The Microbial Metabolite Butyrate Stimulates Bone Formation via T Regulatory Cell-Mediated Regulation of WNT10B Expression

Abdul Malik Tyagi 5 Mingcan Yu 5 Trevor M. Darby 5 M. Neale Weitzmann Rheinallt M. Jones Roberto Pacifici 6 Show all authors Show footnotes Open AccessPublished: November 13, 2018DOI:https://doi.org/10.1016/j.immuni.2018.10.013 Open access funded by National Institutes of Health PlumX Metrics Next Article Distinct Compartmentalization of the Chemokines CXCL1 a … Highlights Summary Graphical Abstract Keywords Introduction Results Discussion STAR★Methods Acknowledgments Supplemental Information References Article Info Figures Related Articles Comments Highlights • Treatment with the probiotic Lactobacillus rhamnosus GG (LGG) increases bone mass in mice by stimulating the production of butyrate • LGG or butyrate expands the pool of Treg cells in the gut and the bone marrow • Treg cells upregulate the expression of osteogenic Wnt ligand Wnt10b by CD8+ T cells • Wnt10b stimulates bone formation by activating Wnt signaling in osteoblasts Summary Nutritional supplementation with probiotics can prevent pathologic bone loss. Here we examined the impact of supplementation with Lactobacillus rhamnosus GG (LGG) on bone homeostasis in eugonadic young mice. Micro-computed tomography revealed that LGG increased trabecular bone volume in mice, which was due to increased bone formation. Butyrate produced in the gut following LGG ingestion, or butyrate fed directly to germ-free mice, induced the expansion of intestinal and bone marrow (BM) regulatory T (Treg) cells. Interaction of BM CD8+ T cells with Treg cells resulted in increased secretion of Wnt10b, a bone anabolic Wnt ligand. Mechanistically, Treg cells promoted the assembly of a NFAT1-SMAD3 transcription complex in CD8+ cells, which drove expression of Wnt10b. Reducing Treg cell numbers, or reconstitution of TCRβ−/− mice with CD8+ T cells from Wnt10b−/− mice, prevented butyrate-induced bone formation and bone mass acquisition. Thus, butyrate concentrations regulate bone anabolism via Treg cell-mediated regulation of CD8+ T cell Wnt10b production. Graphical Abstract Figure thumbnail fx1 View Large Image Figure ViewerDownload Hi-res image Download (PPT) Keywords Lactobacillus rhamnosus GG butyrate microbiota bone formation probiotics short-chain fatty acids Wnt10b NFAT T cells regulatory T cells