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

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

This study investigates the role of DNA methylation in modulating immunosuppression in sepsis patients, aiming to enhance our understanding of the underlying mechanisms impacting patient outcomes.

Using the Infinium Methylation EPIC v1.0 BeadChip Kit (Illumina), leukocyte DNA methylation at different CpG sites and regions were analyzed within 24 hours of admission to the Intensive Care Unit in sepsis patients, septic shock patients, and critically ill patients.

By employing two analysis approaches (DMRcate and mCSEA), the study identified 1,256 differentially methylated regions (DMRs) associated with critical immune system pathways. Analysis of the top 100 differentially methylated positions (DMPs) allowed for clear differentiation among the patient groups.

Notably, 6,657 DMPs were linked to organ dysfunction according to SOFA scale and lactate levels. Further investigation using DNA bisulfite pyrosequencing revealed significant methylation alterations in genes such as IL10, TREM1, IL1B, and TNFAIP8 across diverse patient groups, particularly significant hypomethylation in those genes was found in septic shock.

These findings highlight the dynamic nature of DNA methylation profiles in sepsis patients, emphasizing pronounced alterations in those with septic shock and their close association with the disease process and a strong correlation was observed between global DNA methylation changes in leukocytes and organ dysfunction/lactate levels. 


  • Differentially methylated regions (DMRs) were associated with various aspects of the immune response, including inflammation, immune cell differentiation and activation, and immunosuppression. 
  • Notably, IL10, an anti-inflammatory cytokine (also known as human cytokine synthesis inhibitory factor (CSIF), and S100A8, a calcium- and zinc-binding protein which plays a prominent role in the regulation of inflammatory processes and immune response and is implicated in immunosuppression, exhibited hypomethylation in septic shock patients, highlighting their potential role in the sepsis disease process. 

Funding was provided for this project by INCLIVA, AEI (ISCIII) within the project PI19/00994, DTS21/00193 and PI22/00481 (co-financed by the ERDF).

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).

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