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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

基本信息

批准号：
10713381
负责人：
JOHN P BILEZIKIAN
金额：
$ 6.94万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2023-04-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10713381
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

项目摘要

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