Xiaowen Tian, Haoran Hua, Jie Zhang, Peng Zhao
Abstract Cardiovascular disease (CVD) retains a substantial residual burden despite control of conventional risk factors, indicating contributions from additional metabolic, inflammatory and host–microbial pathways. The gut microbiota–bile acid axis links diet and environmental exposures to microbial metabolism, enterohepatic signalling and cardiovascular homeostasis. However, current evidence is commonly organised around isolated diseases or molecular mechanisms, with limited attention to when this axis becomes detectable, how it should be clinically interpreted and whether it can guide individualised prevention. In this review, we propose a spatiotemporal framework for the gut microbiota–bile acid axis across the health–suboptimal health–disease continuum within predictive, preventive and personalised medicine (PPPM/3PM). Mechanistic evidence is most developed for atherosclerosis and atherothrombosis, whereas evidence for atrial fibrillation, heart failure, pulmonary hypertension and cerebrovascular outcomes is more heterogeneous and less mature. Microbial bile salt hydrolase activity and downstream bile acid transformations reshape compartment-specific bile acid pools, with potential effects on cholesterol catabolism, inflammatory and barrier responses, vascular homeostasis, platelet activation and myocardial stress. For 3PM, molecular profiles should be interpreted together with multidomain functional phenotypes, including bowel function and gastrointestinal symptoms, hepatobiliary status, metabolic–inflammatory context, and diet and medication exposure. Microbiota-directed interventions should be function-informed rather than selected by taxonomy alone. Translation requires longitudinal multi-omics, standardised multi-compartment bile acid profiling, causal validation in human-relevant models and prospective studies determining whether phenotype-guided strategies add predictive or preventive value beyond established cardiovascular care.