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

项目总结/摘要 长期使用糖皮质激素可导致糖皮质激素诱导的骨质疏松症（GIO）， 三个月内就有骨折的危险目前对抗GIO的药物治疗是有效的， 然而，它们具有显著的副作用，并且成本高，导致历史上较差的依从率。 因此，发现具有成本效益且副作用少的新型治疗剂既是期望的， 必要已知肠道微生物群在GIO的发病机制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证明，肠道微生物群是促进骨骼发育的新治疗靶点， 健康李子是一种天然水果李子的干燥形式，已被证明对骨骼健康有益。 原发性骨质疏松症的临床前和人类模型，尽管其机制尚未完全了解。在 在初步研究中，我们证明了西梅可以预防小鼠的GIO。李子显著改变了 它们是肠道微生物群的主要组成部分，也被肠道微生物群广泛代谢。此外，Prunes 富含对骨骼健康很重要的色氨酸。在其他研究中，我们发现微生物来源的 血清中色氨酸代谢物与骨体积正相关。到目前为止，梅干和它们的 微生物衍生的代谢物尚未在GIO预防的背景下进行研究。长期 本项目的目的是建立修剪引起的变化的机制基础， 肠道微生物群组成及其相应的色氨酸代谢物防止GIO。 对于这个奖学金，我提出了两个目标：目标1将证明肠道的关键和直接作用 微生物群在介导饮食西梅在GIO中的有益作用。子目标1A将审查 通过使用粪便移植模型研究西梅改善骨密度和预防GIO的肠道微生物群 （mouse à mouse）.为了建立翻译相关性，子目标1B将调查修剪是否对 人类微生物群可转移到小鼠体内（人类→小鼠粪便移植），并改善骨骼健康。目的2 将证明来自西梅的微生物衍生的色氨酸代谢物是否可以独立地改善骨骼 密度和防止GIO。子目标2A将研究色氨酸代谢物对防止成骨细胞 目的2B将在体外进一步研究它们的机制。 这项培训奖学金将履行国家补充和综合健康中心的所有方面， 使命：确定互补和综合健康的基础科学、有用性和安全性 方法及其在改善健康方面的作用。总的来说，这个奖学金将促进机械的理解 一种新的治疗方法来对抗GIO，并对降低医疗成本产生直接影响， 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.