Mediating role of blood metabolites in the relationship between immune cell traits and sepsis: a Mendelian randomization and mediation analysis.

Background: A significant association between immune cells and sepsis has been suggested by observational studies. However, the precise biological mechanisms underlying this association remain unclear. Therefore, we employed a Mendelian randomization (MR) approach to investigate the causal relationship between immune cells and genetic susceptibility to sepsis, and to explore the potential mediating role of blood metabolites.

Methods: A large cohort based on publicly available genome-wide association study datasets from European populations was utilized for the MR study. The primary model employed was the inverse variance weighted (IVW) model, assessing heterogeneity and pleiotropy. Moreover, a two-step MR approach was adopted to evaluate the potential mediating role of factors in the causal effects between immune cells and sepsis.

Results: Results from the IVW model indicated that the genetic prediction of CD62L on CD62L+ plasmacytoid dendritic cells (DC) (OR = 0.959, 95% CI [0.922-0.999], P = 0.043) was associated with a reduced risk of sepsis. Conversely, MR analysis with sepsis as the exposure and CD62L on CD62L+ plasmacytoid DC as the outcome did not demonstrate a significant causal relationship. Thus, mediation analysis was conducted, showing that the genetic prediction of CD62L on CD62L+ plasmacytoid DC (OR = 1.064, 95% CI [1.016-1.114], P = 0.008) was associated with increased levels of the metabolite N-palmitoyl-sphingadienine (d18:2/16:0). Similarly, MR analysis with N-palmitoyl-sphingadienine (d18:2/16:0) levels as the exposure and sepsis as the outcome found that the genetic prediction of N-palmitoyl-sphingadienine (d18:2/16:0) levels (OR = 0.843, 95% CI [0.748-0.950], p = 0.005) was associated with a reduced risk of sepsis. Furthermore, the results indicated that N-palmitoyl-sphingadienine (d18:2/16:0) levels mediated the causal impact of CD62L on CD62L+ plasmacytoid DC on sepsis, with a mediation proportion of 25.6% (95% CI [55.7%, - 4.51%]).

Discussion: These findings support the evidence of a causal relationship between the genetic prediction of CD62L on CD62L+ plasmacytoid DC and a reduced risk of sepsis, with N-palmitoyl-sphingadienine (d18:2/16:0) levels playing a mediating role in this pathway. These insights may inform prevention strategies and interventions targeting sepsis. Future research should explore additional potential biological mechanisms.