<p>Metabolic syndrome (MetS)—encompassing obesity, insulin resistance, dyslipidemia, and hypertension—is prevalent in both humans and horses, offering a unique opportunity to explore shared pathophysiological mechanisms across species in a controlled model organism. In this first report from the Pioneer 100 Horse Health Project (P100HHP), we conducted a longitudinal, multi-omic analysis of 108 deeply phenotyped horses to interrogate individual health trajectories for precision insights into MetS. We identified two primary metabotypes: one characterized by elevated unsaturated triglycerides (TGs) and the other by increased levels of primary bile acids (BAs), notably taurocholic acid and taurochenodeoxycholic acid. Horses with higher circulating levels of taurocholic acid had significantly higher plasma insulin concentrations, especially after an oral sugar challenge (P = 0.01), indicating that specific BAs are associated with hyperinsulinemia—a key phenotype of MetS. Metabolomic signatures predicted body condition score (relative adiposity) with high performance, underscoring their potential for precision diagnostics. Seasonal variations influenced BA levels and were associated with shifts in the fecal microbiota, particularly in <i>Clostridium</i> and <i>Proteobacteria</i> populations. Additionally, we observed an inverse relationship between genetic diversity—measured by runs of homozygosity—and insulin levels, suggesting a genetic component to MetS susceptibility. Our findings demonstrate the power of deep phenotyping and multi-omic approaches to effectively delineate MetS subtypes in horses, highlighting the pivotal roles of bile acids and the microbiome in MetS pathogenesis. These insights not only advance the understanding of equine MetS but also establish the horse as a valuable translational model for human MetS, with potential implications for targeted diagnostics and therapeutics in both veterinary and human medicine</p>