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

基本信息

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
项目类别：
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

项目摘要

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.

概括骨矿物质密度（BMD）低是骨质疏松症的一个关键特征，骨质疏松症是由骨骼缺陷引起的发育和/或加速骨质流失。有趣的是，不同地区的 BMD 存在很大程度的差异。人群中，大约一半的 BMD 差异归因于遗传因素。然而，剩余的人群内 BMD 差异的原因仍然是个谜。在人类微生物组计划的帮助下，我们现在了解到微生物组在健康和保健方面发挥着至关重要的作用。暗示微生物组作为 BMD 的调节剂，有报道称在无菌 (GF) 条件下饲养的小鼠的骨骼发生了改变与传统小鼠相比的密度。许多元素影响微生物群的组成，包括基因组因素和非基因组因素。在非基因组因素中，最近发现一种普遍存在的因素影响是与家庭成员同居，微生物在同居者之间水平转移，或者从父母到后代垂直。这些观察结果是我们令人信服的假设的基础，即微生物组是 BMD 遗传性的非基因组贡献者，会影响骨骼质量的效率发展。我们的数据证实了这一假设，显示 BMD 水平和频率具有不同微生物组组成的同基因小鼠之间的破骨细胞 Th17 细胞有所不同。关键的是，我们还表明，通过共同饲养这些小鼠来平衡微生物群平衡了 Th17 细胞的频率，并平衡两组之间的骨密度。在本提案中，我们将确定微生物组如何出生后获得的多样性决定了 BMD 和骨骼质量的获得。在目标 1 中，我们将确定肠道微生物群对产后骨骼质量获得和峰值骨密度的贡献。在这里，我们将利用无菌和免疫学方法，扩展经过验证的跨学科合作伙伴关系询问早期肠道微生物演替的精确控制模型，以确定肠道微生物的作用母体微生物组将产前微生物组的影响传递给后代。在目标 2 中，我们将确定肠道细菌激活 Th17 细胞对产后骨骼发育的作用。最近的证据研究表明，肠道微生物组在骨疾病中起着因果作用，我们报道称微生物组调节骨骼对性类固醇缺乏的反应。我们的新初步数据显示微生物组也影响骨骼对 PTH 的反应，我们发现 GF 小鼠和抗生素治疗传统小鼠对 PTH 的骨合成代谢作用具有抵抗力。因此，在目标 3 中，我们将确定肠道微生物组和宿主内的功能元件是 PTH 发挥其作用所必需的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 PTH 的获得和骨骼效应将有可能使早期的合理操纵试验成为可能。生命微生物群，消除儿童骨骼质量获取的微生物障碍，从而促进美国民众的最佳骨骼质量发育。