Alterations in leukocyte DNA methylome are associated to immunosuppression in severe clinical phenotypes of septic patients

15 Pág.Sepsis patients experience a complex interplay of host pro- and anti-inflammatory processes which compromise the clinical outcome. Despite considering the latest clinical and scientific research, our comprehension of the immunosuppressive events in septic episodes remains incomplete. Additionally, a lack of data exists regarding the role of epigenetics in modulating immunosuppression, subsequently impacting patient survival.The author(s) declare financial support was received for the research, authorship, and/or publication of this article. RO-V is supported by Contratos PFIS grant (FI20/00202) from AES-ISCIII and co-financed by the European Regional Development Fund (ERDF). JG-G and FP thank INCLIVA, AEI (ISCIII) for project PI19/00994, DTS21/00193 and PI22/00481 (co-financed by the ERDF). GC-V thanks Agencia Valenciana de Innovación for the grant INNTA3/2022/22. EN-S is supported by Contratos APOTI/2022 under grant CIAPOT/2021/15 from Conselleria de Innovación, Universidades, Ciencia y Sociedad Digital. The project leading to these results has received funding from “la Caixa” Foundation (ID 100010434), under agreement CI18-0009. MR-G was supported by the Competitiveness Programme for the Promotion of Talent and its Employability in R+D+I Torres Quevedo grant from Spanish Ministerio de Ciencia e Innovación (PTQ2019-010552).Peer reviewe

Alterations in leukocyte DNA methylome are associated to immunosuppression in severe clinical phenotypes of septic patients

IntroductionSepsis patients experience a complex interplay of host pro- and anti-inflammatory processes which compromise the clinical outcome. Despite considering the latest clinical and scientific research, our comprehension of the immunosuppressive events in septic episodes remains incomplete. Additionally, a lack of data exists regarding the role of epigenetics in modulating immunosuppression, subsequently impacting patient survival.MethodsTo advance the current understanding of the mechanisms underlying immunosuppression, in this study we explored the dynamics of DNA methylation using the Infinium Methylation EPIC v1.0 BeadChip Kit in leukocytes from patients suffering from sepsis, septic shock, and critically ill patients as controls, within the first 24 h after admission in the Intensive Care Unit of a tertiary hospital.Results and discussionEmploying two distinct analysis approaches (DMRcate and mCSEA) in comparing septic shock and critically ill patients, we identified 1,256 differentially methylated regions (DMRs) intricately linked to critical immune system pathways. The examination of the top 100 differentially methylated positions (DMPs) between septic shock and critically ill patients facilitated a clear demarcation among the three patient groups. Notably, the top 6,657 DMPs exhibited associations with organ dysfunction and lactate levels. Among the individual genes displaying significant differential methylation, IL10, TREM1, IL1B, and TNFAIP8 emerged with the most pronounced methylation alterations across the diverse patient groups when subjected to DNA bisulfite pyrosequencing analysis. These findings underscore the dynamic nature of DNA methylation profiles, highlighting the most pronounced alterations in patients with septic shock, and revealing their close association with the disease