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Updated: Sep 11, 2025
Microbiota Analysis Using Two-step PCR and Next-generation 16S rRNA Gene Sequencing
Published on: October 15, 2019
Mediators linking gut microbiota and sporadic Creutzfeldt-Jakob disease: a Mendelian randomization study
Jie Shao1, Tengfei Su2, Jinyan Wang3
1Department of Neurology, The First Hospital of Jilin University, Changchun, China. shaojie1994@jlu.edu.cn.
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.
Insights
Gut bacteria influence sporadic Creutzfeldt-Jakob disease (sCJD) risk, with some microbes offering protection and others posing a threat. S-methylcysteine was identified as a key mediator in the pathogenic pathway, offering new therapeutic targets.
Area of Science:
- Neuroscience
- Microbiology
- Genetics
Background:
- The gut microbiome's role in sporadic Creutzfeldt-Jakob disease (sCJD) is acknowledged, but causal links and the involvement of cerebrospinal fluid (CSF) metabolites are not fully understood.
- Existing research lacks established mechanisms connecting gut microbial composition to sCJD pathogenesis and progression.
Purpose of the Study:
- To investigate the causal relationship between gut microbiota composition and the risk of developing sporadic Creutzfeldt-Jakob disease (sCJD).
- To explore the mediating role of cerebrospinal fluid (CSF) metabolites in the gut microbiome-sCJD axis.
- To identify potential microbial biomarkers for sCJD risk stratification and therapeutic targets.
Main Methods:
- Utilized bidirectional Mendelian randomization (MR) analysis integrating genome-wide association study (GWAS) summary statistics.
- Included data on gut microbiota composition (FINRISK 2002 cohort, n=5,959), CSF metabolites (Wisconsin ADRC and WRPC, n=291), and sCJD cases and controls (5,208 vs. 511,675).
- Employed mediation analysis to assess the role of S-methylcysteine in the pathway between specific microbial taxa and sCJD risk.
Main Results:
- Identified five microbial taxa associated with sCJD risk: Atopobiaceae (protective), Enterococcus faecalis (protective), Lactobacillus (group B) (protective), Bacteroides eggerthii (pathogenic), and Chloroflexales (pathogenic).
- Demonstrated that S-methylcysteine significantly mediates 8.8% of the effect of Chloroflexales on sCJD risk.
- Established protective effects for Atopobiaceae (OR=0.527), E. faecalis (OR=0.647), and Lactobacillus (OR=0.768), and pathogenic effects for B. eggerthii (OR=1.228) and Chloroflexales (OR=3.455).
Conclusions:
- The study establishes a mechanistic link between gut microbiota, CSF metabolites, and sCJD, highlighting specific microbes as risk modifiers.
- Findings suggest potential for using identified microbial taxa as biomarkers for early sCJD risk assessment and as probiotic candidates for prevention.
- Modulating the S-methylcysteine pathway presents a potential therapeutic strategy for sCJD, offering insights into disrupting gut-to-brain transmission in prion diseases.
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