Squid cartilage-derived chondroitin sulfate from Uroteuthis chinensis: a novel marine prebiotic modulating gut microbiota and ameliorating ulcerative colitis

This study evaluated the prebiotic potential of chondroitin sulfate (CS) derived from the cartilage of the squid Uroteuthis chinensis, and its protective effects against dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice. Dietary intervention with squid-derived CS significantly attenuated characteristic UC symptoms, including body weight loss, colon shortening, and histopathological damage. Mechanistic analyses revealed that squid-derived CS exerted potent anti-inflammatory effects by downregulating key pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and alleviated oxidative stress by enhancing colonic antioxidant capacity, as evidenced by increased activities of catalase (CAT) and superoxide dismutase (SOD) and reduced myeloperoxidase (MPO) activity. Integrated 16S rRNA gene sequencing and metabolomics analyses demonstrated that squid-derived CS profoundly restructured gut microbial community composition by enriching putative beneficial bacteria (e.g., Bifidobacterium, Clostridium, Blautia) while reducing opportunistic pathogens (e.g., Enterococcus, Sutterellaceae, Clostridia_UCG-014). This favorable microbial shift was accompanied by a reconfiguration of the intestinal metabolome, characterized by elevated production of beneficial short-chain fatty acids (SCFAs) and decreased levels of pro-inflammatory metabolites such as tyramine. Furthermore, squid-derived CS effectively enhanced intestinal barrier integrity by upregulating key tight junction proteins (ZO-1, occludin, claudin-1), thereby preventing bacterial lipopolysaccharide (LPS) translocation and associated liver injury, as indicated by reduced serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Collectively, these findings demonstrate that dietary squid-derived CS protects against UC by modulating gut microbiota composition to enrich beneficial taxa, restoring microbial metabolite homeostasis, reinforcing the intestinal epithelial barrier, and suppressing inflammatory responses and oxidative stress. This study provides the first evidence that squid-derived CS acts as a novel and promising marine prebiotic candidate for gut health promotion, highlighting its potential as a sustainable functional ingredient derived from processing waste for gut-health-promoting foods.