Minocycline-induced disruption of the intestinal FXR/FGF15 axis impairs osteogenesis in mice
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 e...
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2023-01-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.160578 |
| _version_ | 1797634352427827200 |
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| author | Matthew D. Carson Amy J. Warner Jessica D. Hathaway-Schrader Vincenza L. Geiser Joseph Kim Joy E. Gerasco William D. Hill John J. Lemasters Alexander V. Alekseyenko Yongren Wu Hai Yao J. Ignacio Aguirre Caroline Westwater Chad M. Novince |
| author_facet | Matthew D. Carson Amy J. Warner Jessica D. Hathaway-Schrader Vincenza L. Geiser Joseph Kim Joy E. Gerasco William D. Hill John J. Lemasters Alexander V. Alekseyenko Yongren Wu Hai Yao J. Ignacio Aguirre Caroline Westwater Chad M. Novince |
| author_sort | Matthew D. Carson |
| collection | DOAJ |
| description | 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. Our 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/fibroblast growth factor 15 axis, a gut/liver endocrine axis supporting systemic bile acid homeostasis. Minocycline-treated SPF mice had increased serum conjugated bile acids that were farnesoid X receptor (FXR) antagonists, suppressed osteoblast function, decreased bone mass, and 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 potentially novel mediator of gut/liver signaling actions contributing to gut microbiota effects on bone. |
| first_indexed | 2024-03-11T12:06:28Z |
| format | Article |
| id | doaj.art-3d9af3f7271a4cf4a793aa66405e8d7f |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:06:28Z |
| publishDate | 2023-01-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-3d9af3f7271a4cf4a793aa66405e8d7f2023-11-07T16:25:02ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-01-0181Minocycline-induced disruption of the intestinal FXR/FGF15 axis impairs osteogenesis in miceMatthew D. CarsonAmy J. WarnerJessica D. Hathaway-SchraderVincenza L. GeiserJoseph KimJoy E. GerascoWilliam D. HillJohn J. LemastersAlexander V. AlekseyenkoYongren WuHai YaoJ. Ignacio AguirreCaroline WestwaterChad M. NovinceAntibiotic-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. Our 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/fibroblast growth factor 15 axis, a gut/liver endocrine axis supporting systemic bile acid homeostasis. Minocycline-treated SPF mice had increased serum conjugated bile acids that were farnesoid X receptor (FXR) antagonists, suppressed osteoblast function, decreased bone mass, and 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 potentially novel mediator of gut/liver signaling actions contributing to gut microbiota effects on bone.https://doi.org/10.1172/jci.insight.160578Bone biologyEndocrinology |
| spellingShingle | Matthew D. Carson Amy J. Warner Jessica D. Hathaway-Schrader Vincenza L. Geiser Joseph Kim Joy E. Gerasco William D. Hill John J. Lemasters Alexander V. Alekseyenko Yongren Wu Hai Yao J. Ignacio Aguirre Caroline Westwater Chad M. Novince Minocycline-induced disruption of the intestinal FXR/FGF15 axis impairs osteogenesis in mice JCI Insight Bone biology Endocrinology |
| title | Minocycline-induced disruption of the intestinal FXR/FGF15 axis impairs osteogenesis in mice |
| title_full | Minocycline-induced disruption of the intestinal FXR/FGF15 axis impairs osteogenesis in mice |
| title_fullStr | Minocycline-induced disruption of the intestinal FXR/FGF15 axis impairs osteogenesis in mice |
| title_full_unstemmed | Minocycline-induced disruption of the intestinal FXR/FGF15 axis impairs osteogenesis in mice |
| title_short | Minocycline-induced disruption of the intestinal FXR/FGF15 axis impairs osteogenesis in mice |
| title_sort | minocycline induced disruption of the intestinal fxr fgf15 axis impairs osteogenesis in mice |
| topic | Bone biology Endocrinology |
| url | https://doi.org/10.1172/jci.insight.160578 |
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