Genetically predicted N-Acetyl-L-Alanine mediates the association between CD3 on activated and secreting Tregs and Guillain-Barre syndrome.

Objective: This study sought to explore the potential causal relationships among immune cell traits, Guillain-Barre syndrome (GBS) and metabolites.

Methods: Employing a two-sample Mendelian randomization (MR) approach, the study investigated the causal associations between 731 immune cell traits, 1400 metabolite levels and GBS leveraging summary-level data from a genome-wide association study (GWAS). To ensure the reliability of our findings, we further assessed horizontal pleiotropy and heterogeneity and evaluated the stability of MR results using the Leave-one-out method.

Results: This study revealed a causal relationship between CD3 on activated & secreting Tregs and GBS. Higher CD3 on activated and secreting Regulatory Tregs increased the risk of GBS (primary MR analysis odds ratio (OR) 1.31/SD increase, 95% confidence interval (CI) 1.08-1.58, = 0.005). There was no reverse causality for GBS on CD3 on activated & secreting Tregs ( = 0.36). Plasma metabolite N-Acetyl-L-Alanine (ALA) was significantly positively correlated with GBS by using the IVW method (OR = 2.04, 95% CI, 1.26-3.30; = 0.00038). CD3 on activated & secreting Tregs was found to be positively associated with ALA risk (IVW method, OR, 1.04; [95% CI, 1.01-1.07], = 0.0078). Mediation MR analysis indicated the mediated proportion of CD3 on activated & secreting Tregs mediated by ALA was 10% (95%CI 2.63%, 17.4%).

Conclusion: In conclusion, our study identified a causal relationship between the level of CD3 on activated & secreting Tregs and GBS by genetic means, with a considerable proportion of the effect mediated by ALA. In clinical practice, thus providing guidance for future clinical research.