Agarotriose Alleviates Colitis by Promoting <i>Akkermansia muciniphila</i> -Derived Spermidine Production to Suppress PI3K/AKT/NF-κB Signaling

Agarotriose (A3), a marine-derived oligosaccharide from agar, has shown anti-inflammatory potential, yet the involvement of gut microbiota remains incompletely understood. Using a dextran sulfate sodium-induced colitis mouse model combined with antibiotic depletion and fecal microbiota transplantation, we found that the protective effects of A3 were largely dependent on the gut microbiota. Integrated multiomics analyses indicated that A3 preferentially enriched <i>Akkermansia muciniphila</i> and was associated with increased intraluminal spermidine levels. Spermidine abundance correlated with <i>A. muciniphila</i> enrichment and improvement of colitis-related phenotypes. In vitro, A3 promoted the growth of <i>A. muciniphila</i> and enhanced spermidine production. Transcriptomic and cellular analyses further suggested that spermidine attenuated inflammatory responses, at least in part, through modulation of the PI3K/AKT/NF-κB signaling pathway. Collectively, these results support a potential "A3-<i>A. muciniphila</i>-spermidine-host signaling" axis and suggest that A3 may serve as a promising marine-derived prebiotic for intestinal health.