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Commensal oral microbiota induces osteoimmunomodulatory effects separate from systemic microbiome in mice.

ABSTRACT: Commensal microbes critically regulate skeletal homeostasis, yet the impact of specific microbiota communities on osteoimmune response mechanisms is unknown. To discern osteoimmunomodulatory effects imparted by the commensal oral microbiota that are distinct from the systemic microbiota, osteoimmunology studies were performed in both alveolar bone and nonoral skeletal sites of specific pathogen-free (SPF) versus germ-free (GF) mice and SPF mice subjected to saline versus chlorhexidine oral rinses. SPF versus GF mice had reduced cortical/trabecular bone and an enhanced pro-osteoclastic phenotype in alveolar bone. TLR signaling and Th17 cells that have known pro-osteoclastic actions were increased in alveolar BM, but not long BM, of SPF versus GF mice. MHC II antigen presentation genes and activated DCs and CD4+ T cells were elevated in alveolar BM, but not long BM, of SPF versus GF mice. These findings were substantiated by in vitro allostimulation studies demonstrating increased activated DCs derived from alveolar BM, but not long BM, of SPF versus GF mice. Chlorhexidine antiseptic rinse depleted the oral, but not gut, bacteriome in SPF mice. Findings from saline- versus chlorhexidine-treated SPF mice corroborated outcomes from SPF versus GF mice, which reveals that the commensal oral microbiota imparts osteoimmunomodulatory effects separate from the systemic microbiome.

SUBMITTER: Hathaway-Schrader JD

PROVIDER: S-EPMC8876522 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Commensal oral microbiota induces osteoimmunomodulatory effects separate from systemic microbiome in mice.

Hathaway-Schrader Jessica D JD Aartun Johannes D JD Poulides Nicole A NA Kuhn Megan B MB McCormick Blakely E BE Chew Michael E ME Huang Emily E Darveau Richard P RP Westwater Caroline C Novince Chad M CM

JCI insight 20220222 4

Commensal microbes critically regulate skeletal homeostasis, yet the impact of specific microbiota communities on osteoimmune response mechanisms is unknown. To discern osteoimmunomodulatory effects imparted by the commensal oral microbiota that are distinct from the systemic microbiota, osteoimmunology studies were performed in both alveolar bone and nonoral skeletal sites of specific pathogen-free (SPF) versus germ-free (GF) mice and SPF mice subjected to saline versus chlorhexidine oral rinse ...[more]

PMID: 35077397

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Project description:The effect of oral microbiota on the intestinal microbiota has garnered growing attention as a mechanism linking periodontal diseases to systemic diseases. However, the salivary microbiota is diverse and comprises numerous bacteria with a largely similar composition in healthy individuals and periodontitis patients. Thus, the systemic effects of small differences in the oral microbiota are unclear. In this study, we explored how health-associated and periodontitis-associated salivary microbiota differently colonized the intestine and their subsequent systemic effects by analyzing the hepatic gene expression and serum metabolomic profiles. The salivary microbiota was collected from a healthy individual and a periodontitis patient and gavaged into C57BL/6NJcl[GF] mice. Samples were collected five weeks after administration. Gut microbial communities were analyzed by 16S ribosomal RNA gene sequencing. Hepatic gene expression profiles were analyzed using a DNA microarray and quantitative polymerase chain reaction. Serum metabolites were analyzed by capillary electrophoresis time-of-flight mass spectrometry. The gut microbial composition at the genus level was significantly different between periodontitis-associated microbiota-administered (PAO) and health-associated oral microbiota-administered (HAO) mice. The hepatic gene expression profile demonstrated a distinct pattern between the two groups, with higher expression of Neat1, Mt1, Mt2, and Spindlin1, which are involved in lipid and glucose metabolism. Disease-associated metabolites such as 2-hydroxyisobutyric acid and hydroxybenzoic acid were elevated in PAO mice. These metabolites were significantly correlated with Bifidobacterium, Atomobium, Campylobacter, and Haemophilus, which are characteristic taxa in PAO mice. Conversely, health-associated oral microbiota were associated with higher levels of beneficial serum metabolites in HAO mice. The multi-omics approach used in this study revealed that periodontitis-associated oral microbiota is associated with the induction of disease phenotype when they colonized the gut of germ-free mice.

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.

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Commensal oral microbiota induces osteoimmunomodulatory effects separate from systemic microbiome in mice.

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Commensal oral microbiota induces osteoimmunomodulatory effects separate from systemic microbiome in mice.

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