Impact of Tetracycline Antibiotics on Skeletal Maturation

四环素抗生素对骨骼成熟的影响

基本信息

批准号：
10660594
负责人：
Caroline Westwater
金额：
$ 53.21万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10660594
关键词：
Accounting Acne Adolescence Adolescent Affect Age Agonist Animals Antibiotics Attenuated Bacteria Bile Acid Biosynthesis Pathway Bile Acids C57BL/6 Mouse CYP7A1 gene Cell physiology Circulation Development Distant Dose Doxycycline Endocrine Enterocytes Euthanasia Excretory function FGFR4 gene Fibroblast Growth Factor Fracture Germ-Free Hepatic Hepatocyte High Prevalence Homeostasis Hydrolase Impairment In Situ Indigenous Intestines Knockout Mice Life Liver Mediating Metagenomics Minocycline Mus Osteoblasts Osteogenesis Osteopenia Osteoporosis Phase Phenotype Production Publishing Reporting Research Resistance Role Serum Signal Transduction Site Skeleton Tamoxifen Testing Tetracyclines Work antagonist bacteriome bile salts bone bone cell bone health bone mass bone metabolism clinically relevant critical developmental period dysbiosis fecal microbiota fexaramine fracture risk germ free condition gut bacteria gut dysbiosis gut microbes gut microbiota in vivo inhibitor mechanical properties microbiota novel osteoclastogenesis skeletal skeletal maturation

Accounting Acne Adolescence Adolescent Affect Age Agonist Animals Antibiotics Attenuated Bacteria Bile Acid Biosynthesis Pathway Bile Acids C57BL/6 Mouse CYP7A1 gene Cell physiology Circulation Development Distant Dose Doxycycline Endocrine Enterocytes Euthanasia Excretory function FGFR4 gene Fibroblast Growth Factor Fracture Germ-Free Hepatic Hepatocyte High Prevalence Homeostasis Hydrolase Impairment In Situ Indigenous Intestines Knockout Mice Life Liver Mediating Metagenomics Minocycline Mus Osteoblasts Osteogenesis Osteopenia Osteoporosis Phase Phenotype Production Publishing Reporting Research Resistance Role Serum Signal Transduction Site Skeleton Tamoxifen Testing Tetracyclines Work antagonist bacteriome bile salts bone bone cell bone health bone mass bone metabolism clinically relevant critical developmental period dysbiosis fecal microbiota fexaramine fracture risk germ free condition gut bacteria gut dysbiosis gut microbes gut microbiota in vivo inhibitor mechanical properties microbiota novel osteoclastogenesis skeletal skeletal maturation

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项目摘要

PROJECT SUMMARY/ABSTRACT Roughly 1/3 of bone mass accrual during life is realized during adolescence. Disruption of this critical window of skeletal maturation has lifelong implications for bone health and fracture risk. Systemic tetracyclines (i.e., minocycline, doxycycline) are commonly used to treat acne in adolescents, but the impact on bone is unclear. Preliminary studies were performed treating C57BL/6 mice with a clinically relevant dose of doxycycline or minocycline during pubertal/postpubertal development. Administering doxycycline or minocycline to specific- pathogen-free (SPF) mice caused dysbiotic shifts in the gut bacteriome and impaired skeletal maturation. Administering minocycline to mice reared under germ-free (GF) conditions did not affect the skeletal phenotype, which supports that tetracyclines’ effects on the maturing skeleton depend on the gut microbiota. Bile acids were identified as a novel candidate regulator contributing to gut microbiota effects on bone metabolism. Bile acids are synthesized in the liver and excreted into the intestine, where bacteria metabolize them. The intestinal FXR-FGF15 axis is a gut-liver endocrine axis that supports bile acid homeostasis. Bile acid activation of enterocyte-FXR induces the production of FGF15, which signals at hepatocyte-FGFR4 to inhibit CYP7A1- mediated bile acid synthesis. Bacteria have unique bile salt hydrolases (BSHs) that differentially deconjugate bile acids. Conjugation status affects bile acids’ potential to activate FXR. Shifts in intestinal bacteria composition alter BSHs' deconjugation of bile acids, which can disrupt the intestinal FXR-FGF15 axis. Preliminary studies showed that minocycline treatment blunted ileal FGF15 and enhanced hepatic Cyp7a1, which implies tetracyclines disrupt the intestinal FXR-FGF15 axis. Minocycline increased serum bile acids that are FXR antagonists, and this altered bile acid profile attenuated osteogenesis in cultured primary osteoblasts. Two aims will test the overall hypothesis: Tetracycline-induced gut dysbiosis disrupts the intestinal FXR- FGF15 axis, which impairs skeletal maturation through dysregulated serum bile acids that attenuate osteoblast- FXR signaling or reduced serum FGF15 activation of osteoblast-FGFR4 signaling. Aim 1 will utilize metagenomic approaches and fecal microbiota transfer from SPF to GF mice. Studies will delineate how minocycline- and doxycycline-induced changes in gut bacteria alter the transformation of intestinal bile acids to affect the FXR- FGF15 axis. Aim 2 relies on administering an intestinal-specific FXR agonist to define the role of the FXR-FGF15 axis in minocycline effects on the skeleton. Tamoxifen inducible osteoblast null mice will be used to delineate the role of osteoblast-FXR / osteoblast-FGFR4 in minocycline’s actions suppressing osteogenesis. The proposed work will define the relationship between tetracycline-induced gut dysbiosis, the FXR-FGF15 axis, osteoblast- FXR/FGFR4 signaling, and skeletal maturation. Adolescents are commonly prescribed systemic antibiotics for acne, and >70% receive tetracyclines. Gut and liver conditions have a higher prevalence of osteopenia / osteoporosis, which underscores the need to define the role of bile acids in gut microbiota effects on bone.

