A Shenling Baizhu San polysaccharide fraction (SLP-2)-based synbiotic alleviates lactose-induced gut dysfunction via a microbiota-metabolite-barrier axis.

Lactose intolerance (LI) is a common digestive disorder, and its management still relies largely on dietary restriction. Because gut microbial fermentation and barrier dysfunction contribute to LI-related symptoms, microbiota-targeted prebiotic or synbiotic strategies may provide complementary approaches. However, the active plant-polysaccharide fractions and their microbial partners remain unclear. This study aimed to identify the bioactive polysaccharide fraction from Shenling Baizhu San and evaluate its pairing with responder bacteria for alleviating high-lactose diet (HLD)-induced intestinal dysfunction. Stepwise ethanol precipitation yielded SLP-2, which was subsequently identified as the principal bioactive fraction through human fecal fermentation, monoculture assays, and an HLD rat model. SLP-2 enriched Eubacterium-associated taxa and supported the growth of Akkermansia muciniphila in monoculture and in vivo. Building on this, a synbiotic combining SLP-2 with A. muciniphila and E. rectale alleviated HLD-induced gut dysfunction; the antibiotic-matched comparison with the probiotics-only group supported an SLP-2-associated contribution. The synbiotic intervention was associated with increased tight junction proteins, MUC2 expression, improved intestinal architecture, and thicker mucus layers. Multi-omics analysis linked co-metabolites, including intestinal 6-MGG and HTy-Ac and systemic DHPV-G, with barrier restoration and an immune profile characterized by increased IL-10 and lower TLR4 expression. These findings suggest that SLP-2-based synbiotic intervention alleviates HLD-induced intestinal dysfunction through microbiota-metabolite-barrier modulation, providing preclinical evidence for future functional-food strategies pending human validation.