The Microbiome and Bone Strength

微生物组和骨骼强度

• 批准号: 10854518
• 负责人: Christopher John Hernandez
• 金额: $ 64万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10854518
• 关键词: Activities of Daily Living; Address; Adult; Age; Animals; Antibiotics; Bacteria; Binding; Biochemical; Biomechanics; Bone Density; Bone Matrix; Bone Tissue; Chemicals; Dependence; Development; Diagnostic; Disease; Estrogens; Genes; Genetic; Geometry; Germ-Free; Gnotobiotic; Goals; Growth; Human; Impairment; Individual; Knock-out; Link; Longevity; Measures; Mechanics; Metagenomics; Microbe; Microbial Genetics; Microbial Taxonomy; Minerals; Modification; Mus; Organ; Organism; Orthologous Gene; Osteocalcin; Osteoporosis prevention; Pathway interactions; Performance; Phenotype; Phylogeny; Process; Production; Proteins; Regulation; Reporting; Role; SXR receptor; Skeleton; Taxonomy; Testing; Therapeutic; Time; Tissues; Vitamin K; Work; aged; bone; bone fragility; bone loss; bone mass; bone quality; bone strength; density; experimental study; fracture risk; gut microbiome; gut microbiota; improved; mature animal; microbial; microbial community; microbiome; microbiome research; microbiome therapeutics; microbiota; nanoscale; novel; osteoporosis with pathological fracture; preclinical study; pregnane X receptor; prevent; side effect; skeletal; targeted treatment

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.

7.项目总结 微生物组与全身的疾病过程有关，因此是一种 治疗和诊断的耐人寻味的目标。多项临床前研究表明，微生物组 可以影响骨骼。我们先前的工作表明，在骨获取过程中对微生物组的修改 可以通过改变骨组织质量来影响骨强度。“骨骼质量”指的是骨骼的某些方面 骨密度(BMD)的测量不能很好地反映这一点。我们的发现提出了耐人寻味的可能性 基于微生物组的疗法可能能够改善骨组织质量--这对骨骼强度有贡献 这并不是现有疗法直接针对的目标。在这项拟议的工作中，我们提出了以下问题： 肠道微生物区系是导致骨骼强度和组织质量变化的原因吗？连接的路径是什么？ 肠道微生物区系对骨骼强度和组织质量的影响？微生物群对骨骼有何影响？ 力量取决于年龄和骨骼成熟的阶段(生长阶段与骨骼成熟阶段)？建议数 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损伤 骨强度变化较大的微生物分类和遗传组成以及受损 肠道微生物区系产生维生素K和基质结合骨钙素(一种维生素K)丰度降低 依赖蛋白质)。拟议的工作有三个目标：1)确定肠道微生物区系的组成 从而导致骨强度和骨质量受损；2)决定了微生物组诱导的依赖性 微生物来源的维生素K对骨组织质量的降低；以及3)决定骨的修饰 由成年骨骼中的微生物群相对于成长中的骨骼中的微生物群的变化而引起的基质。这个 拟议的工作包括通过在动物之间转移肠道菌群来操纵肠道微生物区系。 利用窄谱技术对肠道微生物区系中的微生物(“敲除”)进行筛选 抗生素。肠道微生物区系的分类和功能特征及其结果的检验 骨的生物力学、化学和几何表型在整个器官、显微和 纳米级的。通过建立微生物群和骨强度之间的机械关系， 对于正在成长和成年的骨骼，拟议的工作将执行必要的第一步，以确定 调节骨组织质量以降低骨脆性的微生物组疗法。