Role of the gut microbiome in the bone loss induced by hyperparathyroidism in mice and humans

肠道微生物组在小鼠和人类甲状旁腺功能亢进引起的骨质流失中的作用

• 批准号: 10115891
• 负责人: JOHN P BILEZIKIAN
• 金额: $ 57.29万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10115891
• 关键词: Affect; Bacteria; Bifidobacterium; Biological Markers; Blood; Bone Density; Bone Marrow; CCL20 gene; CCR6 gene; Cell Differentiation process; Cell Maturation; Cells; Data; Disease; Etiology; FDA approved; Feces; Frequencies; Future; Germ-Free; Heterogeneity; Hormones; Human; Human Microbiome; Hyperparathyroidism; Inflammatory; Infusion procedures; Interleukin-17; Intestines; Lamina Propria; Lead; Ligands; Measures; Mediating; Modeling; Mus; Nature; Osteoporosis; PTH gene; Parathyroid gland; Patients; Phenotype; Photosensitivity; Population; Process; Production; Reporting; Reproduction spores; Role; Stream; Stromal Cells; T-Lymphocyte; TNFSF11 gene; Testing; Tissues; Up-Regulation; Variant; antimicrobial; base; bone; bone loss; cell motility; chemokine; enteric infection; experience; fecal microbiome; fecal transplantation; fracture risk; gut microbiome; inhibitor/antagonist; microbial; microbiome; microbiome sequencing; migration; mouse model; novel; novel strategies; pathogen; prevent; skeletal; trafficking

SUMMARY Primary hyperparathyroidism (PHPT) is a condition caused by the excessive secretion of parathyroid hormone (PTH) that can lead to aggressive bone loss, osteoporosis and increased risk of fractures. Intriguingly, PHPT is a heterogeneous disease where some patients go on to develop bone loss while others do not, and few biomarkers are available to predict the course of the disease. We recently reported in Nat. Comm. that the intestinal microbiome is a potent factor governing the capacity of PTH to induce bone loss. Specifically, we showed in mice that elevated levels of PTH in combination with microbial-released products potentiates the activation of pro-inflammatory TNF producing T cells in gut tissue, which then migrate from the gut to the bone marrow (BM). In a process that only occur if specific species of bacteria are present in the microbiome, intestinal TNF producing T cells induce the expansion of Th17 cells in the gut. Elevated TNF in the BM induce the expression of chemokine ligands that attract Th17 cells to the BM. Once in the BM, Th17 cells release the osteoclastogenic factor IL-17 which causes RANKL-mediated bone loss. In human populations, there is significant heterogeneity in gut microbiome diversity, including considerable variation in the frequency of presence of specific bacteria that activate Th17 cell maturation. We hypothesize that this heterogeneity directly accounts for the heterogeneous nature of PHPT-associated bone loss within populations, where only patients that are colonized with Th17 cell-inducing bacteria experience PHPT-induced bone loss. In support of this hypothesis, we show compelling new data that the relative frequency of a specific strain of the Th17 cell- inducing bacteria Bifidobacterium longum correlates inversely with bone density in PHPT patients. In Aim 1, we will test if the propensity of human patients with PHPT to develop bone loss can be predicted by the composition of the gut microbiome. Furthermore, to demonstrate causality, we will colonize germ-free mice with either the microbiome of PHTP patients, or Bifidobacterium longum and determine if the PHPT-induced, and gut bacterial-dependent bone loss phenotype is transferable within the microbiome. These studies will demonstrate that stool microbiome sequencing may be used as a novel screen to predict which PHPT patients develop bone loss. In addition, identification of the bacteria that endow PTH with the capacity to induce bone loss will provide a rationale for future studies where targeted antimicrobial approaches aimed at eradicating Th17 cell-inducing bacteria may be used to prevent bone loss in PHPT patients. In Aim 2, we will use a powerful new photosensitive murine model where we can visualize the trafficking cells, to measure the effects of PTH on the migration of TNF producing T cells, and Th17 cells from the gut to the BM. The identification of the mechanisms of human microbiome-induced T cells migration from the gut to the BM will yield essential data to inform novel strategies for preventing skeletal complications associated with PHPT, based on the use of FDA approved agents that block the egress of T cells from the gut and/or their influx into the BM.

总结 原发性甲状旁腺功能亢进（PHPT）是一种由甲状旁腺激素分泌过多引起的疾病 (PTH)这会导致严重的骨质流失、骨质疏松和骨折风险增加。有趣的是，PHPT是 一种异质性疾病，其中一些患者继续发展骨丢失，而另一些则没有，并且很少 生物标志物可用于预测疾病的进程。我们最近在《国家通讯》上报道说， 肠道微生物组是控制PTH诱导骨丢失能力的有效因素。我们特别 在小鼠中显示，PTH水平升高与微生物释放的产物相结合， 激活肠道组织中产生促炎性TNF的T细胞，然后从肠道迁移到骨骼 骨髓（BM）。在一个只有在微生物组中存在特定细菌物种时才发生的过程中， 肠内产生TNF的T细胞诱导肠道中Th 17细胞的扩增。BM中TNF升高诱导 趋化因子配体的表达将Th 17细胞吸引到BM。一旦进入骨髓，Th 17细胞释放出 破骨细胞生成因子IL-17导致RANKL介导的骨丢失。在人类中， 肠道微生物组多样性的显著异质性，包括 存在激活Th 17细胞成熟的特定细菌。我们假设这种异质性直接 解释了PHPT相关骨丢失在人群中的异质性， 被Th 17细胞诱导细菌定殖的小鼠经历PHPT诱导的骨丢失。为支持这一 假设，我们展示了令人信服的新数据，即Th 17细胞特定菌株的相对频率- 诱导细菌长双歧杆菌与PHPT患者的骨密度呈负相关。目标1： 将测试PHPT患者发生骨丢失的倾向是否可以通过 肠道微生物组的组成。此外，为了证明因果关系，我们将无菌小鼠 与PHTP患者的微生物组或长双歧杆菌接触，并确定PHPT诱导的， 并且肠道细菌依赖性骨丢失表型在微生物组内是可转移的。这些研究将 证明粪便微生物组测序可用作一种新的筛选，以预测哪些PHPT患者 骨质流失此外，鉴定赋予PTH诱导骨形成能力的细菌， 损失将为未来的研究提供理论基础， Th 17细胞诱导细菌可用于预防PHPT患者的骨丢失。在目标2中，我们将使用 强大的新的光敏小鼠模型，我们可以看到贩运细胞，以衡量影响 PTH对产生TNF的T细胞和Th 17细胞从肠道向BM的迁移的影响。的识别 人类微生物群诱导的T细胞从肠道迁移到BM的机制将产生重要的 基于PHPT的使用，为预防与PHPT相关的骨骼并发症提供新策略的数据 FDA批准的药物，阻止T细胞从肠道流出和/或流入BM。