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

摘要 低骨密度(BMD)是由骨骼不足引起的骨质疏松症的一个重要特征 发育和/或加速骨质流失。有趣的是，人体内的骨密度差异很大。 大约一半的骨密度差异可归因于遗传因素。然而，剩下的 人群内骨密度差异的原因仍然是个谜。在人类微生物组计划的帮助下， 我们现在知道，微生物群在健康和健康中发挥着关键作用。牵涉到微生物组 作为骨密度的调节因素，有报道称，在无菌(GF)条件下饲养的小鼠骨骼发生了改变 与常规小鼠相比，其密度更高。许多元素影响微生物区系的组成， 包括基因组因素和非基因组因素。在非基因组因素中，一种最近意识到的流行 影响是与家庭成员同居，微生物在同居居民之间水平转移，或者 垂直地从父母传给后代。这些观察结果是我们令人信服的假设的基础 微生物组是骨密度遗传性的非基因组贡献者，它影响骨骼质量的效率。 发展。我们的数据证实了这一假设，数据显示，骨密度水平和 破骨细胞Th17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。关键的是，我们 还表明，通过共住这些小鼠来平衡微生物群平衡了Th17细胞的频率， 并在两组之间平衡骨密度。在这项提案中，我们将确定微生物组是如何 随着出生形状、骨密度和骨骼质量获得而获得的多样性。在目标1中，我们将确定 肠道微生物区系对出生后骨量获取和峰值骨密度的贡献。在这里，我们将 利用诺生菌和免疫学方法，将经过验证的跨学科合作伙伴关系扩展到 询问早期肠道微生物演替的精确控制模型，以确定 母体微生物组在将产前微生物组的影响传递给后代中的作用。在《目标2》中我们将 确定肠道细菌激活Th17细胞在出生后骨骼发育中的作用。最近的证据 已经表明肠道微生物群在骨骼疾病中起着因果作用，我们在那里报告了 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， 微生物组也影响骨骼对甲状旁腺激素的反应，我们的研究表明，GF小鼠和抗生素治疗 传统的小鼠对甲状旁腺素的骨合成代谢作用有抵抗力。因此，在目标3中，我们将确定 肠道微生物群和宿主内甲状旁腺激素发挥其功能所必需的功能元件 对骨骼动态平衡的调节作用。了解肠道微生物群如何调节骨骼质量 甲状旁腺素的获得和骨骼效应可能使早期理性操纵的试验成为可能。 生命微生物群，消除阻碍儿童骨骼获取的微生物障碍，从而促进 美国人骨量的最佳发育。

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.