The stimulative effect of Cordyceps sinensis functionalized selenium nanoparticles on bone development in growing mice: involvement of the gut microbiota-bone axis

Achieving optimal peak bone mass (PBM) during adolescence through adequate intake of trace element such as selenium is crucial for reducing osteoporosis risk in later life. We previously developed novel functionalized selenium nanoparticles (Cs4-SeNPs) utilizing polysaccharide-protein complex isolated from Cordyceps sinensis for prevention of osteoporosis. The gut microbiota, functioning as the "second gene pool", plays a crucial role in maintaining bone homeostasis. However, how Cs4-SeNPs regulate bone metabolism via the gut microbiota-bone axis remains unclear.

To elucidate how the gut microbiota and microbial metabolites mediate the bone-promoting effect of Cs4-SeNPs.

Growing mice model was used to assess the effect of Cs4-SeNPs on bone development. Metagenomics, metabolomics, and proteomics analyses were conducted to uncover the mechanism of action of Cs4-SeNPs. In vitro osteoblast and osteoclast models were employed to validate the effects of key gut microbial metabolites regulated by Cs4-SeNPs on osteogenesis and osteoclastogenesis. Pseudo-germ-free mice model treated with antibiotics was employed to determine the role of gut microbiota in bone-promoting effects of Cs4-SeNPs.

We found that Cs4-SeNPs significantly enhanced bone mass in growing mice, as evidenced by improved bone microarchitecture and increased expression of bone extracellular matrix-related markers. Notably, antibiotic treatment-induced microbial depletion abolished the effects of Cs4-SeNPs on bone development in growing mice. Increased abundance of beneficial gut bacterial genera, notably Adlercreutzia and Parvibacter, were observed following Cs4-SeNPs administration. Proteomics analysis and subsequent verification experiments demonstrated that Cs4-SeNPs inhibited the TNF-R1/TAB2/NF-κB inflammatory pathway and upregulated the expression of antioxidant proteins including SERPINA3K, GPX1, and SOD in the bone tissue. Metabolomic analysis revealed that Cs4-SeNPs treatment significantly elevated fecal and serum levels of two key metabolites: kynurenic acid and trehalose. Further in vitro studies confirmed that kynurenic acid and trehalose could reproduce the effects of Cs4-SeNPs on osteoblastic and osteoclastic differentiation.

Our findings suggest that Cs4-SeNPs optimize PBM and promote bone development in growing mice by improving the osteoblast/osteoclast balance via the modulation of the inflammatory TNF-R1/TAB2/NF-κB axis and the enhancement of antioxidant activity through the elevated levels of gut microbial metabolites kynurenic acid and trehalose in a gut microbiota-dependent manner.