Li Ang, Kou Ruixin, Wang Jin, Zhang Bowei, Zhang Yan, Liu Jingmin, Hu Yaozhong, Wang Shuo
School of Medicine, Nankai University, Tianjin, China.
School of Medicine, Nankai University, Tianjin, China.
J Adv Res. 2024 Nov 14. doi: 10.1016/j.jare.2024.11.017.
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.
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.
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.
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.
These findings highlight the preventive effect of 2'-FL on aging-associated osteoporosis by regulating gut microbial homeostasis and innate immune responses.
与衰老相关的骨质疏松症被认为是中老年人严重的公共卫生问题，其发病机制复杂，包括最近发现的衰老诱导的免疫功能障碍和肠道微生物紊乱。建议基于膳食益生元进行干预，以维持骨骼健康并延缓骨质疏松症的进展。
作为一种明确的益生元，2'-岩藻糖基乳糖（2'-FL）已被充分验证对全身健康具有积极作用，本研究提出揭示其对与衰老相关的骨质疏松症的干预作用，以及涉及肠道微生态和先天免疫的潜在机制。
通过评估自然衰老小鼠的骨质流失严重程度和微观结构损伤，确定膳食2'-FL对骨质疏松症表型的影响。分析依赖先天免疫谱、肠道屏障功能和肠道微生物稳态的机制，以阐明信号轴。基于脂多糖刺激的RAW 264.7小鼠巨噬细胞验证详细的分子信号。
结果表明，12周的2'-FL干预可恢复自然衰老小鼠的骨质流失和微观结构损伤。此外，2'-FL减轻了衰老诱导的结肠炎症、肠道屏障功能障碍和肠道紧密连接蛋白的异常表达。通过恢复肠道微生物群多样性、恢复双歧杆菌、普雷沃氏菌科和阿克曼氏菌的丰度以及抑制嗜麦芽窄食单胞菌的生长，验证了2'-FL治疗对衰老诱导的肠道微生物失调的影响。流式细胞术分析显示，树突状细胞（DC）和巨噬细胞亚群随年龄变化，在2'-FL处理的老年小鼠和RAW264.7细胞中观察到M1极化巨噬细胞减少，这可能是通过与Toll样受体4（TLR4）相互作用来抑制NF-κB信号传导和促炎因子的分泌。
这些发现突出了2'-FL通过调节肠道微生物稳态和先天免疫反应对衰老相关骨质疏松症的预防作用。
