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

This study aimed to investigate the potential causal relationship between the inflammatory factor matrix metalloproteinase-1 (MMP-1) and ischemic stroke (IS) using Mendelian randomization (MR), and to examine whether the gut microbiota-derived metabolite lithocholate sulfate (LSL) mediates this association. We performed a 2-sample MR analysis to assess the causal effect of genetically predicted MMP-1 levels (based on 14,744 individuals) on IS risk (39,818 cases and 2,71,817 controls). Genetic instruments were single nucleotide polymorphisms associated with the exposures, sourced from published genome-wide association studies. The causal direction was verified through reverse MR analysis. Furthermore, a multivariable MR analysis was conducted to quantify the mediating effect of LSL on the pathway from MMP-1 to IS. Genetically predicted higher MMP-1 levels were significantly associated with an increased risk of IS (inverse variance weighted odds ratio: 1.085, 95% confidence interval [CI]: 1.031-1.142, P = .002). In contrast, reverse MR analysis provided no evidence for a causal effect of IS on MMP-1 levels (inverse variance weighted odds ratio: 1.034, 95% CI: 0.954-1.120, P = .420). The mediation analysis revealed a significant indirect effect mediated by LSL, with an estimated proportion of 0.0071 (95% CI: 0.0027-0.0168). This MR study provides genetic evidence that elevated MMP-1 is causally associated with an increased risk of IS. Furthermore, we identify LSL as a protective mediator in this pathway. Our findings propose a novel MMP-1 → LSL → IS axis, suggesting a compensatory interaction where a pro-inflammatory signal may upregulate a protective metabolite. This highlights LSL as a potential target for future research into stroke mechanisms and prevention.