The Aro80p-quorum sensing molecule axis governs the probiotic efficacy of Saccharomyces cerevisiae by promoting intestinal homeostasis

The probiotic potential of Saccharomyces cerevisiae is well-recognized, yet its beneficial mechanisms remain unclear. Here, we identify the transcription factor Aro80p as a central regulator of this probiotic activity. Disruption of ARO80 impaired bile salt tolerance, gastrointestinal survival, and cell surface properties, while reducing the production of quorum-sensing molecules (QSMs), including 2-phenylethanol (from 301 μmol/L to 208 μmol/L, a 30.8% decrease) and tyrosol (from 433 μmol/L to 280 μmol/L, a 35.3% decrease). In a zebrafish model of dextran sulfate sodium (DSS)-induced colitis, the wild-type (WT) strain and purified QSMs robustly mitigated intestinal injury, increasing goblet cell numbers by 1.9-fold and 1.65-fold, respectively. Both treatments significantly reduced neutrophil infiltration (to 22% and 24% of the DSS group level) and suppressed oxidative stress. Mechanistically, the WT strain and QSMs restored cytokine balance ( IL-10 increased by 9.3-fold and 3.5-fold), enhanced tight junction integrity ( Occludin-1 increased by 5.8-fold and 5.2-fold), and activated the aryl hydrocarbon receptor (AHR) pathway ( CYP1A1 increased by 9.3-fold and 8.9-fold). Furthermore, they restored gut microbial diversity (Shannon index increased by 1.83-fold and 2.26-fold). The Δ ARO80 mutant consistently showed weaker protection across all parameters measured, confirming that Aro80p-directed QSM production is essential for full probiotic efficacy. In vitro experiments using RAW 264.7 macrophages further demonstrated that the Aro80p-QSM axis directly promotes an anti-inflammatory M2-like phenotype. Our findings establish the Aro80p-QSM axis as a critical pathway underlying the probiotic function of S. cerevisiae , highlighting the potential of yeast-derived QSMs as novel dietary bioactive compounds for managing intestinal inflammation.