Mutualistic probiotic–drug oral-delivery system targeting the gut–brain axis for alleviating colitis-associated mental disorders

Individuals with inflammatory bowel disease (IBD) are particularly susceptible to psychosocial disturbances, including depression and anxiety. Unfortunately, conventional antidepressants have shown limited efficacy in managing IBD-associated psychosocial disorders, largely due to the intrinsic nature of intestinal diseases and the complex bidirectional communication between the gut and the brain. Herein, we armed the probiotic Escherichia coli Nissle 1917 (EcN) with gamma-aminobutyric acid (GABA)–chitosan nanoparticles (GC NPs) to form a “mutualistic probiotic–drug” oral-delivery system (GC-EcN) for reshaping a healthy microbiota–gut–brain axis. The intestinal colonization ability of the probiotic facilitated the targeted delivery and retention of the nanoparticles, thereby enabling sustained GABA release and the scavenging of excess reactive oxygen species. The resulting reduction in inflammation enhanced bacterial viability, rapidly restored intestinal–barrier function, and rebalanced the gut microbiota. Notably, GC-EcN alleviated anxiety- and depression-like behaviors through the microbiota–gut–brain axis by reducing neuroinflammation, enhancing hippocampal neural plasticity, and modulating immune responses in the hippocampus. This study highlights the critical role of the microbiota–gut–brain axis in the progression of IBD-associated psychiatric comorbidities and proposes a safe, simple, and effective therapeutic approach for managing both IBD and its associated mental disorders.

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