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

BackgroundA 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.MethodsA 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.ResultsResults 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%]).DiscussionThese 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.