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.