Multi-omics analysis of saccharomyces boulardii supplementation reveals coordinated microbiome, metabolic, and immune signaling changes accompanying tumor suppression.

The gut microbiome shapes cancer progression and treatment responses, yet scalable microbiome-targeted interventions remain limited. We screened commercial probiotics for activation of the host aryl hydrocarbon receptor (AhR) and identified the yeast Saccharomyces boulardii as a consistent AhR activator. In an immunocompetent syngeneic colorectal cancer model, daily oral gavage of S. boulardii slowed growth of established subcutaneous tumors without detectable tumor colonization. Integrated profiling of the gut microbiome, circulating metabolites, cytokines, and tumor transcriptomes revealed a coordinated systemic response. S. boulardii increased microbial diversity and functionally rebalanced the gut microbiota, enriching taxa with lower genome-encoded biosynthetic autonomy. These changes were accompanied by elevated plasma levels of several indole metabolites, including the AhR agonists 5-hydroxyindole-3-acetic acid (5-HIAA) and indole-3-propionic acid (IPA). Targeted LC-MS/MS showed that S. boulardii can produce 5-HIAA under culture conditions, whereas IPA was not detected, suggesting that increased plasma levels of these metabolites may arise through a combination of probiotic activity and broader microbiome-associated processes. Circulating IL-17A and CTLA-4 were reduced, and tumors exhibited downregulation of programs linked to invasion, inflammation, and KRAS signaling. Multi-omics integration showed strong covariation across microbial, metabolic, immune signaling, and tumor compartments, highlighting coordinated cross-compartment responses during S. boulardii-associated tumor suppression.