Departments of Orthopaedic Surgery and Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, United States.
Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY, United States.
J Bone Miner Res. 2024 Oct 29;39(11):1621-1632. doi: 10.1093/jbmr/zjae157.
Recent studies in mice have indicated that the gut microbiome can regulate bone tissue strength. However, prior work involved modifications to the gut microbiome in growing animals and it is unclear if the same changes in the microbiome, applied later in life, would change matrix strength. Here we changed the composition of the gut microbiome before and/or after skeletal maturity (16 weeks of age) using oral antibiotics (ampicillin + neomycin). Male and female mice (n = 143 total, n = 12-17/group/sex) were allocated into five study groups: (1) Unaltered, (2) Continuous (dosing 4-24 weeks of age), (3) Delayed (dosing only 16-24 weeks of age), (4) Initial (dosing 4-16 weeks of age, suspended at 16 weeks), and (5) Reconstituted (dosing from 4-16 weeks following by fecal microbiota transplant from Unaltered donors). Animals were euthanized at 24 weeks of age. In males, bone matrix strength in the femur was 25%-35% less than expected by geometry in mice from the Continuous (p = 0.001), Delayed (p = 0.005), and Initial (p = 0.040) groups as compared to Unaltered. Reconstitution of the gut microbiota led to a bone matrix strength similar to Unaltered animals (p = 0.929). In females, microbiome-induced changes in bone matrix strength followed the same trend as males but were not significantly different, demonstrating a sex-dependent response of bone matrix to the gut microbiota. Minor differences in chemical composition of bone matrix were observed with Raman spectroscopy. Our findings indicate that microbiome-induced impairment of bone matrix in males can be initiated and/or reversed after skeletal maturity. The portion of the femoral cortical bone formed after skeletal maturity (16 weeks) was small; suggesting that microbiome-induced changes in bone matrix occurred without osteoblast/osteoclast turnover through a yet unidentified mechanism. These findings provide evidence that the mechanical properties of bone matrix can be altered in the adult skeleton.
最近在小鼠身上的研究表明，肠道微生物组可以调节骨组织强度。然而，之前的工作涉及到在生长中的动物中改变肠道微生物组，并且不清楚在生命后期应用相同的微生物组变化是否会改变基质强度。在这里，我们使用口服抗生素（氨苄青霉素+新霉素）在骨骼成熟（16 周龄）之前和/或之后改变肠道微生物组的组成。雄性和雌性小鼠（共 143 只，每组/性别 12-17 只）被分配到五个研究组：（1）未改变，（2）连续（4-24 周龄给药），（3）延迟（仅 16-24 周龄给药），（4）初始（4-16 周龄给药，16 周龄时暂停）和（5）重建（4-16 周龄给药，然后从未改变的供体进行粪便微生物群移植）。动物在 24 周龄时被安乐死。在雄性中，与未改变组相比，连续组（p=0.001）、延迟组（p=0.005）和初始组（p=0.040）的小鼠股骨骨基质强度低 25%-35%，这是由几何形状预测的。重建肠道微生物组导致骨基质强度与未改变动物相似（p=0.929）。在雌性中，骨基质强度的微生物组诱导变化遵循与雄性相同的趋势，但没有显著差异，这表明骨基质对肠道微生物组的反应存在性别依赖性。通过拉曼光谱观察到骨基质化学组成的微小差异。我们的发现表明，雄性中由微生物组引起的骨基质损伤可以在骨骼成熟后开始和/或逆转。骨骼成熟后（16 周）形成的股骨皮质骨部分较小；这表明微生物组诱导的骨基质变化是在没有成骨细胞/破骨细胞转换的情况下发生的，通过一个尚未确定的机制。这些发现提供了证据，表明骨基质的机械性能可以在成人骨骼中改变。
