Role of Gut Microbiota in Bone Mass Heritability and Skeletal Response to PTH

肠道微生物群在骨量遗传力和骨骼对 PTH 反应中的作用

• 批准号: 10338089
• 负责人: RHEINALLT MELFYN JONES
• 金额: $ 53.75万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-06 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10338089
• 关键词: Affect; Age; American; Antibiotics; Bacteria; Birth; Bone Density; Bone Diseases; Breeding; CD4 Positive T Lymphocytes; Cells; Child; Childhood; Data; Development; Elements; Equilibrium; Estrogens; Family; Family member; Forteo; Frequencies; Generations; Genetic; Genomics; Germ-Free; Gnotobiotic; Goals; Gonadal Steroid Hormones; Health; Heritability; Homeostasis; Housing; Human; Human Microbiome; Hydrogen Sulfide; Immunologics; Inbred Mouse; Interleukin-17; Intervention; Intestines; Knowledge; Laboratories; Lead; Life; Link; Microbe; Modeling; Morbidity - disease rate; Mouse Strains; Mus; Names; Osteoporosis; PTH gene; Parents; Phenotype; Play; Population; Quality of life; Regulatory T-Lymphocyte; Reporting; Research; Resistance; Role; Shapes; Skeletal Development; Skeleton; T-Cell Development; T-Lymphocyte; Testing; Variant; Volatile Fatty Acids; Woman; Work; base; bone; bone health; bone loss; bone mass; bone preservation; clinical care; cytokine; disability; experimental study; feeding; germ free condition; gut bacteria; gut microbiome; gut microbiota; maternal microbiome; maternal microbiota; men; microbial; microbiome; microbiome composition; microbiota; microbiota transplantation; non-genomic; novel; offspring; prenatal; response; skeletal

SUMMARY Low bone mineral density (BMD) is a key feature of osteoporosis that is caused by deficient skeletal development and/or accelerated bone loss. Interestingly, there is a high degree of variation in BMD within populations, with about half of the differences in BMD attributed to genetic factors. However, the remaining causes of BMD variance within populations remain enigmatic. With the help of the Human Microbiome Project, we now understand that the microbiome plays a critical role in health and wellness. Implicating the microbiome as a regulator of BMD are established reports that mice raised in germ-free (GF) conditions have altered bone density compared to conventional mice. A number of elements influence the composition of the microbiota, including both genomic and non-genomic factors. Of the non-genomic factors, a recently realized prevalent influence is cohabitation with family members, where microbes transfer horizontally between co-inhabitants, or vertically from parent to offspring. These observations are the basis of our compelling hypothesis that the microbiome is a non-genomic contributor to BMD heretability, which affects the efficiency of skeletal mass development. Corroborating this hypothesis is our data showing that BMD levels, and the frequency of osteoclastogenic Th17 cells differ between isogenic mice with varying microbiome compositions. Critically, we also show that equalization of the microbiota by co-housing these mice balances the frequency of Th17 cells, and balances the bone density between the two groups. In this proposal, we will identify how microbiome diversity acquired following birth shapes BMD and skeletal mass acquisition. In Aim 1, we will determine the contribution of gut microbiota to post-natal skeletal mass acquisition and peak bone density. Here, we will leverage gnotobiotic and immunological approaches extending a proven transdisciplinary partnership to interrogate precisely controlled models of early-life intestinal microbial succession, to establish the role of the maternal microbiome in transmitting the effects of the pre-natal microbiome to offspring. In Aim 2 we will identify the role of gut bacterial activation of Th17 cells on post-natal skeletal development. Recent evidence has shown that the gut microbiome plays a causal role in bone disease, where we reported that the microbiome regulates the skeletal response to sex steroid deficiency. Our new preliminary data show that the microbiome also influences the skeletal response to PTH, where we show that GF mice and antibiotic treated conventional mice are resistant to the bone anabolic effects of PTH. Therefore, in Aim 3 we will identify the functional elements within the gut microbiome and within the host that are necessary for PTH to exert its modulatory effects on skeletal homeostasis. Understanding how the gut microbiome regulates skeletal mass acquisition and the skeletal effects of PTH would potentially enable trials of rational manipulation of the early life microbiota to remove microbial impediments to childhood skeletal mass acquisition, thereby facilitating optimal skeletal mass development within the American populace.

概括 低骨矿物质密度（BMD）是骨质疏松症的关键特征，这是由骨骼不足引起的 发育和/或加速骨质流失。有趣的是，BMD内部存在高度差异 人群，BMD差异的一半归因于遗传因素。但是，剩下的 人群中BMD差异的原因仍然神秘。在人类微生物组项目的帮助下， 我们现在了解到，微生物组在健康和保健中起着至关重要的作用。暗示微生物组 作为BMD的调节剂，有报道称无菌（GF）条件中饲养的小鼠骨骼改变了 与常规小鼠相比，密度。许多元素影响菌群的组成， 包括基因组和非基因组因子。在非基因组因素中，最近实现的普遍 影响是与家庭成员共同居住的人，其中微生物在共同居民之间水平转移 垂直从父母到后代。这些观察是我们令人信服的假设的基础 微生物组是BMD遗传性的非基因组贡献者，这会影响骨骼质量的效率 发展。确认这一假设的是我们的数据表明BMD水平以及 在不同的微生物组组成的同源小鼠之间，破骨细胞生成的Th17细胞有所不同。批判性，我们 还表明，通过共同设置这些小鼠平衡菌群的均衡，平衡了Th17细胞的频率， 并平衡两组之间的骨密度。在此提案中，我们将确定微生物组如何 出生形状BMD和骨骼质量获取后获得的多样性。在AIM 1中，我们将确定 肠道微生物群对产后骨骼质量恢复和峰值骨密度的贡献。在这里，我们会的 利用gnotobiotic和免疫学方法，将验证的跨学科伙伴关系扩展到 询问早期生命肠道微生物继承的精确控制模型，以确定 母体微生物组将产前微生物组的影响传播到后代。在目标2中，我们将 确定Th17细胞肠道细菌激活对产后骨骼发育的作用。最近的证据 已经表明，肠道微生物组在骨骼疾病中起因作用，我们报告说 微生物组调节对性类固醇缺乏的骨骼反应。我们的新初步数据表明 微生物组还影响对PTH的骨骼反应，在那里我们表明GF小鼠和抗生素处理 常规小鼠对PTH的骨合成代谢作用有抗性。因此，在目标3中，我们将确定 肠道微生物组中的功能元素以及pth所必需的宿主中的功能元素 对骨骼稳态的调节作用。了解肠道微生物组如何调节骨骼质量 获取和PTH的骨骼效应可能有可能实现对早期进行合理操纵的试验 生命微生物群消除对儿童骨骼质量获取的微生物障碍，从而促进 美国民众中的最佳骨骼质量发展。