Despite knowledge the gut microbiota regulates bone mass, mechanisms governing the normal gut microbiota's osteoimmunomodulatory effects on skeletal remodeling and homeostasis are unclear in the healthy adult skeleton. Young adult specific-pathogen-free and germ-free mice were used to delineate the commensal microbiota's immunoregulatory effects on osteoblastogenesis, osteoclastogenesis, marrow T-cell hematopoiesis, and extra-skeletal endocrine organ function. We report the commensal microbiota has anti-anabolic effects suppressing osteoblastogenesis and pro-catabolic effects enhancing osteoclastogenesis, which drive bone loss in health. Suppression of Sp7(Osterix) and Igf1 in bone, and serum IGF1, in specific-pathogen-free mice suggest the commensal microbiota's anti-osteoblastic actions are mediated via local disruption of IGF1-signaling. Differences in the RANKL/OPG Axis in vivo, and RANKL-induced maturation of osteoclast-precursors in vitro, indicate the commensal microbiota induces sustained changes in RANKL-mediated osteoclastogenesis. Candidate mechanisms mediating commensal microbiota's pro-osteoclastic actions include altered marrow effector CD4 + T-cells and a novel Gut-Liver-Bone Axis. The previously unidentified Gut-LiverBone Axis intriguingly implies the normal gut microbiota's osteoimmunomodulatory actions are partly mediated via immunostimulatory effects in the liver. The molecular underpinnings defining commensal gut microbiota immunomodulatory actions on physiologic bone remodeling are highly relevant in advancing the understanding of normal osteoimmunological processes, having implications for the prevention of skeletal deterioration in health and disease.Gut microbiota interactions with the host modulates gastrointestinal processes, metabolism and immunity 1-5 , having implications for the development and homeostasis of host tissues 6,7 . Extensive research has focused on the commensal gut microbiota immunoregulatory effects in the context of resistance to pathogenic microbes and intestinal homeostasis 8,9 , and more recently investigations have begun to define the normal gut microbiota's role in the pathophysiology of metabolic and autoimmune disease states 4,6,9,10 . Central to this investigation, the commensal gut microbiota's influence on physiologic tissue remodeling and homeostasis at extra-gastrointestinal sites is largely unknown 11 . The study of osteoimmunology has elucidated that innate-immunity, marrow effector T-cells, and diverse endocrine organs regulate osteoclast-osteoblast mediated bone remodeling, both in health and disease [12][13][14][15][16][17] . Bone remodeling is a continuous dynamic skeletal renewal process in which monocyte-myeloid derived osteoclast cells resorb old bone matrix, and mesenchymal derived osteoblast cells subsequently form new bone matrix. Skeletal
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