Abstract
INTRODUCTION: Aging-related osteoporosis is considered as a serious public health concern for middle-aged and elderly people, with an intricated pathogenesis including the recently identified aging-induced immunological dysfunction and gut microbial disorder. The intervention based on dietary prebiotics is recommended to retain bone health and postpone the progression of osteoporosis. OBJECTIVES: As a well-defined prebiotic, 2'-fucosyllactose (2'-FL) has been thoroughly validated with positive effect on systemic health and was proposed in this study to unveil its intervention on aging-related osteoporosis, as well as the underlying mechanisms involving the gut microecology and innate immunity. METHODS: The effects of dietary 2'-FL on osteoporosis phenotypes were identified by evaluating the severity of bone loss and microstructure damage in natural aging mice. The mechanisms relying on innate immune profile, intestinal barrier function, and gut microbial homeostasis, were analyzed to elucidate the signaling axis. The detailed molecular signaling was validated based on LPS-stimulated RAW 264.7 murine macrophages. RESULTS: The results indicated that 12-week 2'-FL intervention retrieved bone loss and microstructure damage in natural aging mice. Also, 2'-FL alleviated aging-induced colonic inflammation, gut barrier dysfunction, and abnormal expression of intestinal tight-junction protein. The impact of 2'-FL treatment on the aging-induced gut microbial dysbiosis was validated by restoring gut microbiota diversity, recovering the abundance of Bifidobacterium, Prevotellaceae and Akkermansia, and inhibiting the growth of Stenotrophomonas. Flow cytometry analysis revealed changes in dendritic cell (DC) and macrophage subsets with age, and a decrease in M1-polarized macrophages was observed in 2'-FL-treated aged mice and RAW264.7 cells potentially through the interaction with toll-like receptor 4 (TLR4) to suppress NF-κB signaling and the secretion of proinflammatory factors. CONCLUSION: These findings highlight the preventive effect of 2'-FL on aging-associated osteoporosis by regulating gut microbial homeostasis and innate immune responses.