Tracking alterations in polar metabolite and lipid levels during anti-tuberculosis (TB) interventions is an emerging biomarker discovery and validation approach due to its sensitivity in capturing changes and reflecting on the host status. Here, we employed deep plasma metabolic phenotyping to explore the TB patient metabolome during three phases of treatment: at baseline, during intensive phase treatment, and upon treatment completion. Differential metabolites (DMs) in each period were determined, and the pathway-level biological alterations were explored by untargeted metabolomics-guided functional interpretations that bypassed identification. We identified 41 DMs and 39 pathways that changed during intensive phase completion. Notably, levels of certain amino acids including histidine, bile acids, and metabolites of purine metabolism were dramatically increased. The altered pathways included those involved in the metabolism of amino acids, glycerophospholipids, and purine. At the end of treatment, 44 DMs were discovered. The levels of glutamine, bile acids, and lysophosphatidylinositol significantly increased compared to baseline; the levels of carboxylates and hypotaurine declined. In addition, 37 pathways principally associated with the metabolism of amino acids, carbohydrates, and glycan altered at treatment completion. The potential of each DM for diagnosing TB was examined using a cohort consisting of TB patients, those with latent infections, and controls. Logistic regression revealed four biomarkers (taurine, methionine, glutamine, and acetyl-carnitine) that exhibited excellent performance in differential diagnosis. In conclusion, we identified metabolites that could serve as useful metabolic signatures for TB management and elucidated underlying biological processes affected by the crosstalk between host and TB pathogen during treatment.

中文翻译：

---

代谢表型和整体功能分析有助于发现结核病治疗监测的代谢特征

跟踪抗结核 (TB) 干预期间极性代谢物和脂质水平的变化是一种新兴的生物标志物发现和验证方法，因为它在捕获变化和反映宿主状态方面具有敏感性。在这里，我们采用深层血浆代谢表型分析来探索结核病患者在三个治疗阶段的代谢组：基线、强化治疗期间和治疗完成后。确定了每个时期的差异代谢物（DM），并通过绕过识别的非靶向代谢组学指导的功能解释来探索通路水平的生物学改变。我们确定了 41 个 DM 和 39 个路径在强化阶段完成期间发生了变化。值得注意的是，某些氨基酸（包括组氨酸、胆汁酸和嘌呤代谢产物）的水平显着增加。改变的途径包括涉及氨基酸、甘油磷脂和嘌呤代谢的途径。治疗结束时，发现 44 例 DM。与基线相比，谷氨酰胺、胆汁酸和溶血磷脂酰肌醇的水平显着增加；羧酸盐和亚牛磺酸的水平下降。此外，37 条主要与氨基酸、碳水化合物和聚糖代谢相关的途径在治疗完成后发生了改变。使用由结核病患者、潜伏感染者和对照组成的队列检查了每种 DM 诊断结核病的潜力。逻辑回归显示四种生物标志物（牛磺酸、蛋氨酸、谷氨酰胺和乙酰肉碱）在鉴别诊断中表现出优异的性能。总之，我们确定了可以作为结核病管理有用代谢特征的代谢物，并阐明了治疗期间受宿主和结核病病原体之间的相互作用影响的潜在生物过程。