Commensal modulation of Peri-implant Microbiome Dysbiosis via Veillonella parvula

项目摘要 种植体周围炎是一种普遍存在的破坏性炎症性疾病，可导致牙周围颌骨缺损 种植体和口腔健康相关生活质量的损害。这会引起公众健康的关注， 损失进展迅速，并没有回应传统的牙周抗菌治疗 治疗多项人体研究已经确定植入物卫生和摩擦腐蚀会产生 植入降解产物，如钛微粒，其与炎症相关， 大部分种植体周围炎病例，即，钛（Ti）介导的种植体周围炎。虽然有充分的证据表明 钛微粒主要通过诱导氧化应激改变植入物周围的免疫监视， 这些变化对植入物周围微生物组的影响尚未得到充分研究。 这项研究旨在研究小韦荣氏球菌的遗传机制， 桥接口腔生物膜中的微生物，以存活并交叉保护口腔病原体， 环境氧化应激我们的初步研究表明，增加游离钛水平， 种植体周围菌斑与种植体周围生物膜的生物多样性显著减少相关 这与小弧菌的过度生长有关。强有力的初步数据表明，抗氧化剂过氧化氢酶 由katA基因编码的酶是一个关键的生存系统，使小弧菌的生存， 大多数植入物周围的细菌被钛介导的氧化爆发耗尽。重要的是， 韦荣氏球菌与口腔病原体如牙龈卟啉单胞菌和F.具核 并且其过氧化氢酶保护后者免受氧化损伤，这表明了社区水平的调节作用。在这 项目，我们将确定（i）由V. parvula生存氧化应激的确切机制，（ii）的作用， katA和其他关键的抗氧化酶在调节生物膜氧化耐受性，和（iii）口服的能力， 病原体利用韦荣氏球菌的katA在Ti期间在口腔粘膜软组织屏障中定殖和存活。 介导的炎症。这项工作的长期目标是确定微生物群生态失调的驱动因素， 种植体周围炎，并制定有效的抗菌策略来管理种植体周围炎 疾病拟议的工作的目的是评估的假设，生存机制的 微球菌属，使它们在这一生态位中过度生长的细菌被口腔病原体利用， 定植于植入物周围的微生物群落并导致临床疾病。拟议的目标将是 完成了两个主要目的：1）确定钛介导的炎症如何促进小弧菌 过度生长，和2）以确定在何种程度上V.parvula改变体内多种微生物感染过程。 这些发现将为口腔细菌在调节微生物组中的作用提供重要见解 这将为种植体周围炎的治疗引入新的治疗靶点。

Project Summary Peri-implantitis is a prevalent, destructive, inflammatory disease that leads to loss of jawbone around dental implants and impairments in oral health-related quality of life. It poses a public health concern because bone loss progresses at a rapid rate and does not respond therapeutically to conventional periodontal antibacterial therapies. Multiple human studies have firmly established that implant hygiene and tribocorrosion generate implant degradation products, such as titanium microparticles, which are associated with inflammation in a large fraction of peri-implantitis cases, i.e., Titanium (Ti)-mediated peri-implantitis. While it is well documented that titanium microparticles alter peri-implant immune surveillance primarily by inducing oxidative stress, the effects that these changes have on the peri-implant microbiome have not been adequately investigated. The proposed research aims to investigate the genetic mechanisms employed by Veillonella parvula, a bridging microorganism in oral biofilms, to survive and cross-protect oral pathogens in response to environmental oxidative stress. Our preliminary studies demonstrated that increased free titanium levels in peri-implant plaque are associated with a significant reduction in the biodiversity of the peri-implant biofilms that is coupled with the overgrowth of V. parvula. Strong preliminary data point to an antioxidant catalase enzyme encoded by the katA gene as being a key survival system that enables V. parvula’s survival while most peri-implant commensal bacteria are depleted by Titanium-mediated oxidative burst. Importantly, Veillonella demonstrates widespread mutualism with oral pathogens, such as P. gingivalis and F. nucleatum and its catalase protects the latter from oxidative damage suggesting a community-level regulatory role. In this project, we will determine (i) the exact mechanisms used by V. parvula to survive oxidative stress, (ii) the role of katA and other key antioxidant enzymes in modulating biofilm oxidative tolerance, and (iii) the ability of oral pathogens to leverage Veillonella’s katA to colonize and survive in the oral mucosa soft tissue barrier during Ti- mediated inflammation. The long-term goal of this work is to identify the drivers of microbiome dysbiosis in peri-implantitis and to develop efficacious antimicrobial strategies for the management of peri-implant diseases. The objective of the proposed work is to assess the hypothesis that survival mechanisms of commensal Veillonella spp., which enable their overgrowth in this niche are leveraged by oral pathogens to colonize peri-implant microbial communities and lead to clinical disease. The proposed objective will be completed in two main Aims: 1) to identify how titanium-mediated inflammation promotes V. parvula overgrowth, and 2) to determine the extent to which V. parvula alters polymicrobial infection course in vivo. These findings will provide important insights in the role of oral commensal bacteria in modulating microbiome dysbiosis and will introduce novel therapeutic targets of peri-implantitis treatments.