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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-Liver-Bone 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.

SUBMITTER: Novince CM

PROVIDER: S-EPMC5515851 | biostudies-other | 2017 Jul

REPOSITORIES: biostudies-other

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

Novince Chad M CM Whittow Carolyn R CR Aartun Johannes D JD Hathaway Jessica D JD Poulides Nicole N Chavez Michael B MB Steinkamp Heidi M HM Kirkwood Kaeleigh A KA Huang Emily E Westwater Caroline C Kirkwood Keith L KL

Scientific reports 20170718 1

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 ...[more]

PMID: 28720797

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Project description:The commensal gut microbiota critically regulates immunomodulatory processes that influence normal skeletal growth and maturation. However, the influence of specific microbes on commensal gut microbiota osteoimmunoregulatory actions is unknown. We have shown previously that the commensal gut microbiota enhances TH17/IL17A immune response effects in marrow and liver that have procatabolic/antianabolic actions in the skeleton. Segmented filamentous bacteria (SFB), a specific commensal gut bacterium within phylum Firmicutes, potently induces TH17/IL17A-mediated immunity. The study purpose was to delineate the influence of SFB on commensal gut microbiota immunomodulatory actions regulating normal postpubertal skeletal development. Two murine models were utilized: SFB-monoassociated mice versus germ-free (GF) mice and specific-pathogen-free (SPF) mice +/- SFB. SFB colonization was validated by 16S rDNA analysis, and SFB-induced TH17/IL17A immunity was confirmed by upregulation of Il17a in ileum and IL17A in serum. SFB-colonized mice had an osteopenic trabecular bone phenotype, which was attributed to SFB actions suppressing osteoblastogenesis and enhancing osteoclastogenesis. Intriguingly, SFB-colonized mice had increased expression of proinflammatory chemokines and acute-phase reactants in the liver. Lipocalin-2 (LCN2), an acute-phase reactant and antimicrobial peptide, was substantially elevated in the liver and serum of SFB-colonized mice, which supports the notion that SFB regulation of commensal gut microbiota osteoimmunomodulatory actions are mediated in part through a gut-liver-bone axis. Proinflammatory TH17 and TH1 cells were increased in liver-draining lymph nodes of SFB-colonized mice, which further substantiates that SFB osteoimmune-response effects may be mediated through the liver. SFB-induction of Il17a in the gut and Lcn2 in the liver resulted in increased circulating levels of IL17A and LCN2. Recognizing that IL17A and LCN2 support osteoclastogenesis/suppress osteoblastogenesis, SFB actions impairing postpubertal skeletal development appear to be mediated through immunomodulatory effects in both the gut and liver. This research reveals that specific microbes critically impact commensal gut microbiota immunomodulatory actions regulating normal postpubertal skeletal growth and maturation. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Project description:Microbes colonize anatomical sites in health to form commensal microbial communities (e.g., commensal gut microbiota, commensal skin microbiota, commensal oral microbiota). Commensal microbiota has indirect effects on host growth and maturation through interactions with the host immune system. The commensal microbiota was recently introduced as a novel regulator of skeletal growth and morphology at noncraniofacial sites. Further, we and others have shown that commensal gut microbes, such as segmented filamentous bacteria (SFB), contribute to noncraniofacial skeletal growth and maturation. However, commensal microbiota effects on craniofacial skeletal growth and morphology are unclear. To determine the commensal microbiota's role in craniofacial skeletal growth and morphology, we performed craniometric and bone mineral density analyses on skulls from 9-week-old female C57BL/6T germ-free (GF) mice (no microbes), excluded-flora (EF) specific-pathogen-free mice (commensal microbiota), and murine-pathogen-free (MPF) specific-pathogen-free mice (commensal microbiota with SFB). Investigations comparing EF and GF mice revealed that commensal microbiota impacted the size and shape of the craniofacial skeleton. EF versus GF mice exhibited an elongated gross skull length. Cranial bone length analyses normalized to skull length showed that EF versus GF mice had enhanced frontal bone length and reduced cranial base length. The shortened cranial base in EF mice was attributed to decreased presphenoid, basisphenoid, and basioccipital bone lengths. Investigations comparing MPF mice and EF mice demonstrated that commensal gut microbes played a role in craniofacial skeletal morphology. Cranial bone length analyses normalized to skull length showed that MPF versus EF mice had reduced frontal bone length and increased cranial base length. The elongated cranial base in MPF mice was due to enhanced presphenoid bone length. This work, which introduces the commensal microbiota as a contributor to craniofacial skeletal growth, underscores that noninvasive interventions in the gut microbiome could potentially be employed to modify craniofacial skeletal morphology. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Dataset Information

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

Publications

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

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