To evaluate whether gut microorganisms could influence bone responses to mechanical loading, the authors used antibiotics to deplete the gut microbiome in approximately 5-month-old mice. These animals then received a repetitive mechanical pressure to their right leg on a daily basis. As explained by the study’s corresponding author, Da Jing, this model “offers a controllable and precise mechanical stimulus to the bone [and] the use of the non-loaded contralateral limbs [here, the left leg] as controls, thereby mitigating the potential confounding effects due to inter-individual variability.” Normally, mice exhibit a significant gain in bone mass and integrity after two weeks of this mechanical loading task. However, the antibiotic-treated mice showed no changes in bone mass, which suggests that the gut microbiota could affect bone metabolism.
Next, the authors trained adult mice to run on a treadmill and evaluated bone health at baseline or after 6 weeks of daily treadmill training. Jing describes that this treadmill task was “particularly beneficial for identifying the microbial taxa that significantly influence skeletal mechanoresponsiveness during bone-loading exercises … as it more closely mimics natural physical activity.” The authors separated mice into two groups on the basis of whether they showed exceptionally high (>30–40%) or low (<5%) increases in bone mass. They then profiled both the gut microbiome and cecal metabolome of these groups. They identified that Lachnospiraceae bacteria, along with the microbial metabolite l-citrulline, were enriched in mice that exhibited greater changes in bone mass. Consequently, intragastric delivery of Lachnospiraceae into antibiotic-treated mice increased levels of l-citrulline and its derivative, l-arginine. The treatment also enhanced bone mass after mechanical loading. Importantly, the effect was also observed in mice pretreated with just l-arginine. Altogether, these results suggest that the conversion of microbial l-citrulline into l-arginine has a key role in bone responses to mechanical loading.
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