Table_3_Dissecting the mediating role of inflammatory factors in the interaction between metabolites and sepsis: insights from bidirectional Mendelian randomization.xlsx

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（Sepsis）是一种危及生命的病症，其涉及代谢改变、炎症介质与宿主应答之间的复杂相互作用。本研究采用双向孟德尔随机化（Mendelian randomization）方法，探究了1400种代谢物与脓毒症之间的因果关联，以及炎症因子的中介作用。本研究鉴定出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及OSM呈负相关，提示其具有保护作用；而IL-2则呈正相关，表明其可能为危险因素。在上述代谢物中，胡椒碱（Piperine）与9-羟基硬脂酸（9-Hydroxystearate）展现出尤为值得关注的抗脓毒症保护效应。胡椒碱的保护作用通过与AXIN1的相互作用介导，可使脓毒症发病风险降低16.296%。这提示胡椒碱可通过调控AXIN1的表达水平影响脓毒症转归的潜在通路。9-羟基硬脂酸同样表现出抗脓毒症的保护作用，其介导机制为与FGF-19呈正相关、与IL-2呈负相关，分别为其保护效应贡献了9.436%与12.565%的效应量。实验验证结果证实，与健康对照相比，脓毒症患者体内IL-2水平显著升高，而FGF-19、AXIN1、胡椒碱及9-羟基十八烷酸（9-hydroxyoctadecanoic acid）水平则显著降低。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，这一结果验证了孟德尔随机化分析的结论。本研究结果为阐明脓毒症的分子机制提供了新视角，突出了特定代谢物的独特作用与贡献，以及其与炎症介质的相互作用。本研究加深了我们对脓毒症病理生理学的认识，并为脓毒症管理的靶向治疗干预与生物标志物开发开辟了新方向。然而，仍需开展进一步研究以在不同人群中验证上述通路，并全面探究这些代谢物在脓毒症中的具体作用。