Commensal modulation of Peri-implant Microbiome Dysbiosis via Veillonella parvula

小韦荣球菌对种植体周围微生物群失调的共生调节

• 批准号: 10899342
• 负责人: Georgios Kotsakis
• 金额: $ 39.26万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10899342
• 关键词: Address; Affect; Anti-Bacterial Agents; Antibiotic Therapy; Antioxidants; Bacteria; Biodiversity; Biological Models; Biomass; Cell Death; Characteristics; Clinical; Communities; Complex; Coupled; Data; Dental; Dental Implants; Disease; Drug Metabolic Detoxication; Ecology; Enzymes; Excision; Exhibits; Fusobacterium nucleatum; Genes; Genetic; Genetic Transcription; Goals; Growth; Health; Homeostasis; Human; Hygiene; Immunologic Surveillance; Impairment; Implant; Infection; Inflammation; Inflammatory; Investigation; Knowledge; Lytic; Mechanics; Mediating; Methodology; Microbial Biofilms; Modeling; Morbidity - disease rate; Oral health; Oral mucous membrane structure; Orthopedics; Oxidative Stress; Oxidative Stress Induction; Oxygen; Pathogenesis; Pathogenicity; Patients; Periodontitis; Phase; Porphyromonas gingivalis; Public Health; Reactive Oxygen Species; Relapse; Research; Respiratory Burst; Role; Side; Signal Pathway; Stress; System; Testing; Therapeutic; Titanium; Up-Regulation; Veillonella; Veillonella parvula; Work; antimicrobial; antioxidant enzyme; bone loss; catalase; commensal bacteria; cross immunity; dysbiosis; gut dysbiosis; health related quality of life; human data; in vivo; insight; microbial; microbial community; microbiome; microbiome composition; microorganism; mutualism; new therapeutic target; opportunistic pathogen; oral biofilm; oral commensal; oral pathogen; oxidative damage; particle; pathogen; pathogenic bacteria; peri-implantitis; public health relevance; response; soft tissue; synergism; transcriptomics; treatment strategy

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.

项目概要 种植体周围炎是一种普遍的、破坏性的炎症性疾病，会导致牙齿周围的颌骨丢失 种植体和口腔健康相关生活质量的损害引起了公共健康问题，因为骨。 损失进展迅速，并且对传统牙周抗菌药物没有治疗反应 多项人体研究已证实植入物卫生和摩擦腐蚀会产生。 植入物降解产物，例如钛微粒，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，虽然有详细记录。 钛微粒主要通过诱导氧化应激来改变种植体周围的免疫监视， 这些变化对种植体周围微生物组的影响尚未得到充分研究。 拟议的研究旨在调查小韦荣球菌 (Veillonella parvula) 所采用的遗传机制。 在口腔生物膜中桥接微生物，以生存并交叉保护口腔病原体，以应对 我们的初步研究表明，游离钛水平增加。 种植体周围斑块与种植体周围生物膜生物多样性的显着减少有关 强有力的初步数据表明存在抗氧化剂过氧化氢酶。 katA 基因编码的酶是一种关键的生存系统，使 V. parvula 能够在 重要的是，大多数种植体周围的共生细菌都会被钛介导的氧化爆发所耗尽。 韦荣球菌表现出与口腔病原体广泛的共生关系，例如牙龈卟啉单胞菌和具核梭菌 其过氧化氢酶可以保护后者免受氧化损伤，这表明在这方面具有群落水平的调节作用。 项目中，我们将确定 (i) V. parvula 在氧化应激中生存的确切机制，(ii) 的作用 katA 和其他关键抗氧化酶在调节生物膜氧化耐受性中的作用，以及 (iii) 口服 病原体利用韦荣球菌的 katA 在口腔粘膜软组织屏障中定殖并存活。 这项工作的长期目标是确定微生物群失调的驱动因素。 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 所提出的工作的目的是评估疾病的生存机制的假设。 共生韦荣球菌属 (Veillonella spp.)，使其在这个生态位中过度生长，并被口腔病原体利用 定植于种植体周围微生物群落并导致临床疾病。 完成两个主要目标：1）确定钛介导的炎症如何促进小 V. parvula 过度生长，2) 确定 V. parvula 在体内改变多种微生物感染过程的程度。 这些发现将为口腔共生细菌在调节微生物组中的作用提供重要见解 菌群失调，并将引入种植体周围炎治疗的新治疗靶点。