Mediators linking gut microbiota and sporadic Creutzfeldt-Jakob disease: a Mendelian randomization study.

While gut microbiome associations with sporadic Creutzfeldt-Jakob disease (sCJD) are recognized, causal mechanisms and mediation via cerebrospinal fluid (CSF) metabolites remain unestablished. Using bidirectional Mendelian randomization (MR) with mediation analysis and integrating genome-wide association study (GWAS) summary statistics from gut microbiota (​​composition in the FINRISK 2002 prospective cohort, n = 5,959​​), CSF metabolites (from the Wisconsin Alzheimer's Disease Research Center ​​Registry and Wisconsin Registry for Alzheimer's Prevention​​, n = 291), and sCJD case-control data (5,208 cases vs. 511,675 controls), we identified five microbial taxa influencing sCJD risk. Protective effects were observed for the family Atopobiaceae [odds ratio (OR) = 0.527, 95% confidence interval (CI) = 0.321-0.864, P = 0.011], the species Enterococcus faecalis (OR = 0.647, 95% CI = 0.427-0.980, P = 0.040), and the genus Lactobacillus (group B) (OR = 0.768, 95% CI = 0.602-0.981, P = 0.035). Conversely, the species Bacteroides eggerthii (OR = 1.228, 95% CI = 1.027-1.468, P = 0.025) and the order Chloroflexales (OR = 3.455, 95% CI = 1.214-9.835, P = 0.020) were pathogenic. Mediation analysis revealed that S-methylcysteine mediates 8.8% of ​​the effect of order Chloroflexales on sCJD risk​​, establishing it as a significant biological mediator in this pathogenic pathway. These findings provide novel biomarkers for early sCJD risk stratification, identify ​​the family Atopobiaceae, the species Enterococcus faecalis, and the genus Lactobacillus (group B)​​ as probiotic candidates for primary prevention, reveal S-methylcysteine pathway modulation as therapeutic entry points, and establish mechanistic foundations for disrupting gut-CSF transmission​​ in prion diseases.