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: 10899018
• 负责人: JOHN P BILEZIKIAN
• 金额: $ 10万
• 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/10899018
• 关键词: Affect; Bacteria; Bifidobacterium; Biological Markers; Blood; Bone Density; Bone Marrow; CCL20 gene; CCR6 gene; Cell Differentiation process; Cell Maturation; Cell secretion; Cells; Data; Disease; Endowment; Etiology; FDA approved; Feces; Fracture; Frequencies; Future; Germ-Free; Heterogeneity; Hormones; Human; Human Microbiome; Hyperparathyroidism; IL17 gene; Inflammatory; Infusion procedures; Intestinal Mucosa; Intestines; Lamina Propria; Ligands; Measures; Mediating; Modeling; Mus; Nature; Osteocytes; Osteoporosis; PTH gene; Parathyroid gland; Patients; Phenotype; Population; Process; Production; Reporting; Reproduction spores; Role; Stream; Stromal Cells; T-Lymphocyte; TNF gene; TNFSF11 gene; Testing; Tissues; Up-Regulation; Variant; Visualization; antimicrobial; bone; bone loss; cell motility; chemokine; commensal bacteria; 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症（PHPT）是由于甲状旁腺激素分泌过多引起的疾病 (PTH) 可导致严重骨质流失、骨质疏松症和骨折风险增加。有趣的是，PHPT 是 一种异质性疾病，一些患者会继续出现骨质流失，而另一些患者则不会，只有少数患者会出现骨质流失。 生物标志物可用于预测疾病的进程。我们最近在《Nat》上进行了报道。通讯。那 肠道微生物组是控制 PTH 诱导骨质流失能力的有效因素。具体来说，我们 在小鼠中表明，升高的 PTH 水平与微生物释放的产物相结合可增强 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）。在只有当微生物组中存在特定种类的细菌时才会发生的过程中， 肠道内产生 TNF 的 T 细胞会诱导肠道内 Th17 细胞的扩增。 BM 中 TNF 升高诱导 吸引 Th17 细胞至 BM 的趋化因子配体的表达。一旦进入 BM，Th17 细胞就会释放 破骨细胞因子 IL-17 会导致 RANKL 介导的骨质流失。在人类群体中，有 肠道微生物组多样性存在显着异质性，包括发生频率的显着差异 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 解释了人群中 PHPT 相关骨质流失的异质性，其中只有患者 被 Th17 细胞诱导细菌定植的细胞会经历 PHPT 引起的骨质流失。为了支持这一点 假设，我们展示了令人信服的新数据，即 Th17 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。在目标 1 中，我们 将测试是否可以通过以下方法预测患有 PHPT 的人类患者发生骨质流失的倾向 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 PHPT 患者的微生物组或长双歧杆菌进行比较，并确定 PHPT 是否诱导， 肠道细菌依赖性骨质流失表型可以在微生物组内转移。这些研究将 证明粪便微生物组测序可作为一种新的筛选方法来预测哪些 PHPT 患者 出现骨质流失。此外，鉴定赋予 PTH 诱导骨能力的细菌 损失将为未来的研究提供依据，在这些研究中，有针对性的抗菌方法旨在根除 Th17 细胞诱导细菌可用于预防 PHPT 患者的骨质流失。在目标 2 中，我们将使用 强大的新型光敏小鼠模型，我们可以可视化贩运细胞，以测量效果 PTH 对产生 TNF 的 T 细胞和 Th17 细胞从肠道迁移到 BM 的影响。鉴定 人类微生物组诱导 T 细胞从肠道迁移到 BM 的机制将产生重要的结果 数据为预防 PHPT 相关骨骼并发症的新策略提供信息，基于使用 FDA 批准的药物可以阻止 T 细胞从肠道流出和/或流入 BM。