Fucoidan Alleviates Intestinal Inflammation through Microbiota-Associated Citraconic Acid Accumulation to Modulate Ferroptosis-Related Pathways

Abstract Fucoidan has shown potential for intestinal protection; however, its underlying mechanisms remain unclear. This study investigated the protective effects of fucoidan against DSS-induced colitis and explored microbiota-associated metabolic changes that were linked to its protective effects. Fucoidan alleviated colonic injury, improved epithelial barrier integrity, and reshaped the gut microbial profile, including reduced Pseudomonadota levels and the enrichment of beneficial taxa. Targeted metabolomics identified citraconic acid (CA) as a candidate metabolite associated with fucoidan-mediated protection. Antibiotic depletion suggested that fucoidan-associated CA accumulation was partially dependent on the gut microbiota. CA reduced colitis severity, attenuated ferroptosis-related oxidative stress, and improved barrier function, accompanied by enhanced Nrf2-associated antioxidant responses and the restoration of SLC7A11 and GPX4 expression. In vitro, CA reduced mitochondrial Fe2+ accumulation and lipid peroxidation while enhancing tight junction protein expression. These results highlight a microbiota-associated metabolic mechanism underlying fucoidan-mediated intestinal protection and identify CA as a potential mediator of its anti-inflammatory activity.