The Microbiome and Bone Strength

7.项目摘要 微生物组与整个身体的疾病过程有关，因此是一种 治疗学和诊断学的有趣靶点。多项临床前研究表明， 会影响骨骼。我们之前的工作表明，在骨获取过程中对微生物组的修饰 可以通过改变骨组织质量来影响骨强度。“骨质量”描述了骨的各个方面， 骨矿物质密度（BMD）测量值不能很好地代表。我们的发现提出了一种有趣的可能性 基于微生物组的疗法可能能够改善骨组织质量--骨强度的贡献者 现有的治疗方法并不直接针对这些疾病。在拟议的工作中，我们问： 肠道微生物群负责骨强度和组织质量的变化？什么是连接 肠道菌群对骨骼强度和组织质量的影响微生物组对骨骼的影响 力量根据年龄和骨骼成熟的阶段（生长与骨骼成熟）而变化？拟议 这项工作是基于我们的初步研究，在这些研究中，我们将微生物群诱导的 骨强度随着微生物分类学和遗传组成的巨大变化以及受损 肠道微生物群产生维生素K和减少的基质结合骨钙素（维生素K 依赖性蛋白质）。这项工作有三个目标：1）确定肠道微生物群的组成 导致骨强度和质量受损; 2）确定微生物组诱导的 微生物组来源的维生素K导致骨组织质量降低;和3）确定骨中的修饰 与生长中的骨骼相比，由成人骨骼中微生物组的变化引起的基质。的 拟议的工作包括通过在动物之间转移肠道植物群来操纵肠道微生物群， gnotobiotic室和消耗微生物（“敲除”）从肠道微生物群使用窄谱 抗生素肠道微生物群的分类学和功能表征以及对所产生的微生物群的检查 骨生物力学，化学和几何表型是在整个器官，微观和 纳米级的通过在两种情况下建立微生物组和骨强度之间的机制关系， 生长和成年骨骼，拟议的工作将执行必要的第一步，以确定 微生物群系疗法，其调节骨组织质量以降低骨脆性。

7. PROJECT SUMMARY The microbiome has been associated with disease processes throughout the body and is therefore an intriguing target for therapeutics and diagnostics. Multiple preclinical studies have shown that the microbiome can influence bone. Our prior work has indicated that modifications to the microbiome during bone acquisition can influence bone strength by modifying bone tissue quality. “Bone quality” describes aspects of bone that are not well represented by measures of bone mineral density (BMD). Our findings raise the intriguing possibility that microbiome-based therapies may be able to improve bone tissue quality – a contributor to bone strength that is not directly targeted by existing therapies. In the proposed work we ask: What microbial taxa within the gut microbiota are responsible for changes in bone strength and tissue quality? What is the pathway linking the gut microbiota to bone strength and tissue quality? and; How does the influence of the microbiome on bone strength vary based on age and the stage of skeletal maturity (growing v. skeletally mature)? The proposed work is based on our PRELIMINARY STUDIES in which we associated microbiome-induced impairment of bone strength with large changes in the microbial taxonomic and genetic composition as well as impaired production of vitamin K by the gut microbiota and reduced abundance of matrix bound osteocalcin (a vitamin K dependent protein). The proposed work has three aims: 1) Determine the components of the gut microbiota that lead to impaired bone strength and quality; 2) Determine the dependence of microbiome-induced reductions in bone tissue quality on microbiome-derived vitamin K.; and 3) Determine the modifications in bone matrix caused by changes in the microbiome in an adult skeleton as compared to the growing skeleton. The proposed work includes manipulation of the gut microbiota through transfer of gut flora among animals using gnotobiotic chambers and depletion of microbes (“knock out”) from the gut microbiota using narrow spectrum antibiotics. Taxonomic and functional characterization of the gut microbiota and examination of the resulting bone biomechanical, chemical and geometrical phenotypes is performed at the whole organ, micro- and nanoscale. By establishing a mechanistic relationship between the microbiome and bone strength in both the growing and adult skeleton, the proposed work will perform the necessary first steps toward the identification of microbiome therapeutics that modulate bone tissue quality to reduce bone fragility.