Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Front Endocrinol (Lausanne). 2024 Aug 14;15:1377755. doi: 10.3389/fendo.2024.1377755. eCollection 2024.
Sepsis, a life-threatening condition, involves complex interactions among metabolic alterations, inflammatory mediators, and host responses. This study utilized a bidirectional Mendelian randomization approach to investigate the causal relationships between 1400 metabolites and sepsis, and the mediating role of inflammatory factors. We identified 36 metabolites significantly associated with sepsis (p < 0.05), with AXIN1, FGF-19, FGF-23, IL-4, and OSM showing an inverse association, suggesting a protective role, while IL-2 exhibited a positive correlation, indicating a potential risk factor. Among these metabolites, Piperine and 9-Hydroxystearate demonstrated particularly interesting protective effects against sepsis. Piperine's protective effect was mediated through its interaction with AXIN1, contributing to a 16.296% reduction in sepsis risk. This suggests a potential pathway where Piperine influences sepsis outcomes by modulating AXIN1 levels. 9-Hydroxystearate also exhibited a protective role against sepsis, mediated through its positive association with FGF-19 and negative association with IL-2, contributing 9.436% and 12.565%, respectively, to its protective effect. Experimental validation confirmed significantly elevated IL-2 levels and reduced FGF-19, AXIN1, piperine, and 9-hydroxyoctadecanoic acid levels in sepsis patients compared to healthy controls. Piperine levels positively correlated with AXIN1, while 9-hydroxyoctadecanoic acid levels negatively correlated with IL-2 and positively correlated with FGF-19, supporting the Mendelian randomization findings. Our findings provide insights into the molecular mechanisms of sepsis, highlighting the unique roles and contributions of specific metabolites and their interactions with inflammatory mediators. This study enhances our understanding of sepsis pathophysiology and opens avenues for targeted therapeutic interventions and biomarker development for sepsis management. However, further research is essential to validate these pathways across diverse populations and fully explore the roles of these metabolites in sepsis.
脓毒症是一种危及生命的疾病，涉及代谢改变、炎症介质和宿主反应之间的复杂相互作用。本研究采用双向孟德尔随机化方法，研究了 1400 种代谢物与脓毒症之间的因果关系，以及炎症因子的中介作用。我们确定了 36 种与脓毒症显著相关的代谢物（p<0.05），其中 AXIN1、FGF-19、FGF-23、IL-4 和 OSM 呈负相关，表明具有保护作用，而 IL-2 呈正相关，表明可能是危险因素。在这些代谢物中，胡椒碱和 9-羟基硬脂酸对脓毒症表现出特别有趣的保护作用。胡椒碱的保护作用是通过其与 AXIN1 的相互作用介导的，可使脓毒症的风险降低 16.296%。这表明胡椒碱可能通过调节 AXIN1 水平影响脓毒症的结果。9-羟基硬脂酸也对脓毒症表现出保护作用，通过与 FGF-19 呈正相关和与 IL-2 呈负相关介导，分别对其保护作用贡献 9.436%和 12.565%。实验验证证实脓毒症患者的 IL-2 水平显著升高，而 FGF-19、AXIN1、胡椒碱和 9-羟基十八烷酸水平降低，与健康对照组相比。胡椒碱水平与 AXIN1 呈正相关，而 9-羟基十八烷酸水平与 IL-2 呈负相关，与 FGF-19 呈正相关，支持孟德尔随机化的结果。我们的研究结果为脓毒症的分子机制提供了新的见解，突出了特定代谢物的独特作用及其与炎症介质的相互作用。本研究增强了我们对脓毒症病理生理学的理解，为脓毒症的靶向治疗干预和生物标志物开发开辟了新的途径。然而，需要进一步的研究来验证这些途径在不同人群中的作用，并充分探索这些代谢物在脓毒症中的作用。
