Lonicera japonica polysaccharide restores mucosal integrity in ulcerative colitis by increasing microbiota-derived spermidine.

WLJP-025p, a homogeneous polysaccharide from Lonicera japonica Thunb., alleviates experimental ulcerative colitis in mice by reshaping the gut microbiota and restoring intestinal spermidine. Microbial fermentation, microbiota depletion, and microbiota transplantation support a microbiota-dependent mechanism. Microbiota-derived spermidine interacts with HADHA and partially reverses inflammatory HADHA-associated metabolic reprogramming, as shown by restored fatty acid oxidation (FAO), reduced lactate accumulation, improved basal respiration and etomoxir-sensitive oxygen consumption rate (OCR), and preserved epithelial integrity in Caco-2 cells and intestinal organoids. In vivo, WLJP-025p dose-dependently reduces colitis pathology and inflammation, partially reverses FAO-related metabolic disruption, and promotes epithelial maturation and barrier integrity. Serum biochemical and protein analyses further support reduced systemic inflammation and improved mucosal homeostasis. These findings define a microbiota-derived spermidine-HADHA axis that supports mucosal homeostasis in ulcerative colitis.