Abstract

Osteoporosis is a systemic skeletal disease caused by disrupted bone homeostasis. Black-bean-derived oligopeptides have shown promise as natural osteogenic candidates, yet their roles in mitigating osteoporosis based on gut microecology modulation remain poorly understood. In this study, black-bean-hydrolyzed peptides (<1 kDa), KIGT, and KGVG significantly improved bone mass and microarchitecture in ovariectomy (OVX) mice, primarily owing to osteoanabolic activities. All three oligopeptides ameliorated gut microbiota dysbiosis by increasing the abundance of Bacteroides, Bilophila, Bifidobacterium, and Lactobacillus, which were highly associated with the intestinal levels of glutamic acid and α-ketoglutaric acid (α-KG). Notably, α-KG exhibited the strongest positive correlation with bone mass in OVX mice. In vitro assays confirmed that α-KG stimulated bone formation by activating Wnt/β-catenin signaling. This study highlights the antiosteoporosis effects of black-bean oligopeptides via regulation of the gut microbiota and metabolites, providing novel mechanistic insights into peptide-based therapies for bone-related disorders.