Rhodotorula mucilaginosa DM2025 ameliorates obesity through cholesterol binding and the gut mycobiome-BAT PPARγ/UCP1 axis.

Abstract

Obesity is a major global health challenge, necessitating safe and effective therapies. Although probiotics are promising for obesity management, research has focused on bacteria, leaving non-Saccharomyces yeasts underexplored. Here, we investigated the anti‑obesity mechanisms of Rhodotorula mucilaginosa DM2025, isolated from the healthy murine gut. To test whether benefits depend on viable cells, high‑fat diet‑fed mice received either live yeast or its cell‑free supernatant, followed by integrated physiological, genomic, and metabolomic analyzes. Live yeast, but not supernatant, significantly reduced body weight gain, improved serum lipids, and was associated with activation of brown adipose tissue thermogenesis (upregulated PPARγ, PGC1α, UCP1). Though the supernatant lowered total cholesterol, it failed to affect weight or thermogenic genes, indicating cholesterol‑lowering and weight reduction are distinct processes. Live cells were enriched in propionate, indole, and carotenoid‑related metabolites, with genomic support for their biosynthesis. Live yeast reshaped the gut mycobiome, promoting Basidiomycota/Rhodotorula dominance; this fungal restructuring was absent in HFD controls. These findings suggest that R. mucilaginosa DM2025 anti‑obesity efficacy relies on the continuous metabolic activity of live cells, producing thermogenesis‑associated metabolites that may contribute to BAT activation. Additionally, physical cholesterol binding to the yeast cell surface provides a complementary cholesterol‑reduction mechanism. Thus, R. mucilaginosa DM2025 represents a promising live probiotic candidate for obesity intervention.

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