Forsythiae Fructus polysaccharides mitigate DSS colitis by modulating gut microbiota–derived palmitic acid and PI3K/AKT pathway

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with limited therapeutic options, and the contribution of microbiota-associated metabolites to disease progression remains incompletely understood. Here, we demonstrate that Forsythia polysaccharides (FPs) exert protective effects against dextran sulfate sodium (DSS)-induced colitis through coordinated regulation of gut microbiota, microbial metabolism, and inflammatory signaling. FPs treatment markedly alleviated colonic injury and inflammation, restored intestinal barrier integrity, and remodeled the gut microbial community. Metabolomic analyses identified palmitic acid (PA) as a microbiota-associated metabolite that was elevated during colitis but reduced following FPs treatment and fecal microbiota transplantation from FPs-treated donors. Correlation analysis revealed significant associations between PA abundance and DSS-responsive microbial taxa, particularly Desulfovibrio. Mechanistically, PA enhanced neutrophil extracellular trap (NET) formation and activated PI3K/AKT signaling, whereas pharmacological inhibition of PI3K/AKT attenuated PA-induced NETs responses. Consistently, FPs treatment was accompanied by reduced colonic PA levels, suppression of PI3K/AKT signaling, and decreased NETs-associated inflammatory responses. Furthermore, PA supplementation partially counteracted the protective effects of FPs, while PI3K/AKT inhibition mitigated PA-associated disease exacerbation. Collectively, these findings support the involvement of a microbiota-associated PA-PI3K/AKT-NETs signaling network in DSS-induced colitis and highlight FPs as a promising microbiota-targeted therapeutic strategy for IBD.