Polygonatum sibiricum polysaccharide alleviates irritable bowel syndrome via multidimensional phenotypic improvement and sex-specific gut microbiota modulation in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Polygonatum sibiricum polysaccharide (PSP), as a major bioactive component of P. sibiricum Delar. ex Redoute (Liliaceae, PS), holds great potential for treating irritable bowel syndrome (IBS). However, its therapeutic effects and mechanisms remain unknown. AIM OF THIS STUDY: IBS is a prevalent functional gastrointestinal disorder. The limitation and adverse effects of current therapies highlight the need for novel strategies. This study aimed to optimize PSP extraction and evaluate the therapeutic effects of PSP on IBS model mice. MATERIALS AND METHODS: Water-extraction and ethanol-precipitation were optimized via orthogonal experimental design to obtain PSP, which was purified via molecular sieve chromatography. PSP composition was characterized using 1-phenyl-3-methyl-5-pyrazolone precolumn-derivatization HPLC. PSP was administered to IBS model mice, which were evaluated via routine monitoring, blood tests, histopathology, microbiome analysis, network pharmacology and molecular docking. RESULTS: Under optimal extraction conditions of a 1:15 g/ml solid-to-liquid ratio, 80°C, and 150 W ultrasonic power for 120 min, 228.68 mg/g of PSP was obtained, which was mainly composed of six monosaccharides. PSP administration (200-600 mg/kg) significantly alleviated IBS symptoms by normalizing the faecal moisture content and blood indices, decreasing oxidative stress, reversing intestinal mucosal damage and microbiota homeostasis in a sex-based manner. Multiple targets, including DRD1, TRPV1 and HTR2, which theoretically had favourable binding energies with PSP and associated with PLA/PLC-ERK1/2-PKC signalling pathway, were predicted to involve in the therapeutic effects. CONCLUSION: Subchronic PSP intervention promotes mouse recovery from IBS in a sex-specific manner. Putative targets and molecular pathways provide a theoretical direction for future validation.