontal disease whereas others appear to be protected and there is preliminary evidence to suggest that the microbiomes of these animals are different. In the final aim, the effect of transmission of disease-associated and disease-protective microbiomes into previously germ free animals will be examined to directly determine the influence of dysbiosis on the development of disease. This information will provide the basis for understanding the effects of changes which are known to occur to the microbiome in human periodontal disease and will potentially identify those bacterial species which are responsible for the disease and those which may be protective.

人体支持胃肠道和泌尿生殖道以及皮肤表面的各种微生物群落的生长。这些细菌群落被称为人类微生物组。人们普遍认为，人体微生物组通过其对人类发育、生理、免疫和营养的影响在人类生物学中起着重要作用。尽管近年来人类微生物组的组成受到了相当大的关注，但微生物群落介导疾病或预防疾病的精确机制仍然很大程度上不确定。然而，最近的研究表明，胃肠道的几种慢性疾病与肠道微生物组组成的改变有关：被称为生态失调，其中与健康中发现的丰度相比，微生物组的单个组分的相对丰度发生变化。此外，动物研究表明，一些疾病相关的微生物组在转移到健康受体时可以复制疾病，这表明微生物组的生态失调在疾病的病因中很重要。在这项研究中，将研究口腔微生物组的生态失调与牙周病的发展之间的关系。牙周病是人类最常见的炎症性疾病之一，导致约20%的人口牙齿脱落，并给NHS带来巨大成本。它也被认为是发展其他疾病的危险因素，包括心血管疾病和II型糖尿病。本研究的假设是，由宿主的遗传状态或牙周病原体的引入引起的口腔微生物组的生态失调导致通过正常良性口腔微生物组介导的炎性牙周病和骨丢失的发展。为了验证这一假设，本研究将使用小鼠模型研究口腔微生物组的生态失调和疾病的发展。最初，将使用非培养方法表征小鼠口腔微生物组，该方法涉及从本研究中使用的实验室小鼠口腔细菌中分离的16S rRNA基因的DNA序列分析。每个16S rRNA序列都可以诊断单个细菌物种，因此它们将提供一个参考数据库，可用于高通量研究微生物组的变化，其中仅对部分16S rRNA基因进行测序。然后将检查将牙龈卟啉单胞菌（一种经常存在于人类疾病中的牙周细菌）引入小鼠口腔微生物组中的效果。初步的培养研究表明，仅引入低水平的这种微生物会导致小鼠口腔微生物组总量的大幅增加和存在的主要细菌类型的变化，但使用非培养方法将更好地了解整体变化。宿主遗传状态对微生物组的影响也将使用经过基因工程改造以去除牙周组织免疫状态中重要基因的小鼠进行检查。这些基因工程小鼠中的一些更容易患牙周病，而另一些似乎受到保护，并且有初步证据表明这些动物的微生物组是不同的。在最终目标中，将检查疾病相关和疾病保护性微生物组传播到先前无菌动物中的影响，以直接确定生态失调对疾病发展的影响。这些信息将为了解已知在人类牙周病中微生物组发生的变化的影响提供基础，并可能识别出导致疾病的细菌种类和可能具有保护作用的细菌种类。

项目成果

Role of Porphyromonas gingivalis gingipains in multi-species biofilm formation.

• DOI: 10.1186/s12866-014-0258-7
• 发表时间: 2014-10-02
• 期刊: BMC microbiology
• 影响因子: 4.2
• 作者: Bao K;Belibasakis GN;Thurnheer T;Aduse-Opoku J;Curtis MA;Bostanci N
• 通讯作者: Bostanci N

The keystone-pathogen hypothesis.

Keystone-Pathogen假设。

• DOI: 10.1038/nrmicro2873
• 发表时间: 2012-10
• 期刊: Nature reviews. Microbiology

A 16S rRNA Gene and Draft Genome Database for the Murine Oral Bacterial Community.

• DOI: 10.1128/msystems.01222-20
• 发表时间: 2021-02-09
• 期刊: mSystems
• 影响因子: 6.4
• 作者: Joseph S;Aduse-Opoku J;Hashim A;Hanski E;Streich R;Knowles SCL;Pedersen AB;Wade WG;Curtis MA
• 通讯作者: Curtis MA

The Relationship between Mucins and Ulcerative Colitis: A Systematic Review.

• DOI: 10.3390/jcm10091935
• 发表时间: 2021-04-30
• 期刊: Journal of clinical medicine
• 影响因子: 3.9
• 作者: Bankole E;Read E;Curtis MA;Neves JF;Garnett JA
• 通讯作者: Garnett JA