The Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, China; Tianjin Hospital, Tianjin University, Tianjin 300211, China.
Inner Mongolia Medical University, Hohhot 010050, China.
Ageing Res Rev. 2024 Nov;101:102479. doi: 10.1016/j.arr.2024.102479. Epub 2024 Aug 28.
The role of gut bacteria in preventing and delaying osteoporosis has been studied. However, the causal relationship between gut bacteria, plasma proteins, circulating metabolites and osteoporosis (OP) risk has not been fully revealed.
In this study, a two-sample Mendelian randomization study (MR) approach was used to assess the causal associations between gut bacteria, plasma proteins and circulating metabolites, and osteoporosis risk using Genome Wide Association Study (GWAS) data from gut bacteria(n=8208), plasma proteins(n=2263), circulating metabolites (n=123), and osteoporosis (3203 cases and 16380452 controls). Inverse-variance weighted (IVW) was used as the main analytical method to estimate the MR causal effect and to perform directional sensitivity analysis of causality. Finally, the mediating effect values for the influence of gut flora on OP pathogenesis through circulating metabolites were calculated by univariate MR analysis, and multivariate MR analysis. Next, we evaluated the effect of Phosphatidylcholine on the osteogenic function of bone marrow mesenchymal stem cells (BMSCs) through relevant experiments, including Edu detection of cell proliferation, alkaline phosphatase (ALP) staining, Alizarin red staining to evaluate osteogenic function, qPCR and WB detection of osteogenic differentiation related gene expression.
A total of 9 gut microbial taxa, 15 plasma proteins and eight circulating metabolites were analysed for significant causal associations with the development of OP. Significant causal effects of 7 on gut bacteria, plasma proteins and circulating metabolites were analysed by univariate MR analysis and these results were used as exposure factors for subsequent multivariate MR. Multivariate MR analyses yielded a significant effect of circulating metabolites Phosphatidylcholine and other cholines on OP (P<0.05). Further mediation effect analysis showed that the mediation effect of Bifidobacteriaceae affecting OP through the circulating metabolite Phosphatidylcholine and other cholines was -0.0224, with a 95 % confidence interval for the mediation effect that did not include 0, and the complete mediation effect was significant. Phosphatidylcholine can promote BMSCs proliferation and osteogenesis.
Our study demonstrated significant causal associations of gut bacteria, plasma proteins and circulating metabolites on OP, and that Bifidobacteriaceae affect OP through the circulating metabolites Phosphatidylcholine and other cholines. Phosphatidylcholine affects the osteogenic ability of BMSCs. Further exploration of potential microbiota-associated mechanisms of bone metabolism may offer new avenues for osteoporosis prevention and treatment of osteoporosis.
肠道细菌在预防和延缓骨质疏松症方面的作用已被研究。然而，肠道细菌、血浆蛋白、循环代谢物与骨质疏松症（OP）风险之间的因果关系尚未完全揭示。
本研究采用两样本孟德尔随机化研究（MR）方法，利用肠道细菌（n=8208）、血浆蛋白（n=2263）、循环代谢物（n=123）和骨质疏松症（3203 例和 16380452 例对照）的全基因组关联研究（GWAS）数据，评估肠道细菌、血浆蛋白和循环代谢物与骨质疏松症风险之间的因果关系。采用逆方差加权（IVW）作为主要分析方法，估计 MR 因果效应，并进行因果关系的定向敏感性分析。最后，通过单变量 MR 分析和多变量 MR 分析，计算肠道菌群通过循环代谢物对 OP 发病机制影响的中介效应值。接下来，我们通过相关实验评估了磷脂酰胆碱对骨髓间充质干细胞（BMSCs）成骨功能的影响，包括 Edu 检测细胞增殖、碱性磷酸酶（ALP）染色、茜素红染色评估成骨功能、qPCR 和 WB 检测成骨分化相关基因表达。
共分析了 9 种肠道微生物类群、15 种血浆蛋白和 8 种循环代谢物与 OP 发生的显著因果关系。通过单变量 MR 分析发现，7 种肠道细菌、血浆蛋白和循环代谢物对骨质疏松症有显著的因果影响，这些结果被用作后续多变量 MR 的暴露因素。多变量 MR 分析得出，循环代谢物磷脂酰胆碱和其他胆碱对 OP 有显著影响（P<0.05）。进一步的中介效应分析表明，肠道细菌双歧杆菌属通过循环代谢物磷脂酰胆碱和其他胆碱影响 OP 的中介效应值为-0.0224，中介效应值的 95%置信区间不包含 0，完全中介效应显著。磷脂酰胆碱可以促进 BMSCs 的增殖和成骨。
本研究表明肠道细菌、血浆蛋白和循环代谢物与 OP 存在显著的因果关系，双歧杆菌属通过循环代谢物磷脂酰胆碱和其他胆碱影响 OP。磷脂酰胆碱影响 BMSCs 的成骨能力。进一步探索潜在的与肠道菌群相关的骨代谢机制可能为骨质疏松症的预防和治疗提供新的途径。
