Gender-specific and dose-dependent responses to L-se-methylselenocysteine are mediated by the gut microbiota-metabolite axis: implications for intestinal homeostasis and safe clinical application.

Introduction: L-Se-methylselenocysteine is a prominent naturally occurring organic selenium compound with notable health benefits and validated efficacy in managing various diseases. However, its impacts on intestinal microecology and the role of the gut microbiota-metabolite axis in mediating host health outcomes remain unclear. Methods: Sprague-Dawley rats were subjected to a 90-day chronic toxicity study, combined with integrated intestinal microbiome and metabolome analysis, to explore L-Se-methylselenocysteine's effects and underlying mechanisms. Results: L-Se-methylselenocysteine at doses of 0.25-0.75 mg/kg bw/ day enhanced gut microbiota biodiversity, enriched probiotic abundance, ameliorated hematological and serum biochemical indices, and promoted synthesis of beneficial metabolites via modulating the gut microbiota-metabolite axis. Notably, high-dose L-Se-methylselenocysteine (2.25 mg/kg bw/day) induced irreversible hepatosplenic injury in female rats but not males, with gender-specific responses mediated by the axis. Discussion: L-Se-methylselenocysteine confers intestinal health benefits through the gut microbiota-metabolite axis, while defining a safe dosage range. This study provides a solid scientific basis for the rational application of L-Se-methylselenocysteine as a selenium supplement.