Role of the Gut Microbiome in Implant Loosening

全关节置换术失败的主要原因是颗粒诱导的种植体周围无菌性松动。 骨溶解。在美国，每年因破产造成的损失超过100亿美元，到2030年将超过35万美元 每年的患者将需要进行翻修手术。目前的观点是种植体周围骨溶解是由 颗粒诱导的炎症，导致破骨细胞刺激细胞因子的释放。我们建议开始 测试肠道微生物群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溶解过程中不可或缺的部分。肠道微生物群是 肠道中细菌、真菌和病毒的集体遗传物质。肠道生态是可以改变的 受饮食、药物、环境、宿主遗传学和早期微生物暴露的影响。共生关系 肠道微生物和宿主之间的关系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，操纵肠道微生物群会影响肌肉骨骼组织和我们的新数据 在颗粒诱导种植体周骨质溶解和无菌的大鼠模型中肠道微生物组发生改变 患有肠易激疾病的全髋关节置换术患者会加速松动。考虑到这些 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，在这种恶性循环中，最初的炎症反应 肌肉骨骼系统有助于肠道的生物失调，进而加剧肌肉骨骼 炎症过程。我们建议通过两个具体的目标来检验这一假设：(1)确定是否改变 肠道微生物群通过使用益生素膳食补充剂影响颗粒诱导的疾病进展 我们的大鼠种植体周围骨溶解的模型和(2)颗粒如何诱导种植体周围骨溶解的特征 改变肠道微生物群。如果这一新假设是正确的，那么就有两个新的治疗机会 用于预防或治疗种植体周围骨溶解：(1)使用膳食补充剂改变肠道微生物群， 从而改变了肠道-关节反馈环，以及(2)干扰了关节-肠道反馈环。机制： 操纵肠道微生物组以影响远程部位组织的行动包括粘膜介导的 细菌制品的免疫、营养或释放。我们将调查细菌产品的释放情况 直觉作为一种行动机制。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图谱 这是颗粒诱导的骨溶解所独有的，这将为这种情况提供潜在的新的生物标志物。

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.