Multiomics identifies the endothelial SYNPO2/VNN1 axis as a therapeutic target and validates a microbiota-directed vaccine in atherosclerosis

Vollständiger Abstract

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Abstract Background Gut microbiota (GM) dysbiosis is implicated in atherosclerosis (AS), but its causal mechanisms and actionable therapeutic targets remain elusive. This study aims to identify specific GM-host interactions and translate multiomics findings into clinically relevant therapeutic strategies. Methods We developed an integrative multiomics framework combining bidirectional Mendelian randomization (MR) on large-scale GWAS data, bulk and single-cell transcriptomics, and in vivo validation. MR was used to identify causal microbial taxa. Transcriptomic analyses revealed key endothelial genes. A microbiota-targeted vaccine against Klebsiella aerogenes was developed and tested in ApoE-knockout mice fed a high-fat diet to evaluate its therapeutic efficacy on plaque burden, lipid profiles, and hormonal levels. Results Bidirectional MR identified 38 microbial taxa causally linked to AS (14 risk-enhancing and 24 protective). Integrative transcriptomics pinpointed SYNPO2 (downregulated) and VNN1 (upregulated) as key endothelial genes in AS progression. Single-cell RNA sequencing further defined endothelial cells as central mediators, with SYNPO2 dominating early differentiation and VNN1 driving late-stage inflammation. Drug screening identified estradiol and progesterone as dual-target agents. Notably, K. aerogenes was found to degrade atheroprotective estradiol. Vaccination against K. aerogenes preserved serum estradiol levels, reduced aortic plaque burden by approximately 40%, and improved lipid profiles in mice without disrupting overall gut microbial diversity. Conclusions This study defines a SYNPO2-VNN1 dysregulation axis in endothelial cells as a key driver of AS, exacerbated by GM-mediated estradiol depletion. The K. aerogenes -targeted vaccine represents a novel, precision-based therapeutic approach that preserves vasoprotective estradiol and attenuates atherosclerosis. Our findings establish the GM-immune-endothelial axis as a promising and clinically translatable target for precision cardiology, offering new strategies beyond traditional lipid-centered therapies.