Zheng Zhimin, Sun Hao, Zhang Panpan, Cao Fan, Xiao Xuwu, Zhao Tingting
Department of Graduate School, Dalian Medical University, Dalian, Liaoning, China.
Department of Pediatric, Dalian Women and Children's Medical Center (Group), Dalian, Liaoning, China.
Pediatr Res. 2025 Apr 3. doi: 10.1038/s41390-025-03985-3.
Previous evidence suggests close relationships between the gut microbiota and short stature, but the causal relationship between them remains unclear. Our study performed Mendelian randomization (MR) analysis to investigate the causal relationships between gut microbiota, blood metabolites, and short stature, and to identify the potential role of blood metabolites as mediators.
We extracted summary-level data for 119 genera gut microbiota, 309 blood metabolites, and short stature from published genome-wide association studies (GWASs). We applied two-sample MR to infer the causal links, and a two-step MR was employed to quantify the proportion of the effect of gut microbiota on short stature mediated by blood metabolites.
Increased Prevotella9, Alloprevotella, FamilyXIIIAD3011group, 3-(4-hydroxyphenyl) lactate, and cyclo (leu-pro) were potentially associated with higher short stature risk while Parasutterella, Clostridium sensu stricto 1, Roseburia, caffeine, laurate (12:0), and 4-hydroxyhippurate were related to lower short stature risk. Mediation analysis indicated that 4-hydroxyhippurate levels acted as a mediator between Clostridium sensu stricto 1 and short stature, with an indirect effect proportion of 43.03%.
Our study demonstrates the causal relationships among gut microbiota, blood metabolites, and short stature, and computes the proportion of the effect mediated by blood metabolites, provides new insights for studying the gut-bone axis theory in short stature.
Our study used Mendelian randomization to demonstrate a causal relationship between gut microbiota, blood metabolites and short stature and identified a mediating role for metabolites. Current studies on the relationship between gut microbiota and short stature are observational and cannot infer causality, our research provides new evidence for this problem. This is the first Mendelian randomization study of gut microbiota, blood metabolites and short stature, providing new insights into the gut-skeletal axis theory of short stature.
先前的证据表明肠道微生物群与身材矮小之间存在密切关系，但它们之间的因果关系仍不清楚。我们的研究进行了孟德尔随机化（MR）分析，以研究肠道微生物群、血液代谢物与身材矮小之间的因果关系，并确定血液代谢物作为中介的潜在作用。
我们从已发表的全基因组关联研究（GWAS）中提取了119个属的肠道微生物群、309种血液代谢物和身材矮小的汇总水平数据。我们应用两样本MR来推断因果联系，并采用两步MR来量化血液代谢物介导的肠道微生物群对身材矮小影响的比例。
普雷沃氏菌9、别普雷沃氏菌、XIIIAD3011菌群、3-(4-羟基苯基)乳酸和环（亮氨酸-脯氨酸）增加可能与较高的身材矮小风险相关，而副萨特氏菌、严格意义上的梭菌1、罗斯氏菌、咖啡因、月桂酸（12:0）和4-羟基马尿酸与较低的身材矮小风险相关。中介分析表明，4-羟基马尿酸水平在严格意义上的梭菌1和身材矮小之间起中介作用，间接效应比例为43.03%。
我们的研究证明了肠道微生物群、血液代谢物和身材矮小之间的因果关系，并计算了血液代谢物介导的效应比例，为研究身材矮小的肠-骨轴理论提供了新的见解。
我们的研究使用孟德尔随机化证明了肠道微生物群、血液代谢物和身材矮小之间的因果关系，并确定了代谢物的中介作用。目前关于肠道微生物群与身材矮小关系的研究是观察性的，无法推断因果关系，我们的研究为这个问题提供了新的证据。这是第一项关于肠道微生物群、血液代谢物和身材矮小的孟德尔随机化研究，为身材矮小的肠-骨骼轴理论提供了新的见解。
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