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。项目摘要 微生物组与整个身体的疾病过程有关，因此是 有趣的治疗和诊断目标。多次临床前研究表明微生物组 会影响骨头。我们先前的工作表明，在骨骼获取过程中对微生​​物组进行了修改 可以通过修饰骨组织质量来影响骨骼强度。 “骨质质量”描述了骨头的各个方面 不能很好地代表骨矿物质密度（BMD）。我们的发现提出了有趣的可能性 基于微生物组的疗法可能能够提高骨组织质量 - 造成骨骼强度 这不是现有疗法直接针对的。在拟议的工作中，我们问： 肠道菌群负责骨骼强度和组织质量的变化？链接的路径是什么 肠道菌群达到骨骼强度和组织质量？和;微生物组对骨骼的影响如何 强度会根据年龄和骨骼成熟的阶段（生长v。骨骼成熟）而变化？提议 工作是基于我们的初步研究，我们将微生物组诱导的损害相关联 微生物分类学和遗传组成以及受损的骨骼强度发生了巨大变化 肠道菌群生产维生素K，并降低基质结合骨钙素的丰度（维生素K 依赖蛋白）。拟议的工作具有三个目的：1）确定肠道菌群的成分 这导致骨骼强度和质量受损； 2）确定微生物组诱导的依赖性 微生物组衍生的维生素K的骨组织质量的降低； 3）确定骨骼的修饰 与生长的骨骼相比，由成年骨骼的微生物组变化引起的基质。这 拟议的工作包括通过使用肠道菌群在动物中转移肠道菌群的操纵 使用狭窄光谱从肠道微生物群中gnotobiotic腔室和微生物的耗竭（“敲除”） 抗生素。肠道菌群的分类学和功能表征以及对结果的检查 骨生物力学，化学和几何表型在整个器官，微观和微型和 纳米级。通过建立微生物组和骨强度之间的机械关系 生长和成人骨骼，拟议的工作将执行确定的必要第一步 微生物组疗法调节骨组织质量以减少骨骼脆弱性。