Role of the Gut Microbiome in Implant Loosening

肠道微生物组在植入物松动中的作用

• 批准号: 9883720
• 负责人: D Rick Sumner
• 金额: $ 17.27万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9883720
• 关键词: Affect; Attention; Bacteria; Bone Tissue; Burn injury; Data; Degenerative polyarthritis; Diet; Dietary Supplementation; Disease; Ecology; Endotoxemia; Environment; Event; Failure; Feedback; Genetic; Genetic Materials; Growth; Health; Homeostasis; Immune system; Immunity; Implant; Inflammation; Inflammatory; Inflammatory Response; Intestines; Joints; Lead; Leaky Gut; Life; Lipopolysaccharides; Mediating; Metagenomics; Microspheres; Modeling; Mucous Membrane; Musculoskeletal; Musculoskeletal System; Operative Surgical Procedures; Osteoclasts; Osteolysis; Patients; Pharmaceutical Preparations; Probiotics; Process; Property; Rattus; Replacement Arthroplasty; Role; Shotguns; Site; Starch; Stress; Testing; Thinking; Time; Tissues; Total Hip Replacement; Virus; Volatile Fatty Acids; bone; bone strength; bone turnover; circadian; concept mapping; cost; cytokine; design; dietary supplements; dysbiosis; fungus; gastrointestinal; gastrointestinal system; gut microbiome; gut microbiota; hip replacement arthroplasty; improved; inflammatory marker; intestinal barrier; metabolomics; microbial; microbiome; microorganism; novel; novel marker; novel therapeutics; nutrition; particle; peri-implant bone loss; peri-implant osteolysis; prebiotics; prevent; sample fixation

The main cause of total joint replacement failure is aseptic loosening due to particle-induced peri-implant osteolysis. The annual cost of failure is more than $10B/year in the U.S. and by 2030 more than 350,000 patients per year will need revision surgery. The current thinking is that peri-implant osteolysis is caused by particle-induced inflammation, leading to release of osteoclast-stimulating cytokines. We propose to begin testing the novel hypothesis that there is bi-directional cross-talk between the gut microbiome and the implant microenvironment that is integral to the progression of particle-induced osteolysis. The gut microbiome is the collective genetic material of the bacteria, fungi and viruses in the intestinal track. Gut ecology can be altered by diet, drugs, environment, host genetics and early-life microbial exposure. The symbiotic relationship between gut microorganisms and the host is essential to overall health. The scientific premise for the project is the growing recognition that manipulating the gut microbiome affects musculoskeletal tissues and our new data that the gut microbiome is altered in a rat model of particle-induced peri-implant osteolysis and that aseptic loosening is accelerated in total hip replacement patients who have irritable bowel disease. Given these observations we believe there is sufficient evidence to study the possibility of cross-talk between the digestive and musculoskeletal systems, which could lead to a vicious cycle whereby an initial inflammatory response in the musculoskeletal system contributes to gut dysbiosis, which, in turn, exacerbates the musculoskeletal inflammatory process. We propose testing the hypothesis through two specific aims: (1) Determining if altering the gut microbiome through use of a prebiotic dietary supplement affects the progression of particle-induced peri-implant osteolysis in our rat model and (2) Characterizing how particle-induced peri-implant osteolysis alters the gut microbiome. If this new hypothesis is correct, then there are two novel therapeutic opportunities for preventing or treating peri-implant osteolysis: (1) using dietary supplements to alter the gut microbiome, thus altering the gut-joint feedback loop and (2) interfering with the joint-gut feedback loop. Mechanisms of action for manipulation of the gut microbiome profile to affect remote site tissues include mucosal-mediated immunity, nutrition or release of bacterial products. We will investigate release of bacterial products from the gut as a mechanism of action. How the “challenge” in the musculoskeletal system influences the gut is currently not known and we will begin to study this. Finally, it is also possible that there is a gut bacterial profile unique to particle-induced osteolysis, which would provide a potential novel biomarker for this condition.

人工关节置换术失败的主要原因是颗粒物引起的假体周围无菌性松动 骨质溶解美国每年的故障成本超过100亿美元，到2030年将超过35万美元。 每年的患者将需要翻修手术。目前认为种植体周围骨质溶解是由 颗粒诱导的炎症，导致破骨细胞刺激细胞因子的释放。我们提议开始 测试肠道微生物组和植入物之间存在双向串扰的新假设 微环境是颗粒诱导的骨质溶解进展的组成部分。肠道微生物组是 肠道中细菌、真菌和病毒的集体遗传物质。肠道生态可以被改变 饮食、药物、环境、宿主遗传学和生命早期的微生物暴露。的共生关系 肠道微生物和宿主之间的相互作用对整体健康至关重要。该项目的科学前提是 越来越多的人认识到，操纵肠道微生物组会影响肌肉骨骼组织， 肠道微生物组在颗粒诱导的植入物周围骨质溶解的大鼠模型中发生了改变， 在患有过敏性肠病的全髋关节置换患者中，松动加速。鉴于这些 观察，我们相信有足够的证据来研究消化系统之间串扰的可能性。 和肌肉骨骼系统，这可能导致恶性循环， 肌肉骨骼系统导致肠道生态失调，这反过来又加剧了肌肉骨骼系统， 炎症过程。我们建议通过两个具体目标来测试该假设：（1）确定是否改变 通过使用益生元膳食补充剂的肠道微生物组影响颗粒诱导的 在我们的大鼠模型中的种植体周围骨质溶解和（2）表征颗粒如何诱导种植体周围骨质溶解 改变肠道微生物组如果这个新的假设是正确的，那么有两个新的治疗机会， 用于预防或治疗植入物周围骨质溶解：（1）使用膳食补充剂改变肠道微生物组， 从而改变肠-关节反馈回路和（2）干扰关节-肠反馈回路。机制 操纵肠道微生物组谱以影响远端部位组织的作用包括粘膜介导的 免疫力、营养或细菌产物的释放。我们将研究从细菌释放的产物， 肠道作为一种作用机制。肌肉骨骼系统中的“挑战”如何影响肠道， 目前尚不清楚，我们将开始研究这一点。最后，也有可能存在肠道细菌谱 独特的颗粒诱导的骨质溶解，这将提供一个潜在的新的生物标志物，这种情况。