Oral to Gut Microbiome Transmission in Periodontitis and Type 2 Diabetes

项目摘要 牙周炎和II型糖尿病(T2D)是共同发生的疾病，是最常见的疾病之一 在美国，估计有46.5%的成年人患有慢性病，9.4%的成年人患有慢性病 患有后者，62.3%的65岁以上的糖尿病成年人同时患有这两种疾病。T2D，其特征是 慢性全身性炎症状态，可通过失调的宿主免疫反应和 全身性炎症和口腔生物失调之间的正反馈循环。牙周炎的观察 对血糖控制、胰岛素抵抗和糖尿病并发症(如神经病变、心血管疾病)产生不利影响 疾病，甚至死亡都被人们接受，但其潜在的机制尚不清楚。牙周炎已经出现 作为肠道微生物组的潜在修饰者，其在调节全身和代谢健康方面的作用是 越来越多的人认识到。多项研究指出，肠道微生物群失调是代谢的一个贡献者 疾病、炎症性肠病(IBD)、结直肠癌和类风湿关节炎。与 有证据表明，口腔微生物失调与肠道微生物群组成的变化有关，而且，口腔微生物所产生的 上肠道微生物组特征在T2D中，口腔-肠道微生物组轴作为 牙周炎和糖尿病。这项NRSA F30提案的目标是评估牙周炎的影响，以及其 相关的口腔微生物群失调，肠道微生物群对代谢至关重要的代谢途径 精神障碍和T2D。这一建议的首要假设是牙周炎改变了肠道微生物群。 VIS从口腔到肠道的传播导致了T2D的代谢功能障碍和炎症。目的 目的1是确定微生物特定菌株水平的遗传变异和口腔生物失调是否与 肠道微生物群的功能变化。目标2的目的是测试口腔到肠道的菌株传播作为 牙周炎改变肠道微生物群，并导致与T2D相关的不良结局的机制。 使用与受试者相匹配的菌斑和粪便样本，口腔和肠道微生物群将在菌株- 每个微生物组的水平分辨率和代谢谱将被重建。中概述的实验 这项建议将确定特定的口腔菌株和口腔到肠道的菌株传播在促进 T2D所见牙周炎的病理系统效应。这项工作将在布法罗大学进行， 牙科医学院，在帕特里夏·迪亚兹博士的实验室里，他是微生物组研究的专家。这个 培训计划是为发展成为传染病领域的内科科学家而量身定做的，将包括 传染病和内分泌学的临床导师为了获得跨学科的经验， 反映了这项提案的研究目标。这些纵向临床指导将取得成功 医生-科学家，他们也将直接参与拟议的研究，从而提供全面的 在团契的过程中进行指导。

Project Summary Periodontitis and Type II Diabetes (T2D) are co-occurring diseases and among the most prevalent chronic illnesses in the United States with an estimated 46.5% of adults suffering from the former, 9.4% adults suffering from the latter, and 62.3% of diabetic adults older than 65 burdened by both. T2D, characterized by a state of chronic systemic inflammation, can lead to periodontitis via dysregulated host immune responses and a positive feedback loop between systemic inflammation and oral dysbiosis. The observation that periodontitis adversely affects glycemic control, insulin resistance, and diabetic complications like neuropathy, cardiovascular disease, and even death is well accepted, but the underlying mechanism is unknown. Periodontitis has emerged as a potential modifier of the gut microbiome, whose role in regulating systemic and metabolic health is increasingly being recognized. Multiple studies point to gut microbiome dysbiosis as a contributor to metabolic disorders, inflammatory bowel disease (IBD), colorectal cancer and rheumatoid arthritis. Combined with evidence oral dysbiosis is associated with gut microbiome compositional changes, and, that oral microbes make up gut microbiome signatures in T2D, rationale exists for the oral-gut microbiome axis as a link between periodontitis and diabetes. The goal of this NRSA F30 proposal is to evaluate the effect of periodontitis, and its associated mouth microbiome dysbiosis, on metabolic pathways of the gut microbiome important to metabolic disorders and T2D. The overarching hypothesis of this proposal is that periodontitis alters the gut microbiome vis oral-to-gut strain transmission to contribute to metabolic dysfunction and inflammation in T2D. The purpose of Aim 1 is to determine if microbial specific strain-level genetic variation and oral dysbiosis are associated with functional changes in the gut microbiome. The purpose of Aim 2 is to test oral-to-gut strain transmission as a mechanism by which periodontitis alters the gut microbiome, and contributes to poor outcomes related to T2D. Using subject-matched plaque and feces samples, the oral and gut microbiomes will be characterized at strain- level resolution, and metabolic profiles will be reconstructed for each microbiome. The experiments outlined in this proposal will determine the role of specific oral strains and oral-to-gut strain transmission in contributing to the pathologic systemic effects of periodontitis seen in T2D. This work will take place at the University at Buffalo, School of Dental Medicine, in the laboratory of Dr. Patricia Diaz, who is an expert in microbiome research. The training plan is tailored for development as a physician-scientist in the field of infectious disease, and will include clinical preceptorships in infectious disease and endocrinology in order to gain cross-disciplinary experience, reflecting the research goals of this proposal. These longitudinal clinical preceptorships will be with successful physician-scientists, who also will be directly involved in the proposed research, thereby providing integrated mentorship over the course of the fellowship.