Abstract

Abstract Emerging evidence suggests that patients with inflammatory bowel diseases (IBDs) are predisposed to psychosocial disturbances, such as depression and anxiety. Regrettably, clinical antidepressants exhibit unsatisfactory therapeutic efficacy in IBD‐associated psychosocial disturbances, primarily attributed to the inherent intestinal disorders and intricate bidirectional relationship between the gut and the brain. Herein, we report a metal–polyphenol‐based antidepressant to alleviate mental disorders in dextran sulfate sodium‐induced experimental acute colitis mice via modulating the microbiota–gut–brain axis. The antidepressant, termed CSMTC, comprises a core of melittin‐encapsulated natural antioxidant enzymes (i.e., catalase and superoxide dismutase) and a protective shell composed of tannic acid–cerium ion network. Upon oral administration to colitis mice, CSMTC can effectively restore colonic redox balance, reinforce the intestinal barrier, modulate gut microbiota composition, maintain the blood–brain barrier integrity, and regulate systemic immune responses. Notably, behavioral test results reveal that CSMTC significantly alleviates the colitis‐associated mental disorder (e.g., depression‐like behavior) via the microbiota–gut–brain axis by reducing neuroinflammation, enhancing hippocampal neural plasticity, modulating hippocampal immune responses, and restoring neurotransmitter homeostasis. This work may have implications for the development of new nanodrugs for treating inflammation‐associated complications.