Introduction Infective endocarditis (IE) is a life-threatening condition with strong but poorly understood links to oral health. To better define this relationship, we investigated the oral and gut microbial communities, and the systemic and salivary metabolome associated with IE to characterise microbial-metabolic interactions across disease stages, from health through high cardiovascular risk to IE. Methods Participants included patients with confirmed IE, individuals at high risk according to UK guidelines, and healthy controls (>20 samples per group). Shotgun metagenomic sequencing was performed on saliva and stool samples to profile microbial composition and function (identifying enriched/depleted metabolic reaction pathways). NMR-based metabolomics was applied to saliva and plasma samples to assess local and systemic metabolic alterations.  Results IE patients displayed marked oral microbial dysbiosis compared to both high-risk and healthy groups. Five microbial taxa were consistently enriched. Network analysis revealed shifts in the microbiome in high-risk individuals, characterised by greater microbial interconnectedness than either healthy controls or IE patients. Similarly, metabolome analysis showed enrichment of key metabolic pathways, including gluconeogenesis, in IE and high-risk groups. Together, these findings suggest that microbial and metabolic shifts precede clinical disease.  Discussion Distinct microbial and metabolic profiles in saliva, stool and plasma discriminate IE patients, high-risk individuals and healthy controls. These findings provide a new insight into IE development and highlight opportunities for earlier prevention, patient education, and novel risk stratification strategies.