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: 10679360
• 负责人: JOHN P BILEZIKIAN
• 金额: $ 4.18万
• 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/10679360
• 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; 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.

概括 原发性甲状旁腺功能亢进（PHPT）是由甲状旁腺激素分泌过多引起的疾病 （PTH）可能导致侵略性骨质流失，骨质疏松症和裂缝风险增加。有趣的是，PHPT是 某些患者继续发展骨质流失，而另一些则没有，而很少有疾病 生物标志物可以预测疾病的过程。我们最近在NAT报道。通讯。那是 肠道微生物组是一个有效的因素，该因素是PTH诱导骨质流失的能力的有效因素。具体来说，我们 在小鼠中表明，与微生物释放的产品结合使用PTH的水平升高增强 促炎性TNF在肠道组织中产生T细胞的激活，然后从肠道迁移到骨骼 骨髓（BM）。在仅当微生物组中存在特定的细菌时才发生的过程中， 肠道TNF产生T细胞会诱导肠道中Th17细胞的膨胀。 BM中升高的TNF诱导 将Th17细胞吸引到BM的趋化因子配体的表达。进入BM后，Th17细胞释放 骨质质构成因子IL-17，导致RANKL介导的骨质流失。在人口中，有 肠道微生物组多样性的显着异质性，包括频率很大的变化 激活Th17细胞成熟的特定细菌的存在。我们假设这种异质性直接 说明人群中与pHPT相关的骨质流失的异质性质，只有患者 用Th17细胞诱导的细菌定植的经历pHPT诱导的骨质流失。支持这个 假设，我们显示了令人信服的新数据，即Th17细胞特异性菌株的相对频率 诱导细菌双歧杆菌长杆菌与PHPT患者的骨密度相反。在AIM 1中，我们 将测试是否可以预测 肠道微生物组的组成。此外，为了证明因果关系，我们将殖民无菌小鼠 与PHTP患者的微生物组或双歧杆菌长杆菌，并确定PHPT诱导的是 肠道细菌依赖性骨质流失表型在微生物组中可转移。这些研究会 证明粪便微生物组测序可以用作新的屏幕，以预测哪些PHPT患者 发展骨质流失。另外，鉴定具有诱导骨骼能力的细菌 损失将为未来的研究提供基本原理，在该研究中，旨在消除旨在消除的抗菌方法 TH17诱导细菌可用于预防PHPT患者的骨质流失。在AIM 2中，我们将使用 强大的新光敏鼠模型，我们可以在其中可视化运输细胞，以测量效果 PTH在TNF产生T细胞的迁移以及Th17细胞从肠道到BM的迁移。识别 人微生物组诱导的T细胞从肠道迁移到BM的机制将产生必不可少的 根据使用 FDA批准的药物，阻断了T细胞从肠道和/或它们的涌入BM中的出口。