Critical Role of the Gut Microbiota in Prunes’ Prevention of Glucocorticoid Induced Osteoporosis

项目摘要/摘要 长期使用糖皮质激素可导致糖皮质激素性骨质疏松症(GIO)，并随后增加 短短三个月内就有骨折的风险。目前对抗GIO的药物疗法是有效的， 然而，它们具有显著的副作用特征，而且成本高昂，导致依从率创历史新低。 因此，发现既有成本效益又几乎没有副作用的新疗法既是可取的，也是 这是必要的。已知肠道微生物区系在GIO的发病和预防中起着不可或缺的作用 我们的实验室和其他实验室已经表明，肠道微生物区系是促进骨骼的新的治疗目标。 健康。李子是一种天然水果李子的干燥形式，已被证明对两者的骨骼健康都有好处 临床前和人类模型的原发性骨质疏松症，尽管其机制还不是很清楚。在……里面 初步研究表明，李子可以预防小鼠的GIO。李子显著地改变了 肠道微生物区系的组成，也被肠道微生物区系广泛代谢。此外，梅花 富含色氨酸，对骨骼健康很重要。在进一步的研究中，我们发现微生物衍生的 血清色氨酸代谢产物与骨量呈正相关。到目前为止，李子和他们的 微生物衍生的代谢物还没有在预防GIO的背景下进行研究。长期的 本项目的目标是建立修剪诱导植物生长发育变化的机制基础。 肠道微生物区系组成和相应的色氨酸代谢物可防止GIO。 对于这个团契，我提出了两个目标：目标1将展示勇气的关键和直接作用 微生物区系在调节饮食李子对GIO的有益影响中的作用。分目标1A将审查 利用粪便移植模型改善梅干骨密度和预防GIO的肠道微生物区系 (鼠标和鼠标)。为了建立翻译相关性，子目标1B将调查修剪是否对 人类微生物区系可以移植到小鼠身上(人和小鼠的粪便移植)，并改善骨骼健康。目标2 将证明来自李子的微生物衍生的色氨酸代谢物是否可以独立改善骨骼 密度和防止GIO。子目标2A将研究色氨酸代谢产物对预防成骨细胞的作用 细胞凋亡和GIO使用体内模型，而SubAIM 2B将在体外进一步研究它们的机制。 这一培训奖学金将履行国家补充和综合卫生中心的所有方面 确定补充和综合健康的基础科学、有效性和安全性的使命 方法及其在改善健康方面的作用。总体而言，这种友谊将促进机械论的理解。 一种新的治疗方法来对抗GIO，并对降低医疗成本和 改善患者的预后。

PROJECT SUMMARY/ABSTRACT Prolonged glucocorticoid use can lead to glucocorticoid induced osteoporosis (GIO) and subsequently increase fracture risk in as little as three months. Current pharmacological therapies to combat GIO are effective, however they carry significant side effect profiles and are costly, leading to historically poor adherence rates. Thus, discovery of novel therapeutics that are cost effective and carry few side effects are both desirable and necessary. The gut microbiota is known to play an integral role in both the pathogenesis and prevention of GIO and our lab and others have shown that the gut microbiota is a novel therapeutic target for promoting bone health. Prunes are the dried form of a natural fruit, plums, and have been shown to benefit bone health in both pre-clinical and human models of primary osteoporosis, although their mechanism is not well understood. In preliminary studies, we demonstrate that prunes prevent GIO in mice. Prunes significantly alter the composition of gut microbiota and are also extensively metabolized by the gut microbiota. Additionally, prunes are rich in tryptophan which is important in bone health. In additional studies, we found that microbially derived tryptophan metabolites in the serum positively correlate with bone volume. To date, prunes and their microbially derived metabolites have not been studied in the context of GIO prevention. The long-term objective of this project is to establish the mechanistic basis by which prune induced changes in the gut microbiota composition and correspondingly its tryptophan metabolites prevent GIO. For this fellowship, I am proposing 2 aims: Aim 1 will demonstrate the critical and direct role of the gut microbiota in mediating the beneficial effect of dietary prunes in GIO. Sub Aim 1A will examine the role of the gut microbiota in prunes’ improvement of bone density and prevention of GIO by using a fecal transplant model (mouse à mouse). To establish translational relevance, Sub Aim 1B will investigate if prunes effect on the human microbiota are transferable to mice (human à mouse fecal transplant) and improve bone health. Aim 2 will demonstrate if microbially derived tryptophan metabolites from prunes can independently improve bone density and prevent GIO. Sub Aim 2A will investigate tryptophan metabolites effect on preventing osteoblast apoptosis and GIO using an in vivo model while sub aim 2B will further investigate their mechanisms in vitro. This training fellowship will fulfill all aspects of the National Center for Complementary and Integrative Health’s mission to determine the fundamental science, usefulness, and safety of complementary and integrative health approaches and their role in improving health. Overall, this fellowship will advance mechanistic understanding of a novel therapeutic approach to combat GIO and have a direct impact on reducing healthcare costs and improving patient outcomes.