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

总结 低骨矿物质密度（BMD）是骨质疏松症的一个重要特征， 发展和/或加速骨丢失。有趣的是，在不同的年龄段， 人群中，约一半的BMD差异归因于遗传因素。但剩下的 人群中BMD差异的原因仍然是个谜。在人类微生物组项目的帮助下， 我们现在知道微生物组在健康和保健中起着关键作用。暗示微生物组 作为骨密度的调节剂，有报道称，在无菌（GF）条件下饲养的小鼠的骨 与传统小鼠相比。许多因素影响微生物群的组成， 包括基因组和非基因组因素。在非基因组因素中，最近发现的一种流行的 影响是与家庭成员同居，其中微生物在同居者之间水平转移，或 垂直地从父母到后代。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，其影响骨骼质量的效率。 发展我们的数据证实了这一假设，表明BMD水平和骨密度的频率 破骨细胞生成性Th 17细胞在具有不同微生物组组成的同基因小鼠之间存在差异。关键是，我们 还表明通过共同饲养这些小鼠平衡微生物群平衡了Th 17细胞的频率， 并平衡两组之间的骨密度。在这项提案中，我们将确定微生物组如何 出生后获得的多样性形成BMD和骨骼质量获得。在目标1中，我们将确定 肠道微生物群对出生后骨骼质量获得和峰值骨密度的贡献。在这里，我们将 利用gnotobiotic和免疫学的方法，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 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， 确定肠道细菌激活Th 17细胞对出生后骨骼发育的作用。最近的证据 已经表明肠道微生物组在骨骼疾病中起着因果作用，我们报告说， 微生物组调节骨骼对性类固醇缺乏的反应。我们新的初步数据显示， 微生物组也会影响骨骼对PTH的反应，我们发现GF小鼠和抗生素治疗 常规小鼠对PTH的骨合成代谢作用具有抗性。因此，在目标3中，我们将确定 肠道微生物组内和宿主内的功能元件是PTH发挥其 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的获得和骨骼效应可能使合理操作早期 生活微生物群，以消除儿童骨骼质量获得的微生物障碍，从而促进 最佳的骨骼质量发展在美国民众中。

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.