Mechanistic Study of Poria-Mediated Gut Microbiota-Bile Acid-FXR Axis in Improving Phlegm- Dampness-Type Precocious Puberty

Abstract Objective: High-fat diet (HFD) is a significant predisposing factor for central precocious puberty (CPP); however, therapeutically tractable targets along the gut-liver-brain axis remain largely undefined. This study aimed to characterize the therapeutic potential and underlying mechanisms of a Poria cocos–anchored formula intervention, both alone and in combination with intestine-restricted FXR agonism, in a murine model of HFD-induced CPP. Methods: We establish a high-fat-diet model that recapitulates a “phlegm–dampness–type” precocious phenotype and test a Poria cocos–anchored formula—comprising Poria (principal component), Atractylodes rhizome, Coix seed, Anemarrhena rhizome, Phellodendron bark, Pinellia rhizome, dried tangerine peel, selfheal spike, retinervus Luffae fructus, Bulbus Cremastrae seu Pleiones, and raw hawthorn fruit—administered alone or with the intestine-restricted FXR agonist Fexaramine, with genetic validation in FXR −/− mice. We integrate pubertal timing, reproductive histology, endocrine and metabolic endpoints, targeted bile-acid and lipidomic profiling, and microbiome-derived functional readouts. Results: In HFD-fed females, vaginal opening (VO) occurred earlier (median 23 vs 25 days; Δ2 days) with uterine epithelial thickening, an ovarian cystic pattern, hyperinsulinaemia and dyslipidaemia. Poria cocos delayed VO by 2 days and lowered insulin/lipids by approximately 50%. Fexaramine showed modest VO effects but corrected lipids (approximately 40%). The combination returned VO to the control range (median 25 vs 25; ns) and restored metabolic indices to 80-90% of control, with uterine/ovarian pathology reduced by approximately 50%. Concordantly, hypothalamic GnRH/NPY − 50–60% and ileal FXR − approximately 70% (all p