Metagenomic Study of the Periodontal Microbiome in Healthy and Diabetic Subjects

描述（由申请人提供）：2型糖尿病（T2D）是美国人群中一种重要且日益流行的疾病。此外，西班牙裔糖尿病患病率是非西班牙裔的近两倍。糖尿病还与牙周炎的患病率和进展增加有关。目前缺乏与2型糖尿病患者牙周炎相关的微生物群的综合分析，这使得我们对牙周微生物群在该人群牙周炎中的作用的理解存在重大差距。已知t2d患者的宿主免疫反应发生改变，证据表明结缔组织代谢失调。在牙周组织中，这些变化可能是由于相关微生物群的影响而引起的。我们将调查与牙周病和糖尿病高危西班牙裔人群相关的微生物组。我们假设与t2d患者慢性牙周炎相关的龈下微生物群包含细菌种类和遗传元件（基因、代谢途径、插入序列或致病性岛），构成宏基因组特征，与全身健康受试者的慢性牙周炎或有或无t2d受试者的牙周炎或牙周健康不同。我们进一步假设，与非糖尿病患者相比，t2dm慢性牙周炎患者对初始牙周治疗的反应在减少或消除与发病机制相关的物种和遗传因素方面效果较差。为了验证这些假设，我们将对患有或不患有T2D的牙周炎受试者的牙龈下样本进行深度16S rDNA分析（目的1）。对照组将包括牙周健康和牙周治疗（解决牙周炎）的受试者，有或没有T2D。此外，我们将对患有或不患有T2D的牙周炎患者的牙龈下样本进行深度宏基因组序列分析（目的2），并与上述对照组进行对照。最后，我们将验证在Aim 2中发现的顶部和毒力相关的宏基因组特征差异，这些差异来自牙周健康和患病受试者，无论是否患有T2D。我们将评估细菌宏基因组特征分子在宏基因组和亚转录组中的相对丰度（目的3）。本研究将定义微生物群落和宏基因组特征，以区分与2型糖尿病患者慢性牙周炎相关的牙龈下微生物群，以及高危西班牙裔人群中系统健康患者的牙龈下微生物群。这项研究将解决我们对牙周炎高危人群牙周微生物群知识的根本空白，并可能导致进一步研究，以开发诊断、预防和管理糖尿病患者疾病的创新临床方法。

DESCRIPTION (provided by applicant): Type 2 diabetes (T2D) is a significant and increasingly prevalent disease in the US population. In addition, the prevalence of diabetes among Hispanics is nearly twice that of non-Hispanics. Diabetes is further associated with an increase in the prevalence and progression of periodontitis. Comprehensive analysis of the microbiome associated with periodontitis in type 2 diabetics (T2Ds) is lacking, leaving a significant gap in our understanding of the role of the periodontal microbiome in periodontitis in this population. The host immune response in T2Ds is known to be altered and evidence suggests a dysregulation in connective tissue metabolism. In the periodontal tissues these changes may result from, as well as impact, the associated microbiome. We will investigate the microbiome associated with periodontal disease and diabetes in a high- risk Hispanic population. We hypothesize that the subgingival microbiome associated with chronic periodontitis in T2Ds harbors bacterial species and genetic elements (genes, metabolic pathways, insertion sequences or pathogenicity islands) constituting a metagenomic signature that is distinct from that of chronic periodontitis in systemically healthy subjects, or resolved periodontitis or periodontal health in subjects with or without T2Ds. We further hypothesize that the response to initial periodontal treatment in chronic periodontitis of T2Ds will be less effective in reducing or eliminating species and genetic elements associated with pathogenesis as compared that of non-diabetic patients. To test these hypotheses we will conduct deep 16S rDNA analyses on subgingival samples from periodontitis subjects with or without T2D (Aim 1). Controls will include periodontally healthy and periodontally treated (resolved periodontitis) subjects with or without T2D. We will additionally conduct deep metagenomic sequence analysis on subgingival samples from periodontitis patients with or without T2D (Aim 2) with controls as described above. Finally we will validate the top and virulence-related metagenomic signature differences found in Aim 2 in a different sample set from periodontally healthy and diseased subjects with or without T2D. We will assess the relative abundance of the bacterial metagenomic signature molecules in the metagenome and metatranscriptome (Aim 3). This study will define the microbial community and metagenomic signatures that distinguish the subgingival microbiome associated with chronic periodontitis in type 2 diabetics from those of systemically healthy patients in a high risk Hispanic population. This research will address a fundamental gap in our knowledge of the periodontal microbiome in population at high risk for periodontitis and may lead to further studies for the development of innovative clinical approaches to diagnosing, preventing and managing the disease in diabetics. PUBLIC HEALTH RELEVANCE: Type 2 diabetes (T2D) is a significant and increasingly prevalent disease in the US population, particularly among Hispanics, and is further associated with an increase in the prevalence and progression of gum (periodontal) disease caused by periodontal microorganisms. This investigation will comprehensively characterize the periodontal microbial population in subjects with or without T2D. The findings will address a fundamental gap in our understanding of the etiological agents of periodontitis and may lead to innovative strategies for diagnosing, preventing and managing periodontitis.