Blautia-derived L-arginine promotes osteoblast differentiation and alleviates osteoporosis via lactylation modification

Osteoporosis is a systemic metabolic disorder in which the gut microbiota plays a pivotal regulatory role. However, the specific microbial taxa and metabolic pathways involved in bone homeostasis remain poorly understood. This study aimed to explore the contribution of intestinal microbiota, particularly Blautia, and its metabolites in osteoporosis. Fecal samples were collected from 71 osteoporosis patients and 28 healthy controls. Through 16S rRNA and metagenomic shotgun sequencing, a notable decrease in Blautia and disruption of arginine metabolic pathways within this genus were identified in osteoporosis patients. Fecal microbiota transplantation experiments demonstrated that gut microbial composition significantly influences ovariectomy (OVX)-induced bone loss. Colonization with the Blautia model strain, a representative species of the genus, improved bone mineral density and mitigated osteoporosis in OVX mice. Fecal metabolomic analysis revealed systemic alterations in arginine metabolism among patients. Supplementation with L-arginine in OVX mice effectively alleviated bone loss. In vitro studies showed that L-arginine promotes osteoblast differentiation by enhancing lactylation modifications. These findings establish Blautia and its metabolite L-arginine as critical regulators of bone homeostasis, highlighting the potential for targeting Blautia abundance or modulating the arginine-lactylation pathway as therapeutic strategies for osteoporosis.骨质疏松症是一种全身性代谢紊乱，肠道菌群在其中发挥关键调控作用。然而，参与骨稳态的特定微生物类群及代谢通路仍鲜为人知。本研究旨在探究肠道菌群（尤其是布劳特氏菌属（Blautia））及其代谢产物在骨质疏松症中的作用。本研究收集了71名骨质疏松症患者与28名健康对照者的粪便样本。通过16S核糖体RNA（16S rRNA）及宏基因组鸟枪法测序，研究人员在骨质疏松症患者体内发现布劳特氏菌属丰度显著降低，且该菌属内的精氨酸代谢通路发生紊乱。粪便菌群移植实验表明，肠道菌群组成显著影响卵巢切除术（OVX）诱导的骨丢失。定植该菌属的代表性模式菌株后，卵巢切除术小鼠的骨密度得以提升，骨质疏松症症状得到缓解。粪便代谢组学分析显示，患者体内存在精氨酸代谢的全身性改变。给卵巢切除术小鼠补充L-精氨酸（L-arginine）可有效减轻骨丢失。体外实验表明，L-精氨酸可通过增强乳酸化修饰促进成骨细胞分化。本研究结果证实，布劳特氏菌属及其代谢产物L-精氨酸是骨稳态的关键调控因子，提示靶向调控布劳特氏菌属丰度或调节精氨酸-乳酸化通路有望成为骨质疏松症的治疗策略。