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.

项目摘要 植入植入术是一种普遍，破坏性的炎症性疾病，导致牙齿周围失去颌骨 与口腔健康相关的生活质量的恐惧和损害。它提出了公共健康问题，因为骨头 损失以快速速度进行，并且对常规牙周抗细菌没有热反应 疗法。多项人类研究首先确定植入物卫生和二聚态腐蚀会产生 植入物降解产物，例如钛微粒，与A中的炎症有关 大量的植入物炎病例，即钛（Ti）介导的植入术。虽然有据可查 钛微粒通过诱导的氧化应激改变了种植体周日免疫监测的原发性， 这些变化对种植体周期微生物组的影响尚未得到充分研究。 拟议的研究旨在研究Veillonella parvula（A）进行的遗传机制 在口服生物膜中桥接微生物，以响应于 环境氧化应激。我们的初步研究表明，在 种植体周围斑块与植入物生物膜的生物多样性显着降低有关 这是V. parvula的过度生长。强的初步数据指向抗氧化过氧化氢酶 由Kata基因编码的酶是一个关键的生存系统，可实现V. Parvula的生存，而 大多数种植体周日的共生细菌被钛介导的氧化物爆发所耗尽。重要的是， Veillonella用口服病原体（例如牙龈疟原虫和F. nucleatum）表现出广泛的互惠主义 它的过氧化氢酶保护后者免受氧化损害，表明社区水平的监管作用。在这个 项目，我们将确定（i）V。Parvula使用的确切机制在氧化物胁迫下生存，（ii）作用 在调节生物膜氧化耐受性方面的KATAA和其他关键抗氧化剂酶，以及（iii）口服的能力 病原体利用Veillonella的kata在Ti-ti-ti-ti-ti-ti-ti-ti-ti-ti-ti-ti-ti-ti-ti-ti-ti-ti-ti-kata中殖民和生存 介导的炎症。这项工作的长期目标是确定微生物组营养不良的驱动因素 植入植入术并开发有效的抗菌策略来治疗种植剂 疾病。拟议工作的目的是评估以下假设 Comensal Veillonella spp。，使他们在这个利基市场中的过度生长被口腔病原体所利用 定居于种植体周围的微生物群落并导致临床疾病。拟议的目标将是 以两个主要目的完成：1）确定钛介导的炎症如何促进V. parvula 过度生长，以及2）确定V. parvula在体内改变多数菌感染过程的程度。 这些发现将提供重要的见解，以对口服细菌在调节微生物组中的作用 营养不良，并将引入新型的植入周围炎治疗靶标。