Investigation of the Mechanism of Shen‐Ling‐Bai‐Zhu‐San Polysaccharide in Counteracting Lactose Intolerance Diarrhea Via Network Pharmacology, Molecular Docking, and Experimental Validation

Background Lactose intolerance (LI)‐related diarrhea is a prevalent clinical gastrointestinal condition that severely compromises patients’ quality of life. While the traditional Chinese medicine formula Shen‐Ling‐Bai‐Zhu‐San (SL) has proven effective in managing this disorder, whether polysaccharides derived from SL (SLP) produce comparable therapeutic effects and their underlying mechanisms of action require further elucidation. This study investigated the efficacy and pharmacological mechanism of SLP in alleviating LI‐related diarrhea. Methods The monosaccharide composition of SLP was analyzed using high‐performance liquid chromatography (HPLC). Network pharmacology was employed to identify potential SLP targets and LI‐related genes. Core components and targets were validated through molecular docking, molecular dynamics simulations, and both in vivo and in vitro experiments. Result SLP administration significantly alleviated diarrhea induced by LI in rats by reducing fecal water content, increasing fecal pH, and improving grip strength. Network pharmacology analysis identified eight principal molecular targets, including AKR1B1, GLB1, MGAM, LCT, SI, LGALS3, G6PD, and FGF2, as well as eight active monosaccharide components, namely, glucose, galacturonic acid, galactose, xylose, rhamnose, glucuronic acid, mannose, and glucosamine. Molecular docking demonstrated strong binding between key targets (AKR1B1 and GLB1) and the monosaccharides galactose and rhamnose, with molecular dynamics simulations confirming stable interactions. In vitro and in vivo experiments further showed that SLP alleviates diarrhea by suppressing AKR1B1 overexpression, enhancing GLB1 activity (particularly via galactose and rhamnose), and upregulating SGLT1 transporter expression. Conclusions The findings provide strong evidence that SLP exerts pharmacodynamic effects in the treatment of LI‐related diarrhea by modulating AKR1B1 and GLB1. Specifically, SLP regulates the expression and activity of these key molecules to alleviate diarrheal symptoms. Given its bioactivity, SLP shows potential as a dietary supplement that enhances GLB1 expression, promotes lactose digestion, and may be developed for use in functional foods, pharmaceuticals, and health products to manage LI symptoms.