Parathyroid hormone–dependent bone formation requires butyrate production by intestinal microbiota
Jau-Yi Li, … , Rheinallt M. Jones, Roberto Pacifici
Jau-Yi Li, … , Rheinallt M. Jones, Roberto Pacifici
Published January 9, 2020
Citation Information: J Clin Invest. 2020;130(4):1767-1781. https://doi.org/10.1172/JCI133473.
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Research Article Bone biology

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

Abstract

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.

Authors

Jau-Yi Li, Mingcan Yu, Subhashis Pal, Abdul Malik Tyagi, Hamid Dar, Jonathan Adams, M. Neale Weitzmann, Rheinallt M. Jones, Roberto Pacifici

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Figure 6

iPTH and butyrate fail to improve trabecular bone structure, stimulate bone turnover, expand Tregs, and induce Wn10b expression in 12-week-old GPR43–/– mice.

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iPTH and butyrate fail to improve trabecular bone structure, stimulate b...
(A and B) μCT scanning measurements of bone volume fraction (BV/TV) and trabecular thickness (Tb.Th) (n = 10 mice/group). (C and D) Serum osteocalcin and CTX levels (n = 10 mice/group). (E–G) PP and BM Tregs (TCR-β+CD4+Foxp3+ cells) (n = 10 mice/group). (H and I) Wnt10b mRNA levels in whole BM cells and sorted BM CD8+ T cells (n = 5 mice/group). In A–I, GPR43–/– mice and WT littermates (GPR43+/+ mice) were treated with iPTH or vehicle for 4 weeks. Mice were sacrificed and analyzed at 12 weeks of age. (J–L) BV/TV, Tb.Th, and serum osteocalcin in mice treated with vehicle or iPTH, and butyrate (But) for 4 weeks starting at 8 weeks of age. Mice were also treated with antibiotics (Abx) for 6 weeks, starting at 6 weeks of age. Mice were sacrificed and analyzed at 12 weeks of age (n = 5 mice/group). Data were expressed as mean ± SEM. All data were normally distributed according to the Shapiro-Wilk normality test. All data were analyzed by 2-way ANOVA and post hoc tests, applying Bonferroni’s correction for multiple comparisons. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 compared with the indicated group in the post hoc tests.