Impact of Tetracycline Antibiotics on Skeletal Maturation

四环素抗生素对骨骼成熟的影响

• 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
• 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

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 一生中大约三分之一的骨量积累是在青春期实现的。扰乱这一关键的窗口 骨骼成熟对骨骼健康和骨折风险具有终生影响。全身性四环素(即， 二甲胺四环素(二甲胺四环素、强力霉素)是治疗青少年痤疮的常用药物，但对骨骼的影响尚不清楚。 初步研究用临床相关剂量的多西环素治疗C57BL/6小鼠。 米诺环素在青春期/青春期后发育。将多西环素或米诺环素用于特定的- 无病原体(SPF)小鼠导致肠道细菌群的非生物移位，并损害骨骼成熟。 给在无菌(GF)条件下饲养的小鼠注射米诺环素并不影响骨骼表型， 这支持了四环素对成熟骨骼的影响取决于肠道微生物区系。胆汁酸 被确定为一种新的候选调节因子，有助于肠道微生物区系对骨骼代谢的影响。 胆汁酸是在肝脏中合成的，并被排入肠道，细菌在肠道中代谢胆汁酸。这个 肠道FXR-FGF15轴是支持胆汁酸稳态的肠道-肝脏内分泌轴。胆汁酸活化 肠细胞-FXR诱导FGF15的产生，FGFR4信号在肝细胞-FGFR4上抑制CYP7A1- 介导的胆汁酸合成。细菌有独特的胆盐水解酶(BSHS)，可以不同地去结合 胆汁酸。结合状态影响胆汁酸激活FXR的潜力。肠道细菌组成的变化 改变BSHS对胆汁酸的解结合，这可能会扰乱肠道FXR-FGF15轴。 初步研究表明，米诺环素治疗钝化回肠FGF15和增强肝脏Cyp7a1， 这意味着四环素扰乱了肠道FXR-FGF15轴。米诺环素增加血清胆汁酸 是FXR拮抗剂，这种改变的胆汁酸特征减弱了培养的原代成骨细胞的成骨作用。 两个目标将检验整个假设：四环素诱导的肠道生物失调扰乱肠道FXR- FGF15轴，通过失调的血清胆汁酸减弱成骨细胞而损害骨骼成熟- FXR信号转导或血清FGF15激活成骨细胞-FGFR4信号转导。目标1将利用元基因组学 SPF小鼠粪便微生物区系向GF小鼠转移的途径。研究将描绘米诺环素-和 多西环素引起的肠道细菌改变改变了肠道胆汁酸的转化，从而影响FXR- FGF15轴。AIM 2依赖于肠道特异性FXR激动剂来定义FXR-FGF15的作用 二甲胺四环素中的轴对骨骼的影响。他莫昔芬诱导的成骨细胞缺失小鼠将被用于描绘 成骨细胞-FXR/成骨细胞-FGFR4在米诺环素抑制成骨中的作用建议数 工作将确定四环素诱导的肠道生物失调、FXR-FGF15轴、成骨细胞- FXR/FGFR4信号转导与骨骼成熟。青少年通常被开出全身抗生素治疗 粉刺，和&gt；70%接受四环素。肠道和肝脏疾病有较高的骨量减少/ 骨质疏松症，强调需要确定胆汁酸在肠道微生物区系对骨骼的影响中的作用。