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

• Type of Material: Article
• Authors: Jau-Yi Li, Emory University; Benoit Chassaing, Georgia State University; Abdul Malik Tyagi, Emory University; Chiara Vaccaro, Emory University; Tao Luo, Emory University; Jonathan Adams, Emory University; Trevor M. Darby, Emory University; M. Neale Weitzmann, Emory University; Jennifer G. Mulle, Emory University; Andrew Gewirtz, Emory University; Rheinallt Jones, Emory University; Roberto Pacifici, Emory University
• Language: English
• Date: 2016-06-01
• Publisher: American Society for Clinical Investigation
• Publication Version: Final Published Version
• Copyright Statement: © 2016, American Society for Clinical Investigation.
• Final Published Version (URL): http://dx.doi.org/10.1172/JCI86062
• Title of Journal or Parent Work: Journal of Clinical Investigation
• ISSN: 0021-9738
• Volume: 126
• Issue: 6
• Start Page: 2049
• End Page: 2063
• Grant/Funding Information: M.N. Weitzmann was also supported by a grant from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development (5I01BX000105).; This study was supported by grants from the NIH (R. Pacifici: R01AR54625, R01DK091780, DK007298, and RR028009; J.Y. Li: AR061453; R.M. Jones: R01DK098391; M.N. Weitzmann: R01AR059364, R01AG040013, R01AR068157, and R01AR068157).; B. Chassaing is a recipient of the Career Development award from the Crohn’s and Colitis Foundation of America (CCFA).
• Keywords: BLOOD MONONUCLEAR-CELLS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; TNF-ALPHA; Research & Experimental Medicine; Medicine, Research & Experimental; GUT MICROBIOTA; EARLY POSTMENOPAUSAL WOMEN; INTERMITTENT PTH TREATMENT; T-CELLS; ESTROGEN-RECEPTOR-ALPHA; Life Sciences & Biomedicine; INTESTINAL PERMEABILITY; LOSS IN-VIVO; Science & Technology
• Research Categories: Health Sciences, Epidemiology; Health Sciences, General

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.