项目摘要/摘要在青少年期间，生命中大约有1/3的骨质量。这个关键窗口的破坏骨骼成熟对骨骼健康和骨折风险具有终生影响。全身四环素（即米诺环素，强力霉素）通常用于治疗青少年痤疮，但对骨骼的影响尚不清楚。初步研究对用临床相关剂量的强力霉素治疗C57BL/6小鼠青春期/后假期发育期间的米诺环素。给予多西环素或米诺环素至特定无病原体（SPF）小鼠在肠道细菌中引起不适性转移并受损骨骼成熟。对在无菌（GF）条件下饲养的小鼠施用米诺环素不会影响骨骼表型，这支持四环素对成熟骨骼的影响取决于肠道菌群。胆汁酸是被确定为有助于肠道菌群对骨代谢的影响的新型候选调节剂。胆汁酸是在肝脏中合成的，并在肠道中排他性，细菌将其代谢。肠道FXR-FGF15轴是支持胆汁酸稳态的肠肝内分泌轴。胆汁酸激活肠环-FXR的诱导FGF15的产生，该产生在肝细胞-FGFR4处发出信号以抑制CYP7A1- 介导的胆汁酸合成。细菌具有独特的胆汁盐水解酶（BSH）胆汁酸。共轭状态会影响胆汁酸激活FXR的潜力。肠细菌组成的变化改变BSH的胆汁酸的解偶，这会破坏肠道FXR FXR-FGF15轴。初步研究表明，米诺环素治疗使回肠FGF15和增强的肝CYP7A1，增强这意味着四环素破坏了肠道FXR-FGF15轴。米诺环素增加了血清胆汁酸是FXR拮抗剂，这种改变的胆汁酸轮廓减弱了培养的原代成骨细胞中的成骨。两个目的将检验总体假设：四环素诱导的肠道营养不良破坏了肠道FXR- FGF15轴，通过衰减成骨细胞 - FXR信号传导或降低了成骨细胞FGFR4信号传导的血清FGF15激活。 AIM 1将利用宏基因组接近和粪便微生物群从SPF转移到GF小鼠。研究将描述如何米诺环素和强力霉素引起的肠道细菌的变化改变了肠胆汁酸的转化，以影响FXR- FGF15轴。 AIM 2依赖于管理肠道特异性的FXR激动剂来定义FXR-FGF15的作用米诺环素对骨骼的影响。他莫昔芬可诱导的成骨细胞无效小鼠将用于描述成骨细胞-FXR /成骨细胞-FGFR4在抑制成骨的作用中的作用。提议工作将定义四环素诱导的肠道营养不良，FXR-FGF15轴，成骨细胞 - FXR/FGFR4信号传导和骨骼成熟。青少年通常是处方的全身抗生素痤疮，> 70％的人接受四环素。肠道和肝脏条件的骨质减少症患病率更高骨质疏松症，强调了定义胆汁酸在肠道微生物群对骨骼的作用中的作用的必要性。