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Sex steroid deficiency–associated bone loss is microbiota dependent and prevented by probiotics
Jau-Yi Li, … , Rheinallt M. Jones, Roberto Pacifici
Jau-Yi Li, … , Rheinallt M. Jones, Roberto Pacifici
Published April 25, 2016
Citation Information: J Clin Invest. 2016;126(6):2049-2063. https://doi.org/10.1172/JCI86062.
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Research Article Bone Biology Immunology

Sex steroid deficiency–associated bone loss is microbiota dependent and prevented by probiotics

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Abstract

A eubiotic microbiota influences many physiological processes in the metazoan host, including development and intestinal homeostasis. Here, we have shown that the intestinal microbiota modulates inflammatory responses caused by sex steroid deficiency, leading to trabecular bone loss. In murine models, sex steroid deficiency increased gut permeability, expanded Th17 cells, and upregulated the osteoclastogenic cytokines TNFα (TNF), RANKL, and IL-17 in the small intestine and the BM. In germ-free (GF) mice, sex steroid deficiency failed to increase osteoclastogenic cytokine production, stimulate bone resorption, and cause trabecular bone loss, demonstrating that the gut microbiota is central in sex steroid deficiency–induced trabecular bone loss. Furthermore, we demonstrated that twice-weekly treatment of sex steroid–deficient mice with the probiotics Lactobacillus rhamnosus GG (LGG) or the commercially available probiotic supplement VSL#3 reduces gut permeability, dampens intestinal and BM inflammation, and completely protects against bone loss. In contrast, supplementation with a nonprobiotic strain of E. coli or a mutant LGG was not protective. Together, these data highlight the role that the gut luminal microbiota and increased gut permeability play in triggering inflammatory pathways that are critical for inducing bone loss in sex steroid–deficient mice. Our data further suggest that probiotics that decrease gut permeability have potential as a therapeutic strategy for postmenopausal osteoporosis.

Authors

Jau-Yi Li, Benoit Chassaing, Abdul Malik Tyagi, Chiara Vaccaro, Tao Luo, Jonathan Adams, Trevor M. Darby, M. Neale Weitzmann, Jennifer G. Mulle, Andrew T. Gewirtz, Rheinallt M. Jones, Roberto Pacifici

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Figure 1

GF mice are protected against the loss of trabecular bone induced by sex steroid deficiency.

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GF mice are protected against the loss of trabecular bone induced by sex...
Assessment of femoral bone structure by in vitro μCT in Conv.R mice, GF mice, and Col.GF mice following either leuprolide (375 μg/month) or vehicle control treatment for 10 weeks. (A) Images of representative 3-dimensional μCT reconstructions of examined femurs from each group. (B) BV/TV. (C) Ct.V. (D) Ct.Th. (E) Tb.N. (F) Tb.Sp. (G) Tb.Th. n = 10 mice per group in all panels. Data are expressed as mean ± SEM. All data were normally distributed according to the Shapiro-Wilk normality test and analyzed by 2-way ANOVA and post hoc tests applying the Bonferroni correction for multiple comparisons. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 compared with the indicated groups.
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