Grant Abstract: Prebiotic Activity of Fructooligosaccharides and the Immunoregulation of Bone Homeostasis

Grant Number: 3R15AT010725-01
PI Name: Smith
Project Title: Prebiotic Activity of Fructooligosaccharides and the Immunoregulation of Bone Homeostasis

Abstract: Recent reports focused on the gut-bone axis have renewed wide-spread interest in the role of nutritional interventions in osteoporosis prevention. Compelling evidence has shown that probiotics increase short chain fatty acid (SCFA) production, which in turn promotes the differentiation of T regulatory (TREG) cells that mediate the bone protective effects. In contrast, the osteoprotective activity of prebiotics have been traditionally attributed to a SCFA-induced increase in intestinal calcium uptake. However, these new insights into the gut-bone axis raise the question of whether prebiotics target gut commensal microbiota and alter bone homeostasis by similar immunoregulatory mechanisms. Our parent project is focused on investigating whether dietary supplementation with tart cherry, rich in prebiotics (i.e., fructooligosaccharides (FOS) and polyphenolic compounds), mediates its effects on bone homeostasis via butyrate-induced alterations in TREG cells. We propose to build on that work in this administrative supplement application through the use of novel experimental and computational modeling approaches. Our goal is to determine the extent to which a synthetic FOS prebiotic, which contains similar individual fructose fractions as tart cherry, mediates it effects on bone via butyrate- induced alterations in TREG cells. Our preliminary data will demonstrate the advantages of capitalizing on multiscale systems modeling methods when studying interactions between the SCFA produced in the gut, T cells and bone homeostasis. We hypothesize that the benefits of FOS supplementation on bone are mediated, at least in part, by enhanced TREG differentiation resulting from alterations in the gut microbiota and the subsequent increase in butyrate production. This hypothesis will be tested by: Aim 1) determining how dietary supplementation with FOS alters bone homeostasis and the extent to which these effects are mediated by alterations in TREG cells; and Aim 2) investigating the role of butyrate derived from the gut microbiota in this skeletal response. The proposed studies will provide an excellent training opportunity and advance our understanding of how prebiotics mediate their effects on the gut-bone axis. These findings utilizing this combined experimental/computational approach will lay the groundwork for future clinical studies, which is in line with our long-term goal of developing dietary strategies for preventing osteoporosis. PUBLIC HEALTH RELEVANCE: : Despite therapeutic advances, osteoporosis continues to be a major public health problem. This project will investigate whether synthetic prebiotics protect bone by altering the T cell immune response. These findings will allow us to determine if prebiotics can be used to target gut microorganisms as a novel dietary strategy for osteoporosis.

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