Abstract
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.