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However, the field has often relied on a single-metabolite hypothesis, particularly centered on trimethylamine N-oxide (TMAO), which does not fully capture the complexity of host-microbe-organ interactions. In this review, we argue that cardiovascular risk is better understood as a network of interacting gut-derived molecules, in which TMAO functions as a node within a broader system that includes phenylacetylglutamine, indole-related metabolites, short-chain fatty acids, bile acids, and lipopolysaccharide. Within this framework, the TMAO two-hit model, in which pre-existing organ vulnerability (first hit) is exacerbated by metabolite elevations (second hit), exemplifies context-dependent pathogenicity, particularly in chronic kidney disease or other pre-existing cardiometabolic vulnerabilities. We further discuss how this network-based view may refine biomarker interpretation, improve patient stratification, and guide the development of biomarker-guided strategies for microbiome-targeted interventions. 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