Antibiotic Perturbation of Gut Microbiota Dysregulates Osteoimmune Cross Talk in Postpubertal Skeletal Development

Hathaway‐Schrader, Jessica D.; Steinkamp, Heidi M.; Chavez, Michael B.; Poulides, Nicole; Kirkpatrick, Joy E; Chew, Michael E.; Huang, Emily; Alekseyenko, Alexander V.; Aguirre, J. Ignacio; Novince, Chad M.

doi:10.1016/j.ajpath.2018.10.017

Cited by 41 publications

(78 citation statements)

References 136 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To discriminate mineralized tissue, a fixed threshold of 2250 HU was used. Data are reported in accordance with standardized nomenclature as previously described …”

Section: Methodsmentioning

confidence: 99%

“…First passage nonadherent HPCs isolated from long bone marrow cultures were washed, and subsequently incubated with CD11b microbeads (Miltenyi Biotec, Bergisch Gladbach, Germany). An AutoMACS Sorter (Miltenyi Biotec) was employed to separate CD11b neg HPCs as previously described . CD11b neg HPCs were washed, counted, and plated for assays at 1.5 × 10 5 cells/cm 2 in α‐MEM, 10% FBS (Hyclone Laboratories), and 1% PSG.…”

Section: Methodsmentioning

confidence: 99%

“…CD11b neg OCP cultures were subsequently stimulated with fresh control (25 ng/mL CSF1; R&D Systems) or treatment (25 ng/mL CSF1 and 50 ng/mL RANKL; R&D Systems) media for 4 and 6 days; media was changed every other day. Day 4 and day 6 control cultures (25 ng/mL CSF1) and treatment cultures (25 ng/mL CSF1 and 50 ng/mL RANKL) were stained by the TRAP method as reported previously . TRAP stain assay was carried out in triplicate (technical replicate) culture wells; four fields of view were imaged at ×100 per culture well for analysis as previously described .…”

Section: Methodsmentioning

confidence: 99%

“…Gapdh and Rn18s were used as internal controls for studies in livers. Relative quantification of data was performed via the comparative C T method (2 −ΔΔCT ) as previously described …”

Section: Methodsmentioning

confidence: 99%

“…Central to the current report, the commensal gut microbiota has immunoregulatory actions that influence osteoimmune processes in the healthy developing skeleton. 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 .…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

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

et al. 2020

View full text Add to dashboard Cite

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.

show abstract

“…To discriminate mineralized tissue, a fixed threshold of 2250 HU was used. Data are reported in accordance with standardized nomenclature as previously described …”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Gapdh and Rn18s were used as internal controls for studies in livers. Relative quantification of data was performed via the comparative C T method (2 −ΔΔCT ) as previously described …”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2020

View full text Add to dashboard Cite

show abstract

Commensal Microbiota Effects on Craniofacial Skeletal Growth and Morphology

Gerasco,

Hathaway‐Schrader,

Poulides

et al. 2023

JBMR Plus

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Components of the Gut Microbiome That Influence Bone Tissue-Level Strength

Luna

Guss

Vasquez-Bolanos

et al. 2020

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

Modifications to the constituents of the gut microbiome influence bone density and tissue-level strength, but the specific microbial components that influence tissue-level strength in bone are not known. Here, we selectively modify constituents of the gut microbiota using narrow-spectrum antibiotics to identify components of the microbiome associated with changes in bone mechanical and material properties. Male C57BL/6J mice (4 weeks) were divided into seven groups (n = 7-10/group) and had taxa within the gut microbiome removed through dosing with: (i) ampicillin; (ii) neomycin; (iii) vancomycin; (iv) metronidazole; (v) a cocktail of all four antibiotics together (with zero-calorie sweetener to ensure intake); (vi) zero-calorie sweetener only; or (vii) no additive (untreated) for 12 weeks. Individual antibiotics remove only some taxa from the gut, while the cocktail of all four removes almost all microbes. After accounting for differences in geometry, whole bone strength was reduced in animals with gut microbiome modified by neomycin (À28%, p = 0.002) and was increased in the group in which the gut microbiome was altered by sweetener alone (+39%, p < 0.001). Analysis of the fecal microbiota detected seven lower-ranked taxa differentially abundant in animals with impaired tissue-level strength and 14 differentially abundant taxa associated with increased tissue-level strength. Histological and serum markers of bone turnover and trabecular bone volume per tissue volume (BV/TV) did not differ among groups. These findings demonstrate that modifications to the taxonomic components of the gut microbiome have the potential to decrease or increase tissuelevel strength of bone independent of bone quantity and without noticeable changes in bone turnover.

show abstract

Antibiotic Perturbation of Gut Microbiota Dysregulates Osteoimmune Cross Talk in Postpubertal Skeletal Development

Cited by 41 publications

References 136 publications

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

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

Commensal Microbiota Effects on Craniofacial Skeletal Growth and Morphology

Components of the Gut Microbiome That Influence Bone Tissue-Level Strength

Contact Info

Product

Resources

About