Commensal Gut Microbiota Immunomodulatory Actions in Bone Marrow and Liver have Catabolic Effects on Skeletal Homeostasis in Health

Abstract

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

From Osteoimmunology to Osteomicrobiology: How the Microbiota and the Immune System Regulate Bone

“…In keeping with the study of K. Sjogren et al, we reported that 20-week-old female germ-free C57Bl/6 mice have higher trabecular bone volume than congenic age matched mice raised in conventional conditions [66]. These initial observations have been recently confirmed in a study demonstrating that commensal gut microbiota stimulates bone resorption and inhibits bone formation, thus lowering bone mass [67]. …”

“…The exact role of IGF-1 remains controversial because in one study mice raised in conventional conditions were found to have lower bone formation and lower serum and bone marrow levels of IGF-1 compared to GF mice [67]. By contrast, in a second investigation colonization of GF mice with physiologic microbiota increased liver-derived IGF-1 [61, 64].…”

“…However, over a longer period of time (8 months) IGF-1 stimulated bone formation leading to a net gain in bone mass [64]. Investigations have also shown that commensal microbiota induces sustained changes to in RANKL mediated osteoclastogenesis [67]. …”

Specific Commensal Bacterium Critically Regulates Gut Microbiota Osteoimmunomodulatory Actions During Normal Postpubertal Skeletal Growth and Maturation

“…Commensal gut microbiota effects on the skeleton have commonly been proposed to occur through a direct gut–bone axis . Our prior work revealed that the commensal gut microbiota profoundly stimulates innate and adaptive immunity in the liver, which led us to postulate that gut microbiota effects on the skeleton are mediated, in part, by a gut–liver–bone axis . The current report reveals that SFB has pro‐osteoclastic/antiosteoblastic actions impairing postpubertal skeletal development, which appear to be mediated through immunomodulatory effects in both the gut and liver.…”

“…Antibiotic disruption of the normal commensal gut microbiota has been shown to drive a proinflammatory immune response state in lymphoid tissues draining the gut, which results in enhanced osteoclastogenesis and impaired bone mass accrual in the postpubertal growing skeleton . Timely studies employing the germ‐free (GF) mouse model have delineated that the commensal gut microbiota profoundly influences physiologic osteoimmune processes that impact normal skeletal growth and maturation . Our prior work in 12‐week‐old C57BL/6 specific‐pathogen‐free (SPF) versus GF mice revealed that the commensal gut microbiota enhanced osteoclastogenesis and suppressed osteoblastogenesis, driving bone loss in health .…”