The gut-bone axis: how bacterial metabolites bridge the distance

Zaiss, Mario M.; Jones, Rheinallt; Schett, Georg; Pacifici, Roberto

doi:10.1172/jci128521

Cited by 214 publications

(200 citation statements)

References 168 publications

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“…The findings that cPTH and low calcium diet increased BM Tnf and Il17a transcript levels were consistent with the hypothesis that TNF + T cells and Th17 were first produced in the gut in response to the microbiota, and then homed to the BM where they contribute to increase the overall levels of BM TNF and IL-17A. However, we cannot conclusively exclude the possibility that PTH may have increased the production of TNF and IL-17A by resident BM lineages which were activated by microbial metabolites produced in the gut in response to PTH, which then diffused to the BM 48 . An unexpected finding of this study was that the deletion of CXCR3 blocked not only the PTHinduced influx of TNF + T cells in the BM, but also the expansion of these cells in PPs.…”

Section: Discussionmentioning

confidence: 89%

PTH induces bone loss via microbial-dependent expansion of intestinal TNF+ T cells and Th17 cells

Tyagi

et al. 2020

Nat Commun

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113

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Bone loss is a frequent but not universal complication of hyperparathyroidism. Using antibiotic-treated or germ-free mice, we show that parathyroid hormone (PTH) only caused bone loss in mice whose microbiota was enriched by the Th17 cell-inducing taxa segmented filamentous bacteria (SFB). SFB + microbiota enabled PTH to expand intestinal TNF + T and Th17 cells and increase their S1P-receptor-1 mediated egress from the intestine and recruitment to the bone marrow (BM) that causes bone loss. CXCR3-mediated TNF + T cell homing to the BM upregulated the Th17 chemoattractant CCL20, which recruited Th17 cells to the BM. This study reveals mechanisms for microbiota-mediated gut-bone crosstalk in mice models of hyperparathyroidism that may help predict its clinical course. Targeting the gut microbiota or T cell migration may represent therapeutic strategies for hyperparathyroidism.

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Section: Discussionmentioning

confidence: 89%

PTH induces bone loss via microbial-dependent expansion of intestinal TNF+ T cells and Th17 cells

Tyagi

et al. 2020

Nat Commun

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113

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“…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 .…”

Section: Introductionmentioning

confidence: 98%

“…(39)(40)(41)(42) Commensal gut microbiota effects on the skeleton have commonly been proposed to occur through a direct gut-bone axis. (43,44) 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. (13) 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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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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“…Tregs are suppressive helper CD4 + T cells that play an essential role in dampening inflammation and maintaining immune tolerance (20). Reports have highlighted the bone-regulating capacities of Tregs, describing mechanisms where Tregs blunt bone resorption (21,22), stimulate bone formation by promoting the differentiation of osteoblasts (23), and are pivotal for the stimulation of bone formation induced by nutritional supplementation with the probiotic Lactobacillus rhamnosus GG (LGG) (24,25).…”

Section: Introductionmentioning

confidence: 99%

Parathyroid hormone–dependent bone formation requires butyrate production by intestinal microbiota

Pal

et al. 2020

Journal of Clinical Investigation

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105

114

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The gut-bone axis: how bacterial metabolites bridge the distance

Cited by 214 publications

References 168 publications

PTH induces bone loss via microbial-dependent expansion of intestinal TNF+ T cells and Th17 cells

PTH induces bone loss via microbial-dependent expansion of intestinal TNF+ T cells and Th17 cells

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

Parathyroid hormone–dependent bone formation requires butyrate production by intestinal microbiota

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