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

项目总结/文摘

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.