Metabolite enrichment pathways selected by MR.

Purpose
To analyze the causal relationship between 486 human serum metabolites and the active tuberculosis (ATB) in European population.
Methods
In this study, the causal relationship between human serum metabolites and the ATB was analyzed by integrating the genome-wide association study (GWAS). The 486 human serum metabolites were used as the exposure variable, three different ATB GWAS databases in the European population were set as outcome variables, and single nucleotide polymorphisms were used as instrumental variables for Mendelian Randomization. The inverse variance weighting was estimated causality, the MR-Egger intercept to estimate horizontal pleiotropy, and the combined effects of metabolites were also considered in the meta-analysis. Furthermore, the web-based MetaboAnalyst 6.0 was engaged for enrichment pathway analysis, while R (version 4.3.2) software and Review Manager 5.3 were employed for statistical analysis.
Results
A total of 21, 17, and 19 metabolites strongly associated with ATB were found in the three databases after preliminary screening (P < 0.05). The intersecting metabolites across these databases included tryptophan, betaine, 1-linoleoylglycerol (1-monolinolein) (1-LG), 1-eicosatrienoylglycerophosphocholine, and oleoylcarnitine. Among them, betaine (I2 = 24%, P = 0.27) and 1-LG (I2 = 0%, P = 0.62) showed the lowest heterogeneity among the different ATB databases. In addition, the metabolic pathways of phosphatidylethanolamine biosynthesis (P = 0.0068), methionine metabolism (P = 0.0089), betaine metabolism (P = 0.0205) and oxidation of branched-chain fatty acids (P = 0.0309) were also associated with ATB.
Conclusion
Betaine and 1-LG may be biomarkers or auxiliary diagnostic tools for ATB. They may provide new guidance for medical practice in the early diagnosis and surveillance of ATB. In addition, by interfering with phosphatidylethanolamine biosynthesis, methionine metabolism, betaine metabolism, oxidation of branched-chain fatty acids, and other pathways, it is helpful to develop new anti-tuberculosis drugs and explore the virulence or pathogenesis of ATB at a deeper level, providing an effective reference for future studies.

研究目的：分析欧洲人群中486种人体血清代谢物与活动性肺结核（active tuberculosis, ATB）之间的因果关联。
方法：本研究通过整合全基因组关联研究（genome-wide association study, GWAS）数据，分析人体血清代谢物与活动性肺结核之间的因果关联。以486种人体血清代谢物作为暴露变量，以欧洲人群的3个不同活动性肺结核全基因组关联研究数据库作为结局变量，并将单核苷酸多态性作为孟德尔随机化（Mendelian Randomization, MR）的工具变量。采用逆方差加权法估计因果关联，使用MR-Egger截距评估水平多效性，并在荟萃分析中纳入代谢物的联合效应。此外，本研究使用基于网页的MetaboAnalyst 6.0平台进行富集通路分析，并采用R（版本4.3.2）软件与Review Manager 5.3进行统计学分析。
结果：经初步筛选（P < 0.05）后，3个数据库中分别筛选出21、17和19种与活动性肺结核显著相关的代谢物。各数据库共有的重叠代谢物包括色氨酸、甜菜碱、1-亚油酰甘油（1-单油酰甘油，1-LG）、1-二十碳三烯酰甘油磷酸胆碱以及油酰肉碱。其中，甜菜碱（I²=24%，P=0.27）与1-LG（I²=0%，P=0.62）在不同活动性肺结核数据库间的异质性最低。此外，磷脂酰乙醇胺生物合成（P=0.0068）、甲硫氨酸代谢（P=0.0089）、甜菜碱代谢（P=0.0205）以及支链脂肪酸氧化（P=0.0309）等代谢通路也与活动性肺结核存在关联。
结论：甜菜碱与1-LG有望成为活动性肺结核的生物标志物或辅助诊断工具，可为活动性肺结核的早期诊断与监测的临床实践提供新的指导方向。此外，通过调控磷脂酰乙醇胺生物合成、甲硫氨酸代谢、甜菜碱代谢以及支链脂肪酸氧化等通路，有助于开发新型抗结核药物，并从更深层次探究活动性肺结核的致病机制与毒力特征，为后续相关研究提供有效参考依据。