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

肠道微生物群在西梅预防糖皮质激素引起的骨质疏松症中的关键作用

• 批准号: 10678381
• 负责人: Nicholas Chargo
• 金额: $ 5.14万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-06 至 2028-07-05
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678381
• 关键词: Acids; Address; Adherence; Aging; Amaze; Apoptosis; Bone Density; Cells; Clinical Trials; Complementary Health; Data; Diet; Disease; Dose; Dryness; Fellowship; Fiber; Fracture; Fruit; Gene Expression; Gene Expression Profiling; Glucocorticoids; Health; Health Care Costs; Human; In Vitro; Incidence; Integrative Medicine; Intestines; Link; Literature; Mediating; Mission; Modeling; Mus; National Center for Complementary and Integrative Health; Osteoblasts; Osteogenesis; Osteoporosis; Osteoporosis prevention; Outcome; Outcome Measure; Pathogenesis; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Placebos; Play; Plum; Pre-Clinical Model; Prevention; Probiotics; Production; Role; Safety; Science; Serum; Testing; Training; Tryptophan; Tryptophan Metabolism Pathway; adherence rate; bone; bone health; bone turnover; combat; cost; cost effective; density; dietary; fecal transplantation; feeding; fracture risk; gut health; gut microbiota; human microbiota; human model; improved; in vivo; in vivo Model; innovation; metabolomics; microbial; microbiota; mouse model; new therapeutic target; novel therapeutic intervention; novel therapeutics; pharmacologic; pre-clinical; prevent; primary outcome; response; side effect; stool sample; substantia spongiosa; targeted treatment; transplant model

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.

项目概要/摘要 长期使用糖皮质激素可导致糖皮质激素诱发的骨质疏松症 (GIO)，并随后增加 短短三个月内就有骨折风险。目前对抗 GIO 的药物疗法是有效的， 然而，它们具有显着的副作用并且成本高昂，导致历史上的依从率很低。 因此，发现具有成本效益且副作用少的新疗法既是可取的，也是 必要的。众所周知，肠道微生物群在 GIO 的发病机制和预防中发挥着不可或缺的作用 我们的实验室和其他人已经证明肠道微生物群是促进骨骼生长的新治疗靶点 健康。西梅是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体模型，尽管其机制尚不清楚。在 初步研究表明，李子可以预防小鼠的 GIO。梅子显着改变 肠道微生物群的组成，也被肠道微生物群广泛代谢。此外，李子 富含色氨酸，对骨骼健康很重要。在其他研究中，我们发现微生物衍生的 血清中的色氨酸代谢与骨体积呈正相关。迄今为止，李子及其 尚未在 GIO 预防的背景下研究微生物衍生的代谢物。长期来看 该项目的目标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可预防 GIO。 对于这个奖学金，我提出了 2 个目标： 目标 1 将展示肠道的关键和直接作用 微生物群介导 GIO 中膳食李子的有益作用。子目标 1A 将审查 李子中的肠道微生物群通过粪便移植模型改善骨密度并预防 GIO （鼠标→鼠标）。为了建立翻译相关性，子目标 1B 将调查李子是否对 人类微生物群可以转移到小鼠身上（人类→小鼠粪便移植）并改善骨骼健康。目标2 将证明来自李子的微生物色氨酸代谢物是否可以独立改善骨骼 密度并防止GIO。 Sub Aim 2A 将研究色氨酸代谢物对预防成骨细胞的影响 细胞凋亡和GIO使用体内模型，而子目标2B将进一步研究它们的体外机制。 该培训奖学金将实现国家补充和综合健康中心的各个方面 使命是确定补充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，这项研究金将促进机械理解 一种对抗 GIO 的新治疗方法，对降低医疗成本和产生直接影响 改善患者的治疗效果。