Engineered E. coli Nissle 1917 alleviates colitis-associated depression via gut-brain axis restoration.

Inflammatory bowel disease (IBD) patients disproportionately suffer from depression and anxiety, which exacerbate clinical outcomes yet remain inadequately addressed by current anti-tumor necrosis factor (TNF) biologics. To bridge this therapeutic gap, we engineered Escherichia coli Nissle 1917 (eEcN) as a clinically translatable living microbial therapeutics platform for dual-targeted intervention. eEcN is designed to autonomously secrete immunomodulatory outer membrane vesicles (OMVs) bearing TNFα-neutralizing nanobodies (TNFαnb). These bioengineered nanovesicles specifically target inflamed colon tissue, enabling localized TNFα blockade, mucosal healing, and immune regulation. Concurrently, the eEcN remodels the gut microbiota, increasing symbiotic Lactobacillus abundance to elevate intestinal γ-aminobutyric acid (GABA) levels, addressing a core neurotransmitter deficit in IBD-associated depression. In murine colitis models, this integrated strategy surpassed conventional anti-TNF therapy, simultaneously ameliorating intestinal pathology and depression-like behaviors. Mechanistically, eEcN attenuated neuroinflammation and restored hippocampal GABAergic neurotransmission via the gut-brain axis. This engineered living biomaterial platform, synergizing targeted OMVs-mediated nanobody delivery with microbiota-driven neurometabolite production, represents a promising approach for the complex pathophysiology of IBD and its neuropsychiatric comorbidities.