Although mechanical loading is essential for maintaining bone health and combating osteoporosis, its practical application is limited to a large extent by the high variability in bone mechanoresponsiveness. Here, we found that gut microbial depletion promoted a significant reduction in skeletal adaptation to mechanical loading. Among experimental mice, we observed differences between those with high and low responses to exercise with respect to the gut microbial composition, in which the differential abundance of Lachnospiraceae contributed to the differences in bone mechanoresponsiveness. Microbial production of L-citrulline and its conversion into L-arginine were identified as key regulators of bone mechanoadaptation, and administration of these metabolites enhanced bone mechanoresponsiveness in normal, aged, and ovariectomized mice. Mechanistically, L-arginine-mediated enhancement of bone mechanoadaptation was primarily attributable to the activation of a nitric-oxide-calcium positive feedback loop in osteocytes. This study identifies a promising anti-osteoporotic strategy for maximizing mechanical loading-induced skeletal benefits via the microbiota-metabolite axis.

尽管机械负荷对于维持骨骼健康和对抗骨质疏松症至关重要，但其实际应用在很大程度上受到骨机械反应性的高度可变性的限制。在这里，我们发现肠道微生物的消耗导致骨骼对机械负荷的适应显着降低。在实验小鼠中，我们观察到对运动反应高和低的小鼠在肠道微生物组成方面存在差异，其中毛螺菌科的不同丰度导致了骨机械反应性的差异。 L-瓜氨酸的微生物产生及其转化为L-精氨酸被确定为骨机械适应的关键调节剂，并且这些代谢物的施用增强了正常、老年和卵巢切除小鼠的骨机械反应性。从机制上讲，L-精氨酸介导的骨机械适应增强主要归因于骨细胞中一氧化氮-钙正反馈回路的激活。这项研究确定了一种有前途的抗骨质疏松策略，可通过微生物群-代谢轴最大限度地提高机械负荷引起的骨骼益处。