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

The protective effects of agarotriose (A3) against colitis were largely dependent on the gut microbiota.

• A dextran sulfate sodium (DSS)-induced colitis mouse model was used as the experimental system.
• Antibiotic depletion experiments were conducted to deplete gut microbiota.
• Fecal microbiota transplantation (FMT) was used to confirm microbiota-dependent effects.
• These complementary approaches collectively demonstrated that A3's anti-inflammatory protective effects required an intact gut microbiota.

A3 preferentially enriched Akkermansia muciniphila in the gut microbiota of colitis mice.

• Integrated multiomics analyses were used to identify microbial changes associated with A3 treatment.
• A. muciniphila was identified as the key microorganism preferentially enriched by A3.
• In vitro experiments confirmed that A3 promoted the growth of A. muciniphila.
• The enrichment of A. muciniphila was associated with improvement of colitis-related phenotypes.

A3 treatment was associated with increased intraluminal spermidine levels that correlated with A. muciniphila enrichment.

• Multiomics analyses linked A3 treatment to increased spermidine abundance in the gut lumen.
• Spermidine abundance correlated with A. muciniphila enrichment.
• In vitro, A3 promoted A. muciniphila growth and enhanced spermidine production.
• Spermidine abundance also correlated with improvement of colitis-related phenotypes.

Spermidine attenuated inflammatory responses at least in part through modulation of the PI3K/AKT/NF-κB signaling pathway.

• Transcriptomic analyses were used to identify signaling pathways affected by spermidine.
• Cellular analyses confirmed involvement of the PI3K/AKT/NF-κB signaling pathway.
• The anti-inflammatory effects of spermidine were attributed at least in part to suppression of this pathway.
• These findings were established through combined transcriptomic and cellular experimental approaches.

The study supports a potential 'A3-A. muciniphila-spermidine-host signaling' mechanistic axis underlying A3's prebiotic effects.

• The axis involves A3 as a marine-derived oligosaccharide from agar acting as a prebiotic substrate.
• A. muciniphila serves as the key microbiota mediator that metabolizes A3 to produce spermidine.
• Spermidine then acts on host signaling pathways to suppress inflammation.
• The authors suggest A3 may serve as a promising marine-derived prebiotic for intestinal health.