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The efficacy of molecular therapies for colitis-related psychiatric disorders is limited because they typically focus on a single pathway and exhibit significant off-target toxicity to healthy tissues. To address this limitation, bioinformatics methods were used to predict that inflammation and metabolism might be potential targets of brown algae. Guided by this prediction, we developed an oral polysaccharide-engineered nanozyme—Fucoidan-cerium nanocomposite (FucCeNCs), which can target inflamed colon via electrostatic interactions, exert anti-inflammatory effects, and regulate gut microbiota-derived metabolism. In a mouse model of ulcerative colitis-related psychiatric disorders, FucCeNCs demonstrated anti-inflammatory and gut barrier-protective effects, thereby inhibiting the overactivation of microglia/astrocytes and preserving neuronal integrity through the gut-brain axis by delivering anti-inflammatory cytokines.Importantly, FucCeNCs restore the homeostasis of gut microbiota by increasing the relative abundance of probiotics and reducing the proportion of pathogens. This shift significantly weakens the biosynthesis and metabolism of abnormal amino acids in fecal metabolites, which in turn leads to elevated levels of bioactive metabolites such as vanillic acid and γ-aminobutyric acid. These metabolites ultimately alleviate neuroinflammation and mitigate depressive and anxiety-like behaviors through the microbiota-gut-brain axis. These results suggest that the microbiota-gut-brain axis is a key target for treating colitis-associated psychiatric disorders, which can be addressed through polysaccharide-engineered nanoenzymes.
