Gut microbial immunometabolic pathways associated with cardiac arrest risk: genetic evidence and exploratory fecal microbiome profiling

Background Cardiac arrest remains difficult to predict, and upstream biological determinants are poorly defined. Gut microbiota can influence host metabolism, immunity and inflammation, but their relevance to cardiac arrest risk remains unclear. Methods We performed bidirectional two-sample Mendelian randomization to prioritize associations between gut microbial traits and cardiac arrest. Two-step mediation analyses were then used to assess whether circulating metabolites, immune cell phenotypes and inflammatory proteins could represent candidate intermediary pathways. An independent exploratory fecal 16S rRNA cohort of patients with cardiac arrest and healthy controls was analysed to provide descriptive post-arrest microbiome context. Results Mendelian randomization prioritized 14 candidate gut microbial taxa or microbial metabolic pathways associated with cardiac arrest risk. Mediation analyses identified 55 candidate mediation pathways involving 41 candidate mediators, including 10 pathways with comparatively stronger statistical support based on the joint-significance criterion and the Sobel test. Metabolite-related signals accounted for most candidate mediation pathways, with additional contributions from immune cell phenotypes and inflammatory factors. In the exploratory 16S cohort, diversity and ordination patterns did not show robust group separation, whereas descriptive compositional summaries showed partial taxonomic overlap with signals highlighted by the genetic analyses; these observations were not considered directional or causal validation. Conclusion These findings prioritize an immunometabolic framework linking gut microbial variation to cardiac arrest risk, with metabolic mediation representing the predominant candidate layer for follow-up study. The exploratory clinical 16S results provide descriptive post-arrest context rather than independent validation, and the genetic findings should be interpreted as candidate associations requiring larger prospective and experimental confirmation.