Parathyroid hormone–dependent bone formation requires butyrate production by intestinal microbiota

Parathyroid hormone (PTH) is a critical regulator of skeletal development that promotes both bone formation and bone resorption. Using microbiota depletion by wide-spectrum antibiotics and germ-free (GF) female mice, we showed that the microbiota was required for PTH to stimulate bone formation and increase bone mass. Microbiota depletion lowered butyrate levels, a metabolite responsible for gut-bone communication, while reestablishment of physiologic levels of butyrate restored PTH-induced anabolism. The permissive activity of butyrate was mediated by GPR43 signaling in dendritic cells and by GPR43-independent signaling in T cells. Butyrate was required for PTH to increase the number of bone marrow (BM) regulatory T cells (Tregs). Tregs stimulated production of the osteogenic Wnt ligand Wnt10b by BM CD8+ T cells, which activated Wnt-dependent bone formation. Together, these data highlight the role that butyrate produced by gut luminal microbiota plays in triggering regulatory pathways, which are critical for the anabolic action of PTH in bone.