Natural sweetener glycyrrhizin protects against precocious puberty by modulating the gut microbiome

Aims: Precocious puberty (PP) may lead to many adverse outcomes. Recent evidence suggests that PP is a gut–brain disease. On the other hand, the use of glycyrrhizin, a natural sweetener, has become popular in the past decade. Glycyrrhizin possesses various health benefits, but its impact on PP has yet to be investigated. We aimed to explore the protective effects of glycyrrhizin against PP in both humans (observational) and animals (interventional). Materials and methods: In the human cohort, we investigated the association between glycyrrhizin consumption and risk of PP. In the animal experiment, we observed puberty onset after feeding danazol-induced PP rats with glycyrrizin. Blood, fecal, and hypothalamic samples were harvested to evaluate potential mechanistic pathways. We also performed a fecal microbiota transplantation to confirm to causal relationship between glycyrrhizin and PP risk. Key findings: Glycyrrhizin exhibited a protective effect against PP in children (OR 0.60, 95%CI: 0.39–0.89, p = 0.013), primarily driven by its significance in girls, while no significant effect was observed in boys. This effect was consistent with findings in rodents. These benefits were achieved through the modulation of the gut microbiome, which functionally suppressed the hypothalamic–pituitary–gonadal axis and prevented PP progression. A fecal microbiota transplantation indicated that the causal correlation between glycyrrhizin intake and PP is mediated by the gut microbiome alterations. Significance: Our findings suggest that glycyrrhizin can protect against PP by altering the gut microbiome. Long term use of glycyrrhizin is safe and tolerable. Therefore, glycyrrhizin can serve as a safe and affordable complementary therapy for PP.