The Metabolite indole-3-acetic acid of Bacteroides ovatus ameliorates ovariectomy-induced bone loss by activating AhR and inhibiting oxidative stress.

Postmenopausal osteoporosis represents a systemic skeletal condition distinguished by diminished bone mass and heightened skeletal fragility. Emerging evidence has highlighted a significant relationship between bone metabolism and disturbances in gut microbiota (GM) homeostasis. However, the exact mechanisms by which GM dysbiosis contributes to postmenopausal osteoporosis remain insufficiently understood. Herein, integrating weighted gene co-expression network analysis with machine learning, a notable depletion of Bacteroides ovatus (B. ovatus) was identified in the GM of women with postmenopausal osteoporosis. Metagenomic sequencing further validated the reduced abundance of B. ovatus in ovariectomized (OVX) mice. Notably, live B. ovatus (LBO), but not heat-killed B. ovatus (KBO), effectively mitigated bone loss in OVX mice and restored intestinal mucosal barrier integrity. Both untargeted and targeted metabolomic profiling revealed substantial alterations in tryptophan metabolism in OVX mice, particularly a significant reduction in indole-3-acetic acid (IAA). Oral supplementation with IAA notably alleviated bone loss in OVX mice. Mechanistically, IAA stimulated AhR, enhancing NQO1 expression, reducing intracellular ROS buildup, and ultimately suppressing osteoclast differentiation and bone resorption. This investigation demonstrates, for the first time, the protective effects of B. ovatus and its metabolite IAA in counteracting estrogen deficiency-induced bone loss and may present a promising microbial-targeted strategy for osteoporosis prevention.