Mendelian randomization study of lithocholate sulfate mediating the effect of MMP-1 on ischemic stroke.

Genetically predicted higher MMP-1 levels were significantly associated with an increased risk of ischemic stroke.

• Inverse variance weighted odds ratio: 1.085 (95% CI: 1.031–1.142, P = .002)
• MMP-1 genetic instruments were based on 14,744 individuals from published GWAS
• Ischemic stroke outcome data included 39,818 cases and 271,817 controls
• Single nucleotide polymorphisms associated with MMP-1 were used as genetic instruments

Reverse MR analysis found no evidence for a causal effect of ischemic stroke on MMP-1 levels.

• Inverse variance weighted odds ratio: 1.034 (95% CI: 0.954–1.120, P = .420)
• This result supports the directionality of the MMP-1 → IS causal pathway rather than reverse causation

Lithocholate sulfate (LSL) significantly mediated the effect of MMP-1 on ischemic stroke risk.

• The estimated proportion of the effect mediated by LSL was 0.0071 (95% CI: 0.0027–0.0168)
• Mediation analysis was conducted using multivariable MR analysis
• LSL was identified as a protective mediator in the MMP-1 → IS pathway
• LSL is described as a gut microbiota-derived metabolite

The study proposes a novel MMP-1 → LSL → IS axis suggesting a compensatory interaction where a pro-inflammatory signal may upregulate a protective metabolite.

• MMP-1 is characterized as an inflammatory factor (matrix metalloproteinase-1)
• LSL upregulation in response to MMP-1 is interpreted as a compensatory protective response
• The authors highlight LSL as a potential target for future research into stroke mechanisms and prevention