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ORIGINAL RESEARCH article

Front. Endocrinol.
Sec. Systems Endocrinology
Volume 15 - 2024 | doi: 10.3389/fendo.2024.1377755
This article is part of the Research Topic The immunological events of macrophages in the course of sepsis View all 3 articles

Dissecting the Mediating Role of Inflammatory Factors in the Interaction Between Metabolites and Sepsis: Insights from Bidirectional Mendelian Randomization

Provisionally accepted
Fangchen Gong Fangchen Gong 1Wenbin Liu Wenbin Liu 1Lei Pei Lei Pei 1Xiaofeng Wang Xiaofeng Wang 1Xiangtao Zheng Xiangtao Zheng 1Song Yang Song Yang 1Shanzhi Zhao Shanzhi Zhao 1Dan Xu Dan Xu 1Ranran Li Ranran Li 2Zhitao Yang Zhitao Yang 1Enqiang Mao Enqiang Mao 1Erzhen Chen Erzhen Chen 1Ying Chen Ying Chen 3*
  • 1 Department of Emergency, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, Beijing, China
  • 2 Department of Respiratory and Critical Care Medicine, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, Shanghai, China
  • 3 Department of Emergency Medicine, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

The final, formatted version of the article will be published soon.

    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.

    Keywords: Sepsis, Mendelian randomization, Inflammatory factors, Metabolites, Axin1, IL-2, FGF-19

    Received: 28 Jan 2024; Accepted: 15 Jul 2024.

    Copyright: © 2024 Gong, Liu, Pei, Wang, Zheng, Yang, Zhao, Xu, Li, Yang, Mao, Chen and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Ying Chen, Department of Emergency Medicine, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.