Minocycline-induced disruption of the intestinal FXR/FGF15 axis impairs osteogenesis in mice

Abstract

Antibiotic-induced shifts in the indigenous gut microbiota influence normal skeletal maturation. Current theory implies that gut microbiota actions on bone occur through a direct gut-bone signaling axis. However, our prior work supports that a gut-liver signaling axis contributes to gut microbiota effects on bone. Purpose was to investigate the effects of minocycline, a systemic antibiotic treatment for adolescent acne, on pubertal/postpubertal skeletal maturation. Sex-matched specific-pathogen-free(SPF) and germ-free(GF) C57BL/6T mice were administered a clinically relevant minocycline dose from age 6-12 weeks. Minocycline caused dysbiotic shifts in the gut bacteriome and impaired skeletal maturation in SPF mice, but did not alter the skeletal phenotype in GF mice. Minocycline administration in SPF mice disrupted the intestinal farnesoid X receptor(FXR)-fibroblast growth factor 15(FGF15) axis, a gut-liver endocrine axis supporting systemic bile acid homeostasis. Minocyclinetreated SPF mice had increased serum conjugated bile acids that are FXR antagonists, suppressed osteoblast function, decreased bone mass, impaired bone microarchitecture and fracture resistance. Stimulating osteoblasts with the serum bile acid profile from minocycline-treated SPF mice recapitulated the suppressed osteogenic phenotype found in vivo, which was mediated through attenuated FXR-signaling. This work introduces bile acids as a novel mediator of gut-liver signaling actions contributing to gut microbiota effects on bone.

Post-weaning social isolation alters sociability in a sex-specific manner

“…Here we found that both the adolescent group-housed and socially isolated males exposed to adolescent minocycline treatment displayed a decrease in social preference compared to their baseline controls. While this result may seem to conflict with previous findings demonstrating minocycline's protective effects following behavior impairments, administration of the drug has shown to lead to adverse reactions in some cases, potentially attributed to antibiotic induced shifts in the microbiota [42,54,55]. In addition to the potential aversive effects, minocycline treatment has also shown to lead to reductions in locomotor behavior in rodents [56][57][58].…”

Antibiotic prophylaxis dysregulates dental implant placement surgery‐induced osteoimmune wound healing and attenuates the alveolar bone–implant interface in mice

“…Media was changed to stimulate cells with 50 ng/mL phorbol 12‐myristate 13‐acetate (Stemcell Technologies, Vancouver, Canada), 1 μg/mL ionomycin (Stemcell Technologies) and 2 μM monensin (Thermo Fisher Scientific) for 4 h. Cells were harvested, washed, counted and re‐suspended in flow cytometry buffer. Cells were treated with FcR‐block (Miltenyi Biotec, Bergisch Gladbach, Germany) and labelled for surface antibodies, per manufacturer's instructions as previously reported (Carson et al, 2023; Swanson et al, 2021). Dead cells were excluded via labelling with LIVE/DEAD 405‐nm Fixable Yellow Stain (Thermo Fisher Scientific), per manufacturer's instructions.…”

“…cytometry buffer. Cells were treated with FcR-block (Miltenyi Biotec, Bergisch Gladbach, Germany) and labelled for surface antibodies, per manufacturer's instructions as previously reported (Carson et al, 2023;Swanson et al, 2021). Dead cells were excluded via labelling with LIVE/ DEAD 405-nm Fixable Yellow Stain (Thermo Fisher Scientific), per manufacturer's instructions.…”

The associations of gut microbiota, endocrine system and bone metabolism

“…3389/fmicb.2023.1124945 Frontiers in Microbiology 07 frontiersin.org knockout mice exhibits osteopenia phenotype, suggesting its positive effect in bone remodeling (Bozadjieva-Kramer et al, 2021). Application of antibiotics minocycline can lead to impaired skeletal maturation in young mice, likely due to excessive serum conjugated BAs resulted from gut microbiota dysbiosis and disrupted FXR-FGF15 axis (Carson et al, 2022).…